Conditions: Atopic Dermatitis (AD)
Keywords: randomized double-masked (blind) placebo-controlled trial T helper 2 (Th2) effect cutaneous microbial community skin barrier
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 72
Healthy volunteers: no

Brief summary:
The purpose of this study is to understand the effect that T helper 2 (Th2) blockade has on well-described pathophysiological features of Atopic Dermatitis (AD), for example: barrier, epidermal activation, dysbiosis and epidermal lipids.

Detailed description:
This is a multi-center, randomized, double-masked, placebo-controlled trial investigating the effect of 6 weeks of dupilumab treatment on quantitative and qualitative measures of cutaneous microbial community structure, skin barrier biology, and circulating T cell profiles, in adults with chronic moderate-to-severe atopic dermatitis (AD).

After obtaining informed consent, eligible participants will return to clinic for their Treatment Initiation Visit (Day 0) and will be randomized 2:1 active to placebo. Participants will receive three doses of dupilumab or placebo based on their randomization assignment. The first dose (600 mg loading dose of dupilumab or placebo) will be administered on Day 0 and the second and third doses (300 mg dupilumab or placebo) on Day 14 and Day 28, respectively.

Participants will return to clinic on Days 3, 7, and 21 during the double-masked portion of the study. Participants will begin the open-label extension (OLE) at Day 42 and will receive dupilumab (600 mg loading dose \[two 300 mg injections\] for those initially randomized to the placebo group and a 300 mg dose plus placebo injection for those initially randomized to the dupilumab group). Participants will return to clinic on Days 77 and 112 during the OLE portion of the study. During all visits (Day 0-Day 112), Adverse Events (AEs), concomitant medications, and medical history will be assessed and physical exams including assessment of AD severity will be performed. Blood, urine, skin swabs, skin tape strips, and skin biopsies, as applicable, will be collected, and barrier assessments will be performed per the Schedule of Events, per protocol. Samples will be collected prior to dupilumab or placebo administration on Days 0, 14, 28, and 42. After Day 112, a follow-up call (Day 182) will be made to assess for pregnancy, current medications, and adverse events (AEs).

If concerns arise between regularly scheduled visits, participants will be instructed to contact study personnel and may be asked to return to the study site for an "Unscheduled Visit." Participants may be asked to return for Unscheduled Visits, as needed for the duration of the study, to provide additional blood, skin swabs, skin tape strips, or skin biopsies,as applicable, for further mechanistic and functional studies, if biosamples are lost or destroyed, or if insufficient yields were obtained at a previous study visit.

Arms:
arm 1: Participants will receive a loading dose of dupilumab (two 300 mg subcutaneous (subcut) injections (total of 600 mgs)) on Day 0, followed by 300 mg dose of dupilumab by subcut injection every 2 weeks (Days 14 and 28).

Open Label Extension (OLE): Participants will begin a 10 week OLE on Day 42, beginning with a loading dose of two subcut administered injections (one 300 mg dose of dupilumab and one dose of placebo, in order to protect prior masking/blind).Participants will then maintain a regimen of 300 mg of dupilumab by subcut injection every two weeks through Day 98.

The subcut injections will be administered in the abdomen (except for the 2 inches (5 cm) around the navel-not allowed), thighs, or upper arms. Injection sites will be rotated with each dose. arm 2: Participants will receive a loading dose of placebo (two placebo subcutaneous (subcut) injections) on Day 0 followed by one dose of placebo by subcut injections every 2 weeks (Days 14 and 28).

Open Label Extension (OLE): Participants will begin a 10 week OLE on Day 42, beginning with a loading dose of dupilumab (two 300 mg subcut injections (total of 600 mgs)-protection of prior masking/blind maintained). Participants will then maintain a regimen of 300 mg of dupilumab by subcut injection every two weeks through Day 98.

The subcut injections will be administered in the abdomen (except for the 2 inches (5 cm) around the navel-not allowed), thighs, or upper arms. Injection sites will be rotated with each dose.

Interventions: intervention 1: Dupilumab intervention 2: Placebo
Intervention descriptions: intervention 1: Dupilumab, an interleukin (IL)-4 receptor alpha (IL-4Rα) antagonist, is indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. (FDA approved on March 28, 2017.) intervention 2: Placebo will contain the identical formulation as the dupilumab formulation without the active mAb and will be given by exactly the same route and schedule through Day 28.

Protocol document:
SAP_002.pdf: 
DAIT/Rho STATISTICAL ANALYSIS PLAN 
 09 November 2020 
 
ATOPIC DERMATITIS RESEARCH NETWORK 
PROTOCOL-ADRN 09 
Effect of Dupilumab (anti-/>ϰZɲͿŽŶƚŚĞ,ŽƐƚ-Microbe Interface in Atopic ĞƌŵĂƚŝƚŝƐ 
Dupilumab Study 
VERSION:  
1.0 
DATE: 
09 NOV 2020 
SPONSOR: 
Division of Allergy, Immunology, and Transplantation – DAIT 
National Institute of Allergy and Infectious Diseases – NIH 
PREPARED BY: 
Rho 
Rho Building 
 
 


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DAIT/Rho STATISTICAL ANALYSIS PLAN 
ACKNOWLEDGMENT AND SIGNATURE SHEET
Dupilumab 
Approved: 
Approved: 
Approved: 
Approved: 


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ŽĐƵŵĞŶƚ,ŝƐƚŽƌǇ 
 
sĞƌƐŝŽŶ
 
Date
 
ŽŵŵĞŶƚƐͬŚĂŶŐĞƐ 
0.1 
25 AUG 2020 
Initial Draft Version 
0.2 
16 OCT 2020 
Revised Draft Version 
0.3 
04 NOV 2020 
Revised Draft Version 
1.0 
09 NOV 2020 
Initial Version 


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Table of Contents 
 
GLOSSARY OF ABBREVIATIONS......................................................................................6 
1. 
PROTOCOL SYNOPSIS .............................................................................................8 
2. 
INTRODUCTION .........................................................................................................8 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.......................................8 
4. 
ANALYSIS POPULATIONS........................................................................................9 
5. 
STUDY PARTICIPANTS .............................................................................................9 
5.1. 
Disposition of Participants ................................................................................9 
5.2. 
Demographic and Other Baseline Characteristics ..........................................10 
6. 
STUDY OPERATIONS..............................................................................................11 
6.1. 
Protocol Deviations ........................................................................................11 
6.2. 
Treatment Adherence.....................................................................................11 
7. 
ENDPOINT EVALUATION........................................................................................12 
7.1. 
Overview of Efficacy Analysis Methods ..........................................................12 
7.1.1. Multicenter Studies ....................................................................................12 
7.1.2. Assessment Time Windows.......................................................................12 
7.2. 
Primary Endpoint............................................................................................12 
7.2.1. Computation of the Primary Endpoint ........................................................12 
7.2.2. Primary Analysis of the Primary Endpoint..................................................13 
7.2.3. Sensitivity Analyses of the Primary Endpoint .............................................13 
7.3. 
Secondary Endpoints .....................................................................................13 
7.3.1. Secondary Endpoint 1 ...............................................................................13 
7.3.2. Secondary Endpoint 2 ...............................................................................14 
7.3.3. Secondary Endpoint 3 ...............................................................................15 
7.3.4. Secondary Endpoint 4 ...............................................................................15 
7.3.5. Secondary Endpoint 5 ...............................................................................16 
7.3.6. Secondary Endpoints 6-7 ..........................................................................16 
7.3.7. Supportive Analyses of Secondary Endpoints............................................17 
7.4. 
Exploratory Endpoints ....................................................................................17 
7.4.1. Exploratory Endpoint 1 ..............................................................................17 
7.4.2. Exploratory Endpoint 2 ..............................................................................17 
7.4.3. Exploratory Endpoint 3 ..............................................................................17 
7.4.4. Exploratory Endpoint 4 ..............................................................................17 
7.4.5. Exploratory Endpoint 5 ..............................................................................18 
7.4.6. Exploratory Endpoint 6 ..............................................................................18 
7.4.7. Exploratory Endpoint 7 ..............................................................................18 
7.4.8. Exploratory Endpoint 8 ..............................................................................18 
7.4.9. Exploratory Endpoint 9 ..............................................................................18 
7.4.10. Exploratory Endpoint 10 ............................................................................19 
8. 
SAFETY EVALUATION ............................................................................................19 
8.1. 
Overview of Safety Analysis Methods ............................................................19 
8.2. 
Adverse Events..............................................................................................20 
8.3. 
Deaths and Serious Adverse Events..............................................................21 
8.4. 
Clinical Laboratory Evaluation........................................................................21 
8.5. 
Vital Signs, Physical Findings, and Other Observations Related to Safety .....21 


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8.5.1. Vital Signs .................................................................................................21 
8.5.2. Physical Examinations...............................................................................21 
9. 
OTHER ANALYSES..................................................................................................22 
9.1. 
Use of Medications.........................................................................................22 
10. 
INTERIM ANALYSES AND DATA MONITORING ....................................................22 
11. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL...........................22 
12. 
REFERENCES ..........................................................................................................23 
GLOSSARY OF ABBREVIATIONS......................................................................................6 
1. 
PROTOCOL SYNOPSIS .............................................................................................8 
2. 
INTRODUCTION .........................................................................................................8 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.......................................8 
4. 
ANALYSIS POPULATIONS........................................................................................9 
5. 
STUDY PARTICIPANTS .............................................................................................9 
6. 
STUDY OPERATIONS..............................................................................................11 
7. 
ENDPOINT EVALUATION........................................................................................12 
8. 
SAFETY EVALUATION ............................................................................................19 
9. 
OTHER ANALYSES..................................................................................................22 
10. 
INTERIM ANALYSES AND DATA MONITORING ....................................................22 
11. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL...........................22 
12. 
REFERENCES ..........................................................................................................23 
 
 


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GLOSSARY OF ABBREVIATIONS
 
AD 
atopic dermatitis  
ADA 
anti-drug antibodies 
AE 
adverse event 
AUC 
area under the curve 
BMI 
body mass index 
CBC 
complete blood count 
CoNS 
coagulase-negative Staphylococci 
COVID-19 
Coronavirus Disease 2019 
CRF 
case report form 
CSR 
clinical study report 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
EASI 
Eczema Area and Severity Index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ICH 
International Conference on Harmonisation 
ID 
participant identifier 
IGA 
Investigator Global Assessment
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
max 
maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 
mITT 
modified intent-to-treat 
n 
sample size 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NRS 
numerical rating scale 
PBMC 
peripheral blood mononuclear cell 
PP 
per-protocol 
RDBPC 
randomized double-blind placebo-controlled 


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S. aureus
Staphylococcus aureus
SACCC 
Statistical And Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAg 
superantigen
SAP 
Statistical Analysis Plan 
SAR
Suspected Adverse Reaction 
SCORAD 
SCORing Atopic Dermatitis 
SD 
standard deviation 
SNP 
single nucleotide polymorphism 
SOC 
system organ class 
TARC 
thymus and activation-regulated chemokine 
TEAE 
treatment-emergent AE 
TEWL 
transepidermal water loss 
Th2 
T helper 2 
TJs 
tight junctions 
WHO 
World Health Organization 
 


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1.
PROTOCOL SYNOPSIS 
The protocol synopsis is available in the most recent Institutional Review Board (IRB)-approved version 
of the Dupilumab protocol (Version 3.0; 29 August 2019). 
2.
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on Section 13 Statistical Considerations and Analytical Plan of 
the Dupilumab protocol. However, the analyses specified in this document supersede the high-level 
analysis plan described in the protocol. The SAP contains detailed information to aid in the 
implementation of the statistical analyses and reporting of the study results in the clinical study report 
(CSR). This SAP was written with consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline, entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports. 
3.
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following analysis and reporting conventions will be used: 
x
Categorical variables will be summarized using counts (n) and percentages (%) and will be 
presented in the form “n (%).”  Percentages will be rounded to one decimal place. If a count is 0, 
0% will be shown for the percentage. 
x
Continuous variables will be summarized using sample size (n), mean, standard deviation (SD), 
median, first and third quartiles, minimum (min), and maximum (max), as appropriate.  The 
mean will be reported at one more significant digit than the precision of the data, the standard 
deviation will be reported at two more significant digits than the precision of the data, and first 
and third quartiles, minimum, maximum, and median will be reported at the same precision as 
the data. The median will be reported as the average of the two middle numbers if the dataset 
contains an even number of observations. 
x
Test statistics including t, z, and ʖϮtest statistics will be reported to two decimal places.  
x
P-values will be reported to three decimal places if greater than or equal to 0.001.  If less than 
0.001, the value will be reported as “<0.001.”  A p-value can be reported as “1.000” only if it is 
exactly 1.000 without rounding.  A p-value can be reported as “0.000” only if it is exactly 0.000 
without rounding. 
x
Each data listing will be sorted by treatment arm and participant identifier (ID) unless otherwise 
noted. 
x
All analyses described in the SAP will be performed using SAS® System Version 9.4 or later or R 
Version 3.5 or later. 
If departures from these general conventions are presented in the specific evaluations section of this 
SAP, then those conventions will take precedence over these general conventions.  
 


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4.
ANALYSIS POPULATIONS 
Intent-to-ƚƌĞĂƚ;/ddͿƉŽƉƵůĂƚŝŽŶ: All participants who were randomized. Participants will be analyzed 
according to the treatment arm to which they were randomized, regardless of the medication they 
actually received. 
 
Modified intent-to-ƚƌĞĂƚ;ŵ/ddͿpopulation: All participants who were randomized and have 
Staphylococcus aureus (S. aureus) abundance measured at Day 0 and Day 28. Participants will be 
analyzed according to the treatment arm to which they were randomized, regardless of the medication 
they actually received. 
 
Safety population: All participants who were randomized and received at least one dose of study 
treatment. Participants will be analyzed according to the medication they actually received, defined as 
“dupilumab” if a participant received any dose of dupilumab and “placebo for dupilumab” otherwise, 
regardless of the treatment arm to which they were randomized. Non-treatment emergent adverse 
events (e.g., any adverse event (AE) that occurs before the first injection) will be summarized in all 
participants who are enrolled, while treatment emergent adverse events (TEAE) (e.g., any AE that occurs 
on or after the first injection) will be summarized in the safety population.  
 
Per-pƌŽƚŽĐŽů;WWͿpopulation: All participants who were randomized, received the correct medication 
and dosage to which they were randomized, did not have a major protocol deviation, did not miss any 
scheduled injections, did not used any of the medications/procedures listed in Protocol Section 7.3 with 
the exception of topical calcineurin inhibitors (tacrolimus or pimecrolimus), topical corticosteroids, 
topical phosphodiesterase inhibitors (crisaborole) and topical antibiotics if applied to areas of the skin 
not being sampled, and have met sampling criteria. 
5.
STUDY PARTICIPANTS 
5.1.
ŝƐƉŽƐŝƚŝŽŶŽĨWĂƌƚŝĐŝƉĂŶƚƐ  
The disposition of all enrolled participants will be summarized in tables and listed. The following 
disposition information will be summarized:  
 
x
The number of participants screened. 
x
Among screened participants: 
o
The number and percentage of participants who failed Screening, including those who 
attended the Screening Visit but did not meet the inclusion/exclusion criteria. 
x
The number of participants randomized.  
x
Among randomized participants: 
o
The number and percentage of participants in the ITT population.  
o
The number and percentage of participants in the mITT population.  
o
The number and percentage of participants in the safety population.  
o
The number and percentage of participants in the PP population. 
x
Among participants in the mITT population and grouped by treatment arm: 


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o
The number and percentage of participants in the safety population.  
o
The number and percentage of participants in the PP population. 
o
The number and percentage of participants who completed Day 42 (random double-
blind placebo-controlled, RDBPC).  
o
The number and percentage of participants who completed Day 112 (Open-label).  
o
The number and percentage of participants who completed Day 182 (Follow-up). 
o
The number and percentage of participants who withdrew during the study due to: 

Withdrawal by participant 

Lost to follow-up 

Death 

Pregnancy 

Physician decision 

Participant experienced an anaphylactic reaction to study drug injection 

Participant was diagnosed with an exclusionary malignancy  

Participant acquired an opportunistic infection  

Non-compliance with the study protocol 

Participant refused protocol-mandated procedure at the Screening or 
Treatment Initiation Visit 

AE 

Coronavirus Disease 2019 (COVID-19) 

Other 
o
The number and percentage of participants who discontinued study treatment. 
o
The number and percentage of participants who missed visits due to COVID-19. 
o
The number and percentage of participants who had remote visits due to COVID-19. 
 
A data listing of participant disposition will be provided for the ITT population and will include an 
indication of whether the participant is in the mITT population. 
5.2.
ĞŵŽŐƌĂƉŚŝĐĂŶĚKƚŚĞƌĂƐĞůŝŶĞŚĂƌĂĐƚĞƌŝƐƚŝĐƐ  
Descriptive statistics for demographic and baseline characteristics will be summarized for the mITT 
population grouped by randomized treatment arm and overall.  
Demographic data will include age at randomization, sex, race, ethnicity, and clinical site.  
Baseline will be defined as the last measurement prior to or on the day of randomization (beginning 
of Day 0). Baseline characteristics will include: 
x
Body weight 
x
Height 
x
Body Mass Index (BMI) percentile  
x
Atopic Dermatitis (AD) Severity 
o
SCORing Atopic Dermatitis (SCORAD) 
o
Eczema Area and Severity Index (EASI) Score 


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o
EASI Score < 21.1 
o
Nottingham Eczema Severity Score 
o
Investigator Global Assessment (IGA) 
x
Average itch in the past 24 hours as assessed by Pruritus Numerical Rating Scale (NRS) 
x
Self-reported history of Eczema Herpeticum 
x
Self-reported history of Staph infection 
x
Self-reported history of food allergy  
x
Self-reported history of animal allergies 
x
Self-reported pets living in the participant’s home 
x
Self-reported smoking in the participant’s home 
 
 
Demographic and baseline characteristics for continuous variables will be summarized using the 
number of participants, mean, SD, median, and first and third quartiles, and min and max (as 
applicable). Demographic and baseline characteristics for qualitative or categorical variables will be 
summarized by the number and percentage of participants within each category. 
 
A data listing of demographics, baseline characteristics, and medical history will be provided for the 
mITT population. A data listing of any inclusion/exclusion criteria not met will also be provided for all 
screened participants, as well as for all participants in the mITT population separately. A data listing 
of all participants who had visits that were remote or missed due to COVID-19 will be provided for 
the mITT population and will include the number of visits that were remote or missed due to COVID-
19 for each participant.  
6.
STUDY OPERATIONS 
6.1.
WƌŽƚŽĐŽůĞǀŝĂƚŝŽŶƐ 
Protocol deviations will be recorded on the protocol deviation electronic case report form (eCRF) 
page. Major protocol deviations will be identified by the DAIT Medical Monitor and study team prior 
to unblinding of treatment assignment and database freeze/lock. A data listing of all protocol 
deviations sorted by site and participant ID will be provided to the DAIT Medical Monitor and study 
team for the manual identification of major protocol deviations. 
Following database freeze/lock, a data listing will be provided for all protocol deviations. The listing 
will be sorted by site, treatment arm, and participant ID and will also include type of deviation, 
severity of the deviation (major or non-major), date of occurrence, and the reason for the deviation.  
Protocol deviations will be summarized in tabular format by treatment arm and by type of deviation 
(including major deviations).  
6.2.
dƌĞĂƚŵĞŶƚĚŚĞƌĞŶĐĞ
The number and percentage of participants receiving each dose and any dose of blinded study drug 
will be summarized by treatment arm in the safety population. The overall duration of exposure 


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(weeks) and the percentage of expected doses received will be summarized by descriptive statistics 
(mean, SD, median, first and third quartiles, min and max). Duration of exposure will be defined 
based on the difference (in days) between the dates of the first and last dose of blinded study drug 
plus 1 day and then converted to weeks. There are 3 expected doses during the RDBPC portion of the 
study.  
Similarly, the number and percentage of participants receiving each dose and any dose of open-label 
study drug will be summarized in the safety population. Duration of exposure will be defined based 
on the difference (in days) between the dates of the first and last dose of open-label study drug plus 
1 day and then converted to weeks. There are 5 expected doses during the open-label portion of the 
study. 
A data listing will be provided for treatment adherence during the RDBPC portion and the open-label 
portion for the safety population.  
7.
ENDPOINT EVALUATION 
7.1.
Overview of Efficacy ŶĂůǇƐŝƐDĞƚŚŽĚƐ 
Hypothesis testing for all efficacy endpoints will be performed in the mITT population unless 
otherwise specified. For each estimate that is provided, a corresponding 95% confidence interval will 
be included.  
7.1.1.
DƵůƚŝĐĞŶƚĞƌ^ƚƵĚŝĞƐ 
Participants were enrolled at 8 sites. Sub-group analyses of the primary endpoint will be 
performed using each site as a sub-group (see Section 7.2.3). 
7.1.2.
ƐƐĞƐƐŵĞŶƚdŝŵĞtŝŶĚŽǁƐ 
Visit windows for all scheduled visits are provided in Protocol Section 8 and in the Schedule of 
Events (Protocol Appendix A). A visit that occurred outside of the specified visit window will be 
recorded as a non-major protocol deviation. Any data collected outside of a visit window will still 
be included in any analyses of the scheduled visit. 
Data collected during unscheduled visits, outside the visit window, or within the appropriate visit 
window but not on the date of study drug administration (as applicable) will be included in 
listings. 
7.2.
Primary Endpoint 
7.2.1.
ŽŵƉƵƚĂƚŝŽŶŽĨƚŚĞWƌŝŵĂƌǇEndpoint 
S. aureus abundance as measured by microbial DNA (femA qPCR) on lesional skin at Day 28.  


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7.2.2.
WƌŝŵĂƌǇŶĂůǇƐŝƐŽĨƚŚĞWƌŝŵĂƌǇŶĚƉŽŝŶƚ 
The primary analysis will compare S. aureus abundance between treatment arms at Day 28 using 
an ANCOVA model applied to the mITT population. Prior to analysis, a log-10 transformation will 
be applied to S. aureus abundance. If any participant to be included in the analysis has a value of 
zero, the participant’s value will be adjusted by adding a value of 1 prior to transformation. To 
account for the study design induced by the randomization scheme, the model will also include 
fixed effects for clinical site and disease severity at Day 0, as measured ďǇ^/шϮϭ͘ϭŽƌфϮϭ͘ϭ͘dŽ
increase statistical efficiency, the model will also adjust for S. aureus abundance at Day 0. Such a 
model will allow an estimation of the adjusted geometric mean ratio of the abundance of S. aureus 
at Day 28 on lesional skin (and corresponding 95% confidence interval) between the dupilumab 
and placebo arms. A two-sided significance level of 0.05 will be used for this analysis.  
7.2.3.
^ĞŶƐŝƚŝǀŝƚǇŶĂůǇƐĞƐŽĨƚŚĞWƌŝŵĂƌǇŶĚƉŽŝŶƚ 
Analyses for the primary endpoint will be supported by several analyses: 
1.
To evaluate the distributional assumptions made in the primary analysis model, a permutation 
test will be used as a supplementary analysis of the primary analysis (Manly, 1997).   
2.
Rather than exclude participants who were randomized but do not have S. aureus abundance 
measured at Day 0 and Day 28 (as defined by the mITT population), a multiple imputation 
technique will be employed to impute the missing primary endpoint of S. aureus abundance at 
Day 0 or Day 28 in the ITT population. The model specified in Section 7.2.2 will be run on each 
imputed dataset, and results will then be pooled to estimate one geometric mean ratio and 
corresponding 95% CI. 
3.
The model specified in Section 7.2.2 will be adjusted to include clinical site as a random effect, 
rather than a fixed effect.    
4.
To test if the effect of dupilumab on S. aureus abundance at Day 28 is modified by particular 
sub-groups, separate models similar to the model specified in Section 7.2.2 will be developed 
to test the two-way interaction between treatment arm and variables defining the sub-groups 
of interest. Sub-groups that will be investigated include: 
o
Clinical site 
o
ŝƐĞĂƐĞƐĞǀĞƌŝƚǇĂƚĂǇϬ͕ĂƐŵĞĂƐƵƌĞĚďǇ^/шϮϭ͘ϭŽƌфϮϭ͘ϭ 
o
Disease severity at Day 0, as measured above and below the median value of thymus 
and activation-regulated chemokine (TARC)  
5.
The model specified in Section 7.3.1 which excludes Days 77 and 112 will be used to test the 
difference between treatment arms at Day 28.  
7.3.
^ĞĐŽŶĚĂƌǇŶĚƉŽŝŶƚƐ 
7.3.1.
Secondary Endpoint 1 
Variable: S. aureus abundance as measured by microbial DNA (femA qPCR) on lesional skin at Days 
0, 3, 7, 14, 21, 42, 77 and 112 
ŶĂůǇƐŝƐ͗ S. aureus abundance on lesional skin measured at each RDBPC time point (Days 3, 7, 14, 
21, 28, and 42) will be log10-transformed and analyzed using a linear (or nonlinear, if appropriate) 
mixed  model for repeated measures that will include fixed effects for S. aureus abundance on 
ůĞƐŝŽŶĂůƐŬŝŶĂƚĂǇϬ͕ƚƌĞĂƚŵĞŶƚĂƌŵ͕ĐůŝŶŝĐĂůƐŝƚĞ͕ĚŝƐĞĂƐĞƐĞǀĞƌŝƚǇĂƚĂǇϬĂƐŵĞĂƐƵƌĞĚďǇ^/ш
21.1 or < 21.1, time point of measurement (as a categorical variable), and an interaction term 


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between treatment arm and time point of measurement. If any participant has a value of zero, the 
participant’s value will be adjusted by adding a value of 1 prior to transformation. The model will 
be fit using restricted maximum likelihood, and each fixed effect will be tested using an F-test 
statistic, the Kenward-Roger approximation for degrees of freedom, an unstructured covariance 
matrix, and a two-sided significance level of 0.05. The model will be used to estimate the following 
at Days 3, 7, 14, 21, and 42: 
x
The geometric mean of S. aureus abundance on lesional skin in each treatment arm.  
x
The geometric mean ratio of S. aureus abundance on lesional skin between treatment 
arms.  
Additionally, a linear (or nonlinear, if appropriate) mixed model similar to the model specified 
above will be fit for every time point measured (including the open-label portion of the study). The 
model will be used to estimate the following at Days 77 and 112:  
x
The geometric mean of S. aureus abundance on lesional skin in each treatment arm 
x
The geometric mean ratio of S. aureus abundance on lesional skin between treatment 
arms 
x
The geometric mean ratio of S. aureus abundance on lesional skin between Day 77 and 
Day 42 and between Day 112 and Day 42 in each treatment arm 
7.3.2.
Secondary Endpoint 2 
Variable: S. aureus abundance as measured by microbial DNA (femA qPCR) on non-lesional skin at 
Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
ŶĂůǇƐŝƐ͗Using participants in the mITT population, S. aureus abundance on non-lesional skin will 
be log10-transformed and will be evaluated by applying two linear (or nonlinear, if appropriate) 
mixed models for repeated measures (similar to Section 7.3.1). If any participant to be included in 
the analysis has a value of zero, the participant’s value will be adjusted by adding a value of 1 prior 
to transformation. The model excluding Days 77 and 112 will be used to estimate the following at 
Days 3, 7, 14, 21, 28, and 42:  
x
The geometric mean of S. aureus abundance on non-lesional skin in each treatment arm.  
x
The geometric mean ratio of S. aureus abundance on non-lesional skin between treatment 
arms.  
The model including Days 77 and 112 will also be used to estimate the following at Days 77 and 
112:  
x
The geometric mean of S. aureus abundance on non-lesional skin in each treatment arm  
x
The geometric mean ratio of S. aureus abundance on non-lesional skin between treatment 
arms 
x
The geometric mean ratio of S. aureus abundance on lesional skin between Day 77 and 
Day 42 and between Day 112 and Day 42 in each treatment arm 


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7.3.3.
Secondary Endpoint 3 
Variable: Basal (prior to tape stripping) transepidermal water loss (TEWL) of non-lesional and 
lesional skin at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
ŶĂůǇƐŝƐ͗Basal TEWL of non-lesional skin will be evaluated by applying two linear (or nonlinear, if 
appropriate) mixed models for repeated measures (similar to Section 7.3.1) that will include 
random effects for participant and fixed effects for treatment arm, basal TEWL at Day 0, clinical 
ƐŝƚĞ͕ĂŶĚĚŝƐĞĂƐĞƐĞǀĞƌŝƚǇĂƚĂǇϬĂƐŵĞĂƐƵƌĞĚďǇ^/шϮϭ͘ϭŽƌфϮϭ͘ϭ. The model excluding Days 
77 and 112 will be used to estimate the following at Days 3, 7, 14, 21, 28, and 42:  
x
The mean basal TEWL of non-lesional skin in each treatment arm  
x
The mean difference between treatment arms in basal TEWL of non-lesional skin 
 The model including Days 77 and 112 will also be used to estimate the following at Days 77 and 
112:  
x
The mean basal TEWL of non-lesional skin in each treatment arm  
x
The mean difference in basal TEWL of non-lesional skin between treatment arms 
x
The mean difference in basal TEWL of non-lesional skin between Day 77 and Day 42 and 
between Day 112 and Day 42 in each treatment arm 
The same analyses will be performed using basal TEWL of lesional skin. 
7.3.4.
Secondary Endpoint 4 
Variable: TEWL area under the curve (AUC) of non-lesional skin at Days 0, 7, 14, 21, 28, 42, 77 and 
112. TEWL is assessed prior to tape stripping and repeated after 5, 10, and 15 tape strips. TEWL 
AUC will be computed for each participant’s non-lesional skin assessment using the trapezoidal 
rule over the course of their tape strips.  
ŶĂůǇƐŝƐ͗Using participants in the mITT population, TEWL AUC of non-lesional skin will be 
evaluated by applying two linear (or nonlinear, if appropriate) mixed models for repeated 
measures (similar to Section 7.3.1) that will include random effects for participant and fixed 
effects for treatment arm, TEWL AUC at Day 0, clinical site, and disease severity at Day 0 as 
ŵĞĂƐƵƌĞĚďǇ^/шϮϭ͘ϭŽƌфϮϭ͘ϭ. The model excluding Days 77 and 112 will be used to estimate 
the following at Days 3, 7, 14, 21, 28, and 42:  
x
The mean TEWL AUC in each treatment arm  
x
The mean difference between treatment arms in TEWL AUC 
 The model including Days 77 and 112 will also be used to estimate the following at Days 77 and 
112:  
x
The mean TEWL AUC in each treatment arm  
x
The mean difference in TEWL AUC between treatment arms  
x
The mean difference in TEWL AUC between Day 77 and Day 42 and between Day 112 and 
Day 42 in each treatment arm 


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7.3.5.
Secondary Endpoint 5 
Variable: Change in TEWL per every 5 tape strips (i.e. slope) on non-lesional skin at Days 0, 7, 14, 
21, 28, 42, 77 and 112 
ŶĂůǇƐŝƐ͗TEWL on non-lesional skin will be evaluated by applying a separate linear mixed model 
for repeated measures for each day of measurement and will include fixed effects for basal TEWL 
prior to tape stripping, treatment arm, clinical site, disease severity at Day 0 as measured by EASI 
шϮϭ͘ϭŽƌфϮϭ͘ϭ͕ƚĂƉĞƐƚƌŝƉŶƵŵďĞƌ (as a categorical variable), and an interaction term between 
treatment arm and tape strip number. The model will be used to estimate the slope (the 
interaction term of strip and treatment assignment) in each treatment arm.  
7.3.6.
Secondary EndpointƐ 6-7 
Variable: Eczema Area and Severity Index [EASI], Investigator Global Assessment [IGA], SCORing 
Atopic Dermatitis [SCORAD], and Pruritus numerical rating scale [NRS] at Days 0, 3, 7, 14, 21, 28, 
42, 77 and 112. 
ŶĂůǇƐŝƐ͗ EASI (as well as percent change over time in EASI and EASI50), IGA, SCORAD (as well as 
percent change over time in SCORAD), and Pruritus NRS will each be evaluated by applying two 
linear (or logistic for EASI50) mixed models for repeated measures (similar to Section 7.3.1). 
Percent change in EASI and SCORAD will be calculated as 100*(Xpost-baseline – XDay 0) / XDay 0. EASI50 
will be calculated as 1 for participants who have ш 50 percent decrease in EASI and 0 for 
participants who have < 50 percent decrease in EASI. ^/шϮϭ͘ϭŽƌфϮϭ͘ϭ will not be included as a 
fixed effect for the endpoints corresponding to EASI. The model excluding Day 72 and 112 will be 
used to estimate the following:  
x
The mean EASI, IGA, SCORAD, and Pruritus NRS in each treatment arm 
x
The mean percent change from baseline in EASI and SCORAD in each treatment arm 
x
The mean difference in EASI, IGA, SCORAD, and Pruritus NRS between treatment arms 
x
The mean difference in percent change from baseline in EASI and SCORAD between 
treatment arms 
x
The odds ratio comparing  50 percent change in EASI between the treatment arms 
The model including Days 77 and 112 will also be used to estimate the following at Days 77 and 
112:  
x
The mean EASI, IGA, SCORAD, and Pruritus NRS in each treatment arm  
x
The mean difference in EASI, IGA, SCORAD, and Pruritus NRS between treatment arms  
x
The mean difference in EASI, IGA, SCORAD, and Pruritus NRS between Day 77 and Day 42 
and between Day 112 and Day 42 in each treatment arm  
x
The mean percent change from baseline in EASI  and SCORAD in each treatment arm 
x
The mean difference in percent change from baseline in EASI and SCORAD between 
treatment arms  
x
The mean difference in percent change between Day 77 and Day 42 and between Day 112 
and Day 42 in EASI and SCORAD in each treatment arm 
x
The odds ratio comparing  50 percent change in EASI between the treatment arms  


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x
The odds ratio comparing  50 percent change in EASI between Day 77 and Day 42 and 
between Day 112 and Day 42 in each treatment arm 
 
7.3.7.
^ƵƉƉŽƌƚŝǀĞŶĂůǇƐĞƐŽĨ^ĞĐŽŶĚĂƌǇŶĚƉŽŝŶƚƐ 
To compare the cross-sectional and longitudinal effects of S. aureus abundance on disease severity 
between treatment arms, a generalized linear mixed model similar to that described in Chapter 
15.4 of Fitzmaurice et al (2004) will be used. By including an interaction between treatment arm 
and S. aureus abundance at Day 0, as well as an interaction between treatment arm and the 
change in S. aureus abundance over time, this model will allow simultaneous estimation of the 
effect of S. aureus abundance at Day 0 on disease severity at Day 0 in the dupilumab and placebo 
arms separately, as well as the change in S. aureus abundance over time on the change in disease 
severity over time in the dupilumab and placebo arms, separately.  The model will also be adjusted 
for clinical site, skin collection site, and disease severity at Day Ϭ͕ĂƐŵĞĂƐƵƌĞĚďǇ^/шϮϭ͘ϭŽƌф
21.1 (for endpoints other than EASI).         
7.4.
ǆƉůŽƌĂƚŽƌǇŶĚƉŽŝŶƚƐ 
7.4.1.
Exploratory Endpoint 1 
Variable: Composition of bacterial taxa in lesional and non-lesional skin at Days 0, 3, 7, 14, 21, 28, 
42, 77 and 112. 
ŶĂůǇƐŝƐ͗ See Protocol Section 13.4.5.1.1 for analysis plan.   
7.4.2.
Exploratory Endpoint 2 
Variable: Abundance of bacterial taxa in lesional and non-lesional skin at Days 0, 3, 7, 14, 21, 28, 
42, 77 and 112. 
ŶĂůǇƐŝƐ͗ See Protocol Section 13.4.5.1.1 for analysis plan.   
7.4.3.
Exploratory Endpoint 3 
Variable: Gene expression in the skin transcriptome in non-lesional skin at Days 0 and 7, and in 
lesional skin at Days 0, 7, and 21. 
ŶĂůǇƐŝƐ͗ See Protocol Section 13.4.5.2 for analysis plan.   
7.4.4.
Exploratory Endpoint 4 
Variable: Lipid profiles of non-lesional skin at Days 0, 7, 14, 21, 28, 42, 77 and 112 and of lesional 
skin at Days 0, 14, 28, and 112 
ŶĂůǇƐŝƐ͗ For each time point, we will compare lipid profiles between dupilumab and placebo arms 
as previously described (Janssens et al, 2012). Two linear mixed models (one for each collection 
site), similar to that described in Section 7.3.1, will be used to investigate the effect of dupilumab 
on lipid profiles over time. 


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7.4.5.
Exploratory Endpoint 5 
Variable: Expression of S. aureus superantigens (SAg), toxins, lipase, and proteases on lesional and 
non-lesional skin at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
ŶĂůǇƐŝƐ͗ We will compare the expression of each S. aureus SAg, toxin, lipase, and protease over 
time between dupilumab and placebo arms using two linear mixed models for repeated measures 
for each collection site, similar to that described in Section 7.3.1.  
Additionally, each endpoint will be considered as a binary indicator for presence/absence as the 
outcome. Two logistic mixed models that will include fixed effects for presence/absence of the 
ŽƵƚĐŽŵĞĂƚĂǇϬ͕ƚƌĞĂƚŵĞŶƚĂƌŵ͕ĐůŝŶŝĐĂůƐŝƚĞ͕ĚŝƐĞĂƐĞƐĞǀĞƌŝƚǇĂƚĂǇϬĂƐŵĞĂƐƵƌĞĚďǇ^/ш
21.1 or < 21.1, time point of measurement (as a categorical variable), and an interaction term 
between treatment arm and time point of measurement will be fit for all time points prior to Day 
77 and every time point measured (including the open-label portion of the study). The models will 
be used to estimate the odds ratio of presence of the outcome between treatment arms at each 
time point.  
7.4.6.
Exploratory Endpoint 6 
Variable: Confocal imaging of tight junctions (TJs) and relationship to LCs in the epidermis from 
non-lesional skin at Days 0, 7, and 21. 
ŶĂůǇƐŝƐ͗ The number of LCs in the epidermis in the dupilumab and placebo treatment arms will be 
compared at Days 0, 7, and 21 using a two-sample t-test. If the variances are equal a two-sample t-
test assuming equal variances will be used. If the variances are not equal a two sample t-test 
assuming unequal variances will be used. The mean number of LC’s in the epidermis in each 
treatment arm and the mean difference between treatment arms will be estimated. 
7.4.7.
Exploratory Endpoint 7 
Variable: Percent of coagulase-negative staphylococci [CoNS] isolates that kill S. aureus on lesional 
and non-lesional skin at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
ŶĂůǇƐŝƐ͗ The frequency of commensal Staphylococcus species producing antimicrobial activity, as 
measured by the number of colonies with antimicrobial activity against S. aureus per sample, 
between dupilumab and placebo will be compared using two linear mixed models for repeated 
measures for each collection site, similar to that described in Sections 7.3.1. 
7.4.8.
Exploratory Endpoint 8 
Variable: Peripheral Blood Mononuclear Cell (PBMC) immunoprofiling at Days 0, 14 and 28. 
ŶĂůǇƐŝƐ͗ See Protocol Section 13.4.5.8 for analysis plan.   
7.4.9.
Exploratory Endpoint 9
Variable: Levels of serum biomarkers (e.g. T-helper 2 (Th2) biomarkers) at Days 0, 7, 14, 21, 28, 42, 
77 and 112. 


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ŶĂůǇƐŝƐ͗ We will compare serum biomarkers over time between dupilumab and placebo arms 
using two linear mixed models for repeated measures, similar to that described in Section 7.3.1. 
7.4.10.
Exploratory Endpoint 10 
Variable: The presence of single nucleotide polymorphisms (SNPs). 
ŶĂůǇƐŝƐ͗ See Protocol Section 13.4.5.8 for analysis plan.   
8.
SAFETY EVALUATION
8.1.
KǀĞƌǀŝĞǁŽĨ^ĂĨĞƚǇŶĂůǇƐŝƐDĞƚŚŽĚƐ 
The safety analyses will be performed in the safety population defined in Section 4. Safety 
assessment summaries will include: 
x
AEs, defined in Protocol Section 12.2.1. 
x
Suspected Adverse Reactions (SARs), defined in Protocol Section 12.2.1.1. 
x
AEs leading to discontinuation of study drug 
x
AEs leading to withdrawal 
x
Serious adverse events (SAEs), defined in Protocol Section 12.2.3. 
x
Deaths 
x
Clinical laboratory results 
x
Vital signs 
x
Physical examinations 
These analyses will not be stratified by clinical site.  
A TEAE will be defined as any AE not present prior to the initiation of study drug or any AE already 
present that worsens in either intensity or frequency following exposure to study drug. Any change in 
clinical status, electrocardiograms (ECGs), routine labs, x-rays, physical examinations, etc. during 
treatment periods will be considered a treatment-emergent AE. TEAEs will be summarized in the 
safety population.  
Partial dates will be imputed for the purposes of defining TEAEs as follows: 
x
For a missing start day where the month and year are present, the start day will be set to the 
first day of the month, unless: 1) the first day of the month is before the date of administration 
of study drug and the month and year are the same as the month and year of the date of 
administration of study drug; and 2) the end date is on or after the date of administration of 
study drug or the end date is completely missing, in which case the start day will be set to the 
day of administration of study drug.  
x
For a missing start day and month where the year is present, the start day and month will be 
set to January 1st, unless: 1) January 1st is before the date of administration of study drug and 
the year is the same as the year of the date of administration of study drug; and 2) the end 
date is on or after the date of administration of study drug or the end date is completely 


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missing, in which case the start day and month will be set to that of the date of administration 
of study drug. 
x
For a missing end day where the month and year are present, the end day will be set to the 
last day of the month, unless the month and year are the same as the month and year of the 
last contact date for the participant, in which case the end day will be set to that of the 
participant’s last contact date. 
x
For a missing end day and month where the year is present, the end day and month will be set 
to the participant’s last contact date, unless the year of the participant’s last contact date is 
greater than the end year, in which case the end day and month will be set to December 31st. 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, but not 
limited to, a radiograph, an ultrasound, an ECG etc.), a TEAE is defined as an increase in grade from 
baseline or from the last post-baseline value that doesn’t meet grading criteria. Changes in grade 
from screening to treatment initiation at Day 0 will also be recorded as AEs, but are not treatment-
emergent. 
Unless otherwise specified, a data listing for all measurements in Section 8 will be provided for the 
safety population and sorted in order of treatment arm, participant ID, and time of assessment (e.g., 
visit, time, and/or event).
8.2.
ĚǀĞƌƐĞǀĞŶƚƐ 
All AEs will be classified by system organ class (SOC) and preferred term, according to a standardized 
thesaurus (Medical Dictionary for Regulatory Activities [MedDRA]). MedDRA V21.0 or later will be 
used to classify all AEs.  
The severity of AEs will be classified, as applicable, using the criteria set forth in the National Cancer 
Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. 
Each AE will be entered on the eCRF once at the highest severity.  
The relationship, or attribution, of an AE to the study therapy regimen or study procedures is defined 
in Protocol Section 12.3.2. 
Overall summary tables will be developed using the safety population to report the number of events 
and the number and percentage of participants having at least one event in the following categories:  
x
AEs 
x
AEs by maximum grade 
x
AEs by relationship to study drug 
x
AEs by relationship to study procedure 
AEs classified by treatment arm, MedDRA SOC, and preferred term will be summarized in the Safety 
Population for each of the following categories: 
x
AEs 
x
AEs by relationship to study drug 


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Summary tables will present the total number of events as well as the number and percentage of 
participants experiencing the events. If a participant experiences the same AE on multiple occasions, 
the event will be counted once for each occurrence when reporting the number of AEs. When 
reporting the number of participants experiencing the events, a participant will only be counted once 
if they experience an event within the particular SOC or preferred term. Percentages will be based on 
the number of participants in the safety population. 
Similar summaries will be generated for SARs (defined in Protocol Section 12.2.1.1), AEs leading to 
discontinuation of study drug, and AEs leading to study withdrawal separately.  
Data listings will be provided separately for AEs, SARs, AEs leading to discontinuation of study drug, 
and cases of COVID-19. 
8.3.
ĞĂƚŚƐĂŶĚ^ĞƌŝŽƵƐĚǀĞƌƐĞǀĞŶƚƐ 
SAEs will be listed and summarized in the same manner described in Section 8.2. Separate displays 
listing death, including time to death and cause of death, will also be created. 
8.4.
Clinical Laboratory Evaluation 
Clinical laboratory measurements will be performed at Screening and include a complete blood count 
(CBC) and a complete metabolic panel.  Results will be converted to standardized units where 
possible.  For numeric laboratory results, descriptive statistics of laboratory values will be presented 
for each treatment group and overall.  For categorical laboratory results, the number and percentage 
of participants reporting each result will be presented for each treatment group and overall.  A data 
listing of all laboratory measurements including an indication of any abnormal values and clinical 
significance will be provided.  
8.5.
sŝƚĂů^ŝŐŶƐ͕WŚǇƐŝĐĂů&ŝŶĚŝŶŐƐ͕ĂŶĚKƚŚĞƌKďƐĞƌǀĂƚŝŽŶƐZĞůĂƚĞĚƚŽ^ĂĨĞƚǇ 
8.5.1.
sŝƚĂů^ŝŐŶƐ 
Vital sign measurements (including temperature, heart rate, respiratory rate, systolic blood 
pressure, and diastolic blood pressure) will be collected at each clinic visit. Height and weight will 
only be measured at the Screening Visit.  
A data listing of all vital sign measurements including an indication of any abnormal values and 
clinical significance will be provided.  
8.5.2.
WŚǇƐŝĐĂůǆĂŵŝŶĂƚŝŽŶƐ 
A complete physical examination will be performed at the Screening Visit and abbreviated physical 
exams will be performed at all other clinic visits.  
A data listing of all physical examination results including an indication of any abnormal 
observations and clinical significance will be provided. 
 


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9.
OTHER ANALYSES 
9.1.
hƐĞŽĨDĞĚŝĐĂƚŝŽŶƐ 
Medications will be coded according to the latest version of the World Health Organization (WHO) 
Drug Dictionary. Medications reported on the case report form (CRF) will be categorized for analysis 
as prior to or after Treatment Initiation (Day 0) by comparing the medication start and stop dates 
with the date of Treatment Initiation (Day 0). Prior medications will have both the medication start 
and stop dates prior to the date of Treatment Initiation. Partial and completely missing dates will be 
imputed for the purposes of classifying concomitant medications as follows:  
x
Partial dates will be imputed following the same algorithm as above for TEAEs. 
x
For a missing start date (i.e., day, month, and year are missing), the start date will be set to 
the date of Screening unless the stop date is prior to the date of Screening, in which case the 
start date will be set to the stop date. 
x
For a missing stop date (i.e., day, month, and year are missing), the medication will be 
treated as ongoing. 
The number and percentage of participants receiving prior or concomitant medications will be 
presented overall and by medication class. When reporting the number of participants receiving the 
medication, a participant will only be counted once if they ever received the medication within the 
medication class. Percentages will be based on the number of participants in the safety population. 
10.
INTERIM ANALYSES AND DATA MONITORING 
No interim efficacy or futility analyses are planned for this study. However, statistical analyses of 
scientific objectives, to include data through Day 112, are planned to occur as soon as applicable data 
collection is complete. Data will be cleaned and frozen for all visits through Day 112 in order to begin 
analyses.  
No formal interim analysis of safety data will be conducted. The DAIT/NIAID Medical Monitor shall 
receive monthly reports from the DAIT Statistical And Clinical Coordinating Center (SACCC) compiling 
new and accumulating information on AEs, SAEs, and pregnancies recorded by the clinical sites on 
appropriate eCRFs.
The NIAID Allergy and Asthma Data and Safety Monitoring Board (DSMB) will also review safety data at 
least once per year and on an ad hoc basis as needed. Data for the planned safety reviews will include, 
at a minimum, a listing of all reported AEs and SAEs that is created by the DAIT SACCC. 
11.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Not applicable at this time. 
 
 


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12.
R&ZE^ 
Ye C, Beyene J, Browne G, et al. Estimating treatment effects in randomised controlled trials with non-
compliance: a simulation study. BMJ Open 2014;4:e005362. doi: 10.1136/bmjopen-2014-005362 
 
Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. John Wiley & Sons, Inc. Hoboken, 
New Jersey. 2004. 506 pages. 
 
Manly, BFJ. “Randomization”. Bootstrap and Monte Carlo Methods in Biology, 2nd Ed. 1997. London: 
Chapman & Hall. 
 
Janssens M, van Smeden J, Gooris GS, Bras W, Portale G, Caspers PJ, Vreeken RJ, Hankemeier T, Kezic S, 
Wolterbeek R, Lavrijsen AP, Bouwstra JA. “Increase in short-chain ceramides correlates with an altered 
lipid organization and decreased barrier function in atopic eczema patients.” J Lipid Res. 2012; 
53(12):2755-66. 
Twisk J, Bosman L, Hoekstra T, Rijnhart J, Welton M, Heymansm. “Different ways to estimate treatment 
effects in randomized controlled trials.” Contemporary Clinical Trials Communications. 2018.  





Prot_001.pdf: 
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ATOPIC DERMATITIS RESEARCH NETWORK 
PROTOCOL-ADRN 09 
Effect of Dupilumab (anti-IL4Rα) on the Host-Microbe Interface in Atopic Dermatitis 
Dupilumab Study 
VERSION NUMBER 3.0 / VERSION DATE 29 Aug 2019 
Study Sponsor(s):  The National Institute of Allergy and Infectious Diseases (NIAID) 
NIAID Funding Mechanism:  
 
IND Sponsor/ Number:  Not applicable 
Study Drug Manufacturer/Provider:  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of the Protocol Chair, or 
the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases of the National Institutes of 
Health. 
 
 


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INVESTIGATOR SIGNATURE PAGE 
Protocol:  ADRN-09 
  
Version/Date:  
 3.0 / 29 Aug 2019 
Title:  Effect of Dupilumab (anti-IL4Rα) on the Host-Microbe Interface in  
Atopic Dermatitis 
Study Sponsor:  The National Institute of Allergy and Infectious Diseases (NIAID) 
INSTRUCTIONS: The site Principal Investigator should print, sign, and date at the indicated location 
below.  A copy should be kept for your records and the original signature page sent. After signature, 
please return the original of this form by surface mail to:  
 
 
 
 
I confirm that I have read the above protocol in the latest version.  I understand it, and I will work 
according to the principles of Good Clinical Practice (GCP) as described in the United States Code of 
Federal Regulations (CFR) – 45 CFR part 46 and 21 CFR parts 50, 56, and 312, and in the most current 
International Conference on Harmonization (ICH) document Guidance for Industry: E6 Good Clinical 
Practice: Consolidated Guidance.  Further, I will conduct the study in keeping with local legal and 
regulatory requirements. 
As the site Principal Investigator, I agree to carry out the study by the criteria written in the protocol 
and understand that no changes can be made to this protocol without the written permission of the 
IRB and NIAID. 
I understand that information received related to this study is of a sensitive nature, and I shall 
and shall ensure that my team will treat the information received with the same degree of care as 
confidential information.  
 
 
____________________________________     
Site Principal Investigator  (Print) 
 
____________________________________                                      _________________ 
Site Principal Investigator (Signature)                                                          Date 


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Protocol Synopsis 
Title 
Effect of Dupilumab (anti-IL4RD) on the Host-Microbe Interface in 
Atopic Dermatitis 
Short Title 
Dupilumab Study 
Clinical Phase 
Post-Marketing Mechanistic Trial 
Number of Sites 
Up to 16 clinical sites in the United States 
IND Sponsor/Number   
Not Applicable 
Study Objectives 
Primary Objective 
To assess the effect of dupilumab on Staphylococcus aureus (S. 
aureus) abundance on lesional skin as measured by microbial 
deoxyribonucleic acid (DNA)  
Secondary Objectives 
 
1. To assess the effect of dupilumab on S. aureus abundance 
on non-lesional skin as measured by microbial DNA 
2. To assess the effect of dupilumab on epidermal barrier 
function in lesional and non-lesional skin  
3. To assess the effect of dupilumab on disease severity  
Exploratory Objectives 
 
1. To assess the effect of dupilumab on the microbiome and 
metagenome in lesional and non-lesional skin  
2. To assess the effect of dupilumab on the skin 
transcriptome in lesional and non-lesional skin (non-URMC 
participants only) 
3. To assess the effect of dupilumab on epidermal lipids in 
lesional and non-lesional skin  
4. To assess the effect of dupilumab on the expression of S. 
aureus superantigens, toxins, lipase, and proteases on 
lesional and non-lesional skin  
5. To assess the effect of dupilumab on non-lesional skin 
barrier structure and Langerhans cells (LC) by confocal 
imaging (URMC participants only) 
6. To assess the effect of dupilumab on the function of the 
skin microbiome (i.e. ability of Coagulase-negative 
staphylococci isolates [CoNS] to kill S. aureus) in lesional 
and non-lesional skin  


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7. To assess the effect of dupilumab on PBMC 
immunoprofiles.  
8. To assess the effect of dupilumab on serum biomarkers 
(e.g.  Th2 biomarkers)   
9. To explore the association between genetic variation and 
(clinical and mechanistic) responsiveness to dupilumab 
10. To identify networks/pathways associated with 
responsiveness to dupilumab, quantified by disease 
severity, symptoms, and barrier function. 
Study Design 
A multi-center randomized double-blind, placebo-controlled 
(RDBPC) trial investigating the effect of 6 weeks of dupilumab 
treatment on quantitative and qualitative measures of cutaneous 
microbial community structure, skin barrier biology, and circulating 
T cell profiles, followed by a 10 week open-label extension. 
Primary Endpoint(s) 
S. aureus abundance as measured by microbial DNA (femA qPCR) 
on lesional skin at Day 28 
Secondary Endpoints  
1. S. aureus abundance as measured by microbial DNA (femA 
qPCR) on lesional skin at Days 0, 3, 7, 14, 21, 42, 77 and 
112 
2. S. aureus abundance as measured by microbial DNA (femA 
qPCR) on non-lesional skin at Days 0, 3, 7, 14, 21, 28, 42, 
77 and 112 
3. Basal (prior to tape stripping) transepidermal water loss 
(TEWL) of non-lesional and lesional skin at Days 0, 3, 7, 14, 
21, 28, 42, 77 and 112 
4. TEWL area under the curve of non-lesional skin at Days 0, 
7, 14, 21, 28, 42, 77 and 112. TEWL will be assessed prior 
to tape stripping and repeated after 5, 10, and 15 tape 
strips.  
5. Change in TEWL per every 5 tape strips (i.e. slope) on non-
lesional skin at Days 0, 7, 14, 21, 28, 42, 77 and 112 
6. Eczema Area and Severity Index [EASI], Investigator Global 
Assessment [IGA], and SCORing Atopic Dermatitis 
[SCORAD] at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112  
7. Pruritus numerical rating scale [NRS] at Days 0, 3, 7, 14, 21, 
28, 42, 77 and 112  
Exploratory Endpoints 
1. Composition of bacterial taxa in lesional and non-lesional 
skin at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
2. Abundance of bacterial taxa in lesional and non-lesional 
skin at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112   


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3. Gene expression in the skin transcriptome in non-lesional 
skin at Days 0 and 7, and in lesional skin at Days 0, 7, and 
21 
4. Lipid profiles of non-lesional skin at Days 0, 7, 14, 21, 28, 
42, 77 and 112 and of lesional skin at Days 0, 14, 28, and 
112 
5. Expression of S. aureus superantigens, toxins, lipase, and 
proteases on lesional and non-lesional skin at Days 0, 3, 7, 
14, 21, 28, 42, 77 and 112 
6. Confocal imaging of tight junctions (TJs) and relationship to 
LCs in the epidermis from non-lesional skin at Days 0, 7 
and 21 
7. Percent of coagulase-negative staphylococci [CoNS] 
isolates that kill S. aureus on lesional and non-lesional skin 
at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
8. PBMC immunoprofiling at Days 0, 14 and 28 
9. Levels of serum biomarkers (e.g. Th2 biomarkers and anti-
drug antibodies [ADA]) at Days 0, 7, 14, 21, 28, 42, 77 and 
112 
10. The presence of single nucleotide polymorphisms (SNPs) 
Accrual Objective 
This study will enroll approximately 99 adult participants, 18-75 
years of age, with chronic moderate-to-severe atopic dermatitis 
(AD). A 2:1 allocation will be used to assign 66 participants to the 
dupilumab arm and 33 participants to the placebo arm.  
Study Duration 
This study will take approximately 20 months to complete; we 
anticipate that enrollment will take approximately 1 year.  
Treatment Description  
RDBPC Portion 
Active: Dupilumab is a fully human monoclonal antibody (mAb) 
directed against the IL-4 receptor alpha subunit (IL-4Rα), which is a 
common subunit for the Type 1 and Type 2 receptors that mediate 
most of the biological functions of the prototypic Th2 cytokines, IL-
4 and IL-13. Participants will receive a loading dose of two 300 mg 
subcutaneous injections on Day 0 followed by 300 mg 
subcutaneous injections every two weeks (Days 14 and 28). 
Injections can be given in the abdomen, thigh, or upper arm.  
 
Placebo: Placebo will contain the identical formulation as the 
dupilumab formulation without the active mAb and will be given 
by exactly the same route and schedule through Day 28.  
 
Open-label Extension Portion 
All participants will begin a 10 week open-label extension (OLE) on 
Day 42. Participants who were randomized to placebo initially will 


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receive a 600 mg loading dose (two 300 mg injections) of 
dupilumab on Day 42.  Those who were randomized initially to 
dupilumab will receive a 300 mg dupilumab injection plus a 
placebo injection on Day 42 to maintain the blind. Participants or 
their caretaker will self-administer 300 mg of dupilumab by 
subcutaneous injection every two weeks through Day 98. 
Injections will be given in the abdomen, thigh, or upper arm. 
Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for 
enrollment as study participants: 
1. Must be able to understand and provide informed consent 
2. Male or female, 18-75 years inclusive at the Screening Visit 
3. Chronic AD, (according to the Atopic Dermatitis Research 
Network [ADRN] Standard Diagnostic Criteria), that has 
been present for at least 3 years before the Screening Visit 
for individuals aged 18-65 years old OR for at least 5 years 
before the Screening Visit for individuals aged 66-75 years 
old. Individuals aged 66-75 years of age must have 
documentation of a skin biopsy to rule out cutaneous T-
cell lymphoma and other non-AD conditions present in the 
medical record. 
4. EASI score ≥12 at the Screening Visit and ≥16 at the 
Treatment Initiation Visit 
5. IGA score ≥3 (on the 0-4 IGA scale) at the Screening and 
Treatment Initiation Visits 
6. ≥10% body surface area of AD involvement at the 
Screening and Treatment Initiation Visits 
7. Must have active lesions (minimum of 3 of at least 4x4 cm2 
each on the upper or lower extremities or trunk, excluding 
the palms of the hands, soles of the feet, buttock, navel, 
axilla, suprapubic area, and neck) at the Screening and 
Treatment Initiation Visits 
8. Documented recent history (within 6 months before the 
Screening Visit) of inadequate response to outpatient 
treatment with topical corticosteroids of medium to high 
potency (± topical calcineurin inhibitors as appropriate), or 
for whom topical treatments are otherwise inadvisable 
(e.g., because of important side effects or safety risks).  
Acceptable documentation includes contemporaneous 
chart notes that record prescription of topical 
corticosteroids and/or topical calcineurin inhibitors, 
investigator documentation based on communication with 
patient’s treating physician, or medical history provided by 
the patient.  


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9. Must agree to apply a stable dose of a topical emollient 
(moisturizer) at least twice daily for at least 7 days before 
the Treatment Initiation Visit, and must confirm 
application at the Treatment Initiation Visit  
10. Individuals with asthma must adhere to asthma controller 
medication(s) for the duration of the study including the 
open-label and follow-up portions of the study 
11. Females of childbearing potential must have a negative 
pregnancy test at the Screening and Treatment Initiation 
Visits  
12. Females of reproductive potential* and sexually active 
must agree to use Food and Drug Administration (FDA) 
approved methods of birth control for the duration of the 
study including the open-label and follow-up portions of 
the study. These include hormonal contraceptives, 
intrauterine device, double barrier contraception (i.e., 
condom plus diaphragm), or male partner with 
documented vasectomy.  
*Menopause is defined as at least 12 consecutive 
months without menses; if in question, a   
follicle stimulating hormone of ≥25 U/mL must be 
documented. Hysterectomy, bilateral oophorectomy, 
or bilateral tubal ligation must be documented, as 
applicable; if documented, women with these 
conditions are not required to use additional 
contraception. 
13. Males who are sexually active must agree to use an 
acceptable method of birth control (e.g. barrier methods 
with vaginal spermicide, surgical sterilization or surgically 
sterilized partner), or have a female partner practicing an 
approved birth control method for females as described in 
Inclusion Criterion #12. 
14. Willing and able to comply with all clinic visits and study-
related procedures 
15. Able to understand and complete study-related 
questionnaires 
 
Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for 
enrollment as study participants: 
1. Inability or unwillingness of an individual to give written 
informed consent or comply with study protocol 
2. Known systemic hypersensitivity to any of the excipients of 
the dupilumab or placebo study products 


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3. Known or suspected immunosuppression, including history 
of invasive opportunistic infections (e.g., tuberculosis, 
histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, aspergillosis) despite infection resolution, 
or otherwise recurrent immune-compromised status, as 
judged by the investigator 
4. Known history of human immunodeficiency virus (HIV) 
infection 
5. 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 or active case 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 regular use of ocular corticosteroids or 
cyclosporine. 
6. Parasitic infection, except for vaginal trichomoniasis, 
within 12 months of the Treatment Initiation Visit, or high 
risk for contracting parasitic infections (e.g., living in or 
traveling to endemic areas)  
7. Presence of skin comorbidities that may interfere with 
study assessments 
8. History of malignancy within 5 years before the Treatment 
Initiation 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 or 
melanoma in situ 
9. History of non-malignant lymphoproliferative disorders 
10. History of alcohol or drug abuse within 2 years before the 
Screening Visit 
11. Severe concomitant illness(es) that, in the investigator’s 
judgment, would adversely affect the individual’s 
participation in the study. Examples include, but are not 
limited to, individuals with short life expectancy,  
uncontrolled diabetes (HbA1c ≥9%), cardiovascular 
conditions (e.g., stage III or IV cardiac failure according to 
the New York Heart Association classification), severe renal 
conditions (e.g.,  individuals on dialysis), hepato-biliary 
conditions (e.g., Child-Pugh class B or C), neurological 
conditions (e.g., demyelinating diseases), active major 
autoimmune diseases (e.g., lupus, inflammatory bowel 
disease, rheumatoid arthritis, etc.), eosinophilic conditions 
(e.g. eosinophilic granulomatosis with polyangiitis), other 


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severe endocrinological, gastrointestinal, metabolic, 
pulmonary, or lymphatic diseases.  
12. Any other medical or psychological condition including 
relevant laboratory abnormalities at screening that, in the 
opinion of the investigator, suggests 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 
individual’s participation unreliable, or may interfere with 
study assessments. This includes hypersensitivity to local 
anesthetics (e.g., lidocaine or Novocain), bleeding 
disorders, treatment with anticoagulants or other 
conditions that make the biopsy procedure inadvisable.  
13. Planned major surgical procedure during the screening 
period or study treatment (i.e. Screening through Day 112) 
14. Member of the investigational team or his/her immediate 
family 
15. Pregnant or breast-feeding women, or women planning to 
become pregnant or breastfeed during the study including 
the open-label and follow up portions of the study 
16. Individuals unwilling to use adequate birth control, if of 
reproductive potential and sexually active. Adequate birth 
control is defined as agreement to consistently practice an 
approved method of contraception for the duration of the 
study including the open-label and follow up portions of 
the study. Refer to Inclusion criteria #12 and #13.  
17. History of keloid formation 
18. History of serious life-threatening reaction to tape or 
adhesives 
19. Prior treatment with dupilumab  
20. Individuals with asthma who have required use of a 
systemic corticosteroid within 3 months prior to the 
Treatment Initiation Visit or who require a dose greater 
than 880 mcg/day of fluticasone propionate or equivalent 
inhaled corticosteroid to maintain asthma control 
21. Treatment with biologics as follows: 
x 
Any cell-depleting agents, including but not limited 
to rituximab, within 6 months before the 
Treatment Initiation Visit, or until lymphocyte and 
CD 19+ lymphocyte count returns to normal, 
whichever is longer 
x 
Infliximab, adalimumab, golimumab, certolizumab 
pegol, abatacept, etanercept, anakinra within 16 


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weeks before the Treatment Initiation Visit for any 
indication 
x 
Other biologics within 5 half-lives (if known) or 16 
weeks before the Treatment Initiation Visit, 
whichever is longer 
22. Treatment with a live (attenuated) vaccine within 12 
weeks before the Treatment Initiation Visit or planning to 
receive a live vaccine during the study (through Day 182) 
23. Use of an investigational drug within 8 weeks or within 5 
half-lives (if known), whichever is longer, before the 
Treatment Initiation Visit 
24. Chronic or acute infection requiring treatment with 
systemic antibiotics, antivirals, antiparasitics, 
antiprotozoals, or antifungals within 4 weeks before the 
Treatment Initiation Visit, or superficial skin infections 
within 1 week before the Treatment Initiation Visit 
25. The following treatments within 4 weeks before the 
Treatment Initiation Visit, or any condition that, in the 
opinion of the investigator, will likely require such 
treatment(s) during the screening period and study 
treatment (i.e., Screening through Day 112): 
x 
Systemic corticosteroids 
x 
Immunosuppressive/immunomodulating drugs 
(e.g., cyclosporine, mycophenolate-mofetil, IFN-γ, 
Janus kinase inhibitors, azathioprine, or 
methotrexate) 
26. Use of phototherapy (such as narrow band ultraviolet B 
[NBUVB], ultraviolet B [UVB], ultraviolet A1 [UVA1], 
psoralen + UVA [PUVA]) or a tanning booth/parlor within 4 
weeks of the Treatment Initiation Visit 
27. Treatment with bleach bath within 3 weeks before the 
Treatment Initiation Visit 
28. Use of a chlorinated hot tub within 3 weeks before the 
Treatment Initiation Visit 
29. Treatment with topical corticosteroids, phosphodiesterase 
inhibitors (crisaborole), or calcineurin inhibitors 
(tacrolimus or pimecrolimus) within 1 week before the 
Treatment Initiation Visit. Low potency topical 
corticosteroids may be used just on the face up until 48 
hours prior to the Treatment Initiation Visit.  
30. Initiation of treatment of AD with prescription moisturizers 
or moisturizers containing ceramide, hyaluronic acid, urea, 
or filaggrin during the screening period (participants may 


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continue using stable doses of such moisturizers if initiated 
before the Screening Visit) 
31. Planned or anticipated use of any prohibited medications 
or procedures during the screening period and study 
treatment (i.e., Screening through Day 112). Refer to 
Section 7.3 for additional details. 
Study Stopping Rules 
Study enrollment will be suspended pending Division of Allergy, 
Immunology, and Transplantation (DAIT) National Institute of 
Allergy and Infectious Diseases (NIAID) and NIAID Allergy and 
Asthma Data Safety Monitoring Board (DSMB) expedited review of 
all pertinent data if any of the following occur: 
 
1. 1 death, or life-threatening adverse event, that is possibly 
related to dupilumab 
2. A grade 3 or higher adverse event that is possibly related 
to dupilumab in two or more participants 
 
 


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Table of Contents 
Glossary of Abbreviations ..................................................................................................................................................... 18 
1. 
Background and Rationale ........................................................................................................................................ 22 
1.1. 
Background and Scientific Rationale ..................................................................................................................... 22 
1.1.1. 
Skin Colonization with S. aureus ................................................................................................................... 22 
1.1.2. 
Skin Barrier Dysfunction ................................................................................................................................ 23 
1.2. 
Rationale for Selection of Investigational Product or Intervention ...................................................................... 24 
1.2.1 
Dupilumab – Rationale .................................................................................................................................. 24 
1.2.2 
Efficacy and Safety ........................................................................................................................................ 24 
1.2.3 
Dupilumab Mechanistic Studies .................................................................................................................... 24 
1.2.4 
Selection of Dupilumab over Alternative Systemic Biologics Targeting Th2 Cytokines ................................ 24 
1.3. 
Preclinical Experience ........................................................................................................................................... 24 
1.3.1. 
In Vitro Studies .................................................................................................................................................. 25 
1.3.2. 
Animal Pharmacology and Safety Studies ......................................................................................................... 25 
1.3.2.1. 
Pharmacology................................................................................................................................................ 25 
1.3.2.2. 
Absorption, Bioavailability, Distribution, Metabolism and Elimination/Excretion ....................................... 26 
1.3.2.3. 
Toxicology ..................................................................................................................................................... 26 
1.3.2.4. 
Reproductive and Developmental Toxicology .............................................................................................. 26 
1.3.2.5. 
Carcinogenicity .............................................................................................................................................. 26 
1.4. 
Clinical Studies ...................................................................................................................................................... 27 
1.4.1. 
Clinical Pharmacology ....................................................................................................................................... 27 
1.4.1.1. 
Mechanism of Action .................................................................................................................................... 27 
1.4.1.2. 
Pharmacodynamics ....................................................................................................................................... 27 
1.4.1.3. 
Pharmacokinetics .......................................................................................................................................... 27 
1.4.1.3.1. 
Absorption ..................................................................................................................................................... 27 
1.4.1.3.2. 
Distribution ................................................................................................................................................... 27 
1.4.1.3.3. 
Elimination .................................................................................................................................................... 28 
1.4.1.3.4. 
Dose Linearity ................................................................................................................................................ 28 
1.4.1.3.5. 
Weight ........................................................................................................................................................... 28 
1.4.1.3.6. 
Age ................................................................................................................................................................ 28 
1.4.1.3.7. 
Immunogenicity ............................................................................................................................................ 28 
1.4.1.3.8. 
Specific Populations ...................................................................................................................................... 28 
1.4.1.3.9. 
Drug Interaction Studies ............................................................................................................................... 28 
1.4.2. 
Clinical Trials Efficacy ........................................................................................................................................ 29 


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1.4.2.1. 
Clinical Response at Week 16 (Trials 1, 2, and 3) .......................................................................................... 29 
1.4.3. 
Clinical Trials Safety ........................................................................................................................................... 31 
1.4.3.1. 
Weeks 0 to 16 (Trials 1 to 4) ......................................................................................................................... 31 
1.4.3.2. 
Safety through Week 52 (Trial 3) .................................................................................................................. 32 
1.4.3.3. 
Specific Adverse Reactions ............................................................................................................................ 33 
1.4.3.3.1. 
Conjunctivitis  ................................................................................................................................................ 33 
1.4.3.3.2. 
Eczema Herpeticum and Herpes Zoster ........................................................................................................ 33 
1.4.3.3.3. 
Hypersensitivity Reactions ............................................................................................................................ 33 
1.4.3.3.4. 
Eosinophils .................................................................................................................................................... 33 
1.4.3.3.5. 
Cardiovascular ............................................................................................................................................... 33 
2. 
Study Hypothesis/Objectives .................................................................................................................................... 34 
2.1. 
Hypothesis ............................................................................................................................................................. 34 
2.2. 
Primary Objective .................................................................................................................................................. 34 
2.3. 
Secondary Objective(s) ......................................................................................................................................... 34 
2.4. 
Exploratory Objective(s)........................................................................................................................................ 34 
3. 
Study Design .............................................................................................................................................................. 34 
3.1. 
Description of Study Design .................................................................................................................................. 34 
3.2. 
Primary Endpoint(s)/Outcome(s) .......................................................................................................................... 36 
3.3. 
Secondary Endpoint(s)/Outcome(s) ...................................................................................................................... 36 
3.4. 
Exploratory Endpoint(s)/Outcome(s) .................................................................................................................... 36 
3.5. 
Stratification, Randomization, and Blinding/Masking .......................................................................................... 37 
3.6. 
Procedure for Unblinding/Unmasking .................................................................................................................. 37 
4. 
Selection of Participants and Clinical Sites/Laboratories.......................................................................................... 38 
4.1. 
Rationale for Study Population ............................................................................................................................. 38 
4.2. 
Inclusion Criteria ................................................................................................................................................... 38 
4.3. 
Exclusion Criteria ................................................................................................................................................... 39 
4.4. 
Selection of Clinical Sites/Labs .............................................................................................................................. 41 
5. 
Known and Potential Risks and Benefits to Participants .......................................................................................... 41 
5.1. 
Risks of Investigational Product or Intervention as cited in the Package Insert ................................................... 41 
5.2. 
Risks of Investigational Product or Intervention Cited in Medical Literature ....................................................... 42 
5.3. 
Risks of Other Protocol Specified Medications ..................................................................................................... 42 
5.4. 
Risks of Study Procedures ..................................................................................................................................... 42 
5.4.1 
Risks Associated with Stopping the Use of Protocol Prohibited Medications/Procedures .......................... 42 
5.4.2. 
Risks Associated with Physical Exam ............................................................................................................. 42 


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5.4.3. 
Risks Associated with Health Questionnaires ............................................................................................... 42 
5.4.4. 
Risks Associated with Blood Collection ......................................................................................................... 42 
5.4.5. 
Risks Associated with Skin Swab Collection .................................................................................................. 42 
5.4.6  
Risks Associated with Skin Barrier TEWL Measurement ............................................................................... 43 
5.4.7. 
Risks Associated with Skin Tape Strip Collection .......................................................................................... 43 
5.4.8. 
Risks Associated with Skin Biopsies .............................................................................................................. 43 
5.5. 
Potential Benefits .................................................................................................................................................. 43 
6. 
Investigational Agent ................................................................................................................................................ 44 
6.1 
Investigational Agent ............................................................................................................................................ 44 
6.1.1. 
Dupilumab ..................................................................................................................................................... 44 
6.1.2. 
Placebo .......................................................................................................................................................... 45 
6.2. 
Drug Accountability ............................................................................................................................................... 45 
6.3. 
Assessment of Participant Compliance with Investigational Agent ..................................................................... 46 
6.4. 
Toxicity Prevention and Management .................................................................................................................. 46 
6.5. 
Premature Discontinuation of Investigational Agent ........................................................................................... 46 
7. 
Other Medications/Procedures ................................................................................................................................ 47 
7.1. 
Concomitant Medications ..................................................................................................................................... 47 
7.1.1. 
Protocol-mandated ....................................................................................................................................... 47 
7.1.2. 
Other Permitted Concomitant Medications ................................................................................................. 47 
7.2. 
Prophylactic Medications ...................................................................................................................................... 47 
7.3. 
Prohibited Medications/Procedures ..................................................................................................................... 47 
7.4. 
Rescue Medications/Procedures .......................................................................................................................... 49 
8. 
Study Procedures ...................................................................................................................................................... 49 
8.1. 
Recruitment  ......................................................................................................................................................... 49 
8.2. 
Screening (Day -28 to Day -8) ............................................................................................................................... 49 
8.3. 
Treatment Initiation Visit (Day 0, to Occur within 28 Days of Screening) ............................................................ 50 
8.4. 
Day 3 (± 1 Day) ...................................................................................................................................................... 51 
8.5. 
Day 7 (± 2 days) ..................................................................................................................................................... 52 
8.6. 
Day 14 (± 2 days) ................................................................................................................................................... 53 
8.7. 
Day 21 (± 2 days) ................................................................................................................................................... 54 
8.8. 
Day 28 (± 2 days) ................................................................................................................................................... 55 
8.9. 
Day 42 (± 2 days) ................................................................................................................................................... 56 
8.10. 
Day 56 (± 7 days) Home IP Injection ................................................................................................................. 58 
8.11. 
Day 70 (± 7 days) Home IP Injection ................................................................................................................. 58 


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8.12. 
Day 77 (± 2 days) ............................................................................................................................................... 58 
8.13. 
Day 84 (± 7 days) Home IP Injection ................................................................................................................. 59 
8.14. 
Day 98 (± 7 days) Home IP Injection ................................................................................................................. 59 
8.15. 
Day 112 (± 2 days) ............................................................................................................................................. 59 
8.16. 
Day 182 Follow-Up Phone Call (± 5 days) ......................................................................................................... 60 
8.17. 
Unscheduled Visits ............................................................................................................................................ 60 
8.18. 
Visit Windows.................................................................................................................................................... 61 
9. 
Mechanistic Assays ................................................................................................................................................... 61 
9.1. 
Measurement of S. aureus Abundance ................................................................................................................. 61 
9.2. 
Measurement of S. aureus Superantigens, Toxins, Lipase, and Proteases ........................................................... 62 
9.3. 
Analysis of the Skin Microbiome ........................................................................................................................... 62 
9.3.1. 
Microbiome Assessment by 16S rRNA .......................................................................................................... 62 
9.3.2. 
Metagenomic Analysis of Microbiome ......................................................................................................... 63 
9.4. 
Functional Assessment of Coagulase Negative Staphylococcal Species (CoNS) Isolates for Antimicrobial Activity
 
63 
9.5. 
Assessment of Lipid Components ......................................................................................................................... 63 
9.6. 
Confocal Imaging of Skin Biopsies ......................................................................................................................... 64 
9.7. 
Skin Transcriptomics ............................................................................................................................................. 64 
9.8. 
PBMC Immunoprofiling ......................................................................................................................................... 64 
9.9. 
Analysis of Serum Biomarkers ............................................................................................................................... 65 
9.10. 
Genotyping ........................................................................................................................................................ 65 
10. 
Biospecimen Storage................................................................................................................................................. 65 
11. 
Criteria for Participant and Study Completion and Premature Study Termination.................................................. 65 
11.1. 
Participant Completion ..................................................................................................................................... 65 
11.2. 
Participant Stopping Rules and Withdrawal Criteria ........................................................................................ 66 
11.3. 
Participant Replacement ................................................................................................................................... 66 
11.4. 
Follow-up After Early Study Withdrawal........................................................................................................... 66 
11.5. 
Study Stopping Rules ......................................................................................................................................... 66 
12. 
Safety Monitoring and Reporting ............................................................................................................................. 67 
12.1. 
Overview ........................................................................................................................................................... 67 
12.2. 
Definitions ......................................................................................................................................................... 67 
12.2.1. 
Adverse Event (AE) ........................................................................................................................................ 67 
12.2.2. 
Unexpected Adverse Event ........................................................................................................................... 68 
12.2.3. 
Serious Adverse Event (SAE) ......................................................................................................................... 68 


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12.3. 
Grading and Attribution of Adverse Events ...................................................................................................... 69 
12.3.1. 
Grading Criteria ............................................................................................................................................. 69 
12.3.2. 
Attribution Definitions .................................................................................................................................. 69 
12.4. 
Collection and Recording of Adverse Events .................................................................................................... 70 
12.4.1. 
Collection Period ........................................................................................................................................... 70 
12.4.2. 
Collecting Adverse Events ............................................................................................................................. 70 
12.4.3. 
Recording Adverse Events ............................................................................................................................. 70 
12.5. 
Reporting of Serious Adverse Events and Adverse Events ............................................................................... 71 
12.5.1. 
Reporting of Serious Adverse Events to DAIT/NIAID .................................................................................... 71 
12.5.2. 
Reporting to Health Authority ...................................................................................................................... 71 
12.5.3. 
Reporting of Adverse Events to the Central IRB ........................................................................................... 71 
12.6. 
Pregnancy Reporting ......................................................................................................................................... 71 
12.7. 
Reporting of Other Safety Information ............................................................................................................. 72 
12.8. 
Review of Safety Information ........................................................................................................................... 72 
12.8.1. 
Medical Monitor Review ............................................................................................................................... 72 
12.8.2. 
DSMB Review ................................................................................................................................................ 72 
13. 
Statistical Considerations and Analytical Plan .......................................................................................................... 73 
13.1. 
Overview ........................................................................................................................................................... 73 
13.2. 
Endpoints/Outcomes ........................................................................................................................................ 73 
13.3. 
Measures to Minimize Bias ............................................................................................................................... 73 
13.4. 
Analysis Plan ...................................................................................................................................................... 73 
13.4.1. 
Analysis Populations ..................................................................................................................................... 73 
13.4.2. 
Primary Analysis of Primary Endpoint(s)/Outcome(s) .................................................................................. 74 
13.4.3. 
Supportive Analyses of the Primary Endpoint(s)/Outcome(s) ...................................................................... 74 
13.4.4. 
Analyses of Secondary and Other Endpoint(s)/Outcome(s) ......................................................................... 74 
13.4.5. 
Analyses of Exploratory Endpoint(s)/Outcome(s)......................................................................................... 75 
13.4.6. 
Descriptive Analyses ..................................................................................................................................... 78 
13.5. 
Interim Analyses ................................................................................................................................................ 78 
13.5.1. 
Interim Analysis of Efficacy Data ................................................................................................................... 78 
13.5.2. 
Interim Analysis of Safety Data ..................................................................................................................... 78 
13.5.3. 
Futility Analysis ............................................................................................................................................. 78 
13.6. 
Statistical Hypotheses ....................................................................................................................................... 78 
13.7. 
Sample Size Considerations .............................................................................................................................. 78 
14. 
Identification and Access to Source Data ................................................................................................................. 79 


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14.1. 
Source Data ....................................................................................................................................................... 79 
14.2. 
Access to Source Data ....................................................................................................................................... 79 
15. 
Protocol Deviations ................................................................................................................................................... 79 
15.1. 
Protocol Deviation Definitions .......................................................................................................................... 79 
15.2. 
Reporting and Managing Protocol Deviations .................................................................................................. 80 
16. 
Ethical Considerations and Compliance with Good Clinical Practice ........................................................................ 80 
16.1. 
Quality Control and Quality Assurance ............................................................................................................. 80 
16.2. 
Statement of Compliance ................................................................................................................................. 80 
16.3. 
Informed Consent Process ................................................................................................................................ 80 
16.4. 
Privacy and Confidentiality ............................................................................................................................... 81 
17. 
Publication Policy ...................................................................................................................................................... 81 
18. 
References ................................................................................................................................................................ 82 
Appendix A: Schedule of Events ........................................................................................................................................... 88 
 


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Glossary of Abbreviations 
AAD 
American Academy of Dermatology 
Ab 
Antibody 
AD 
Atopic Dermatitis 
ADA 
Anti-drug Antibodies 
ADR 
Adverse Drug Reaction 
ADRN 
Atopic Dermatitis Research Network 
ADVN 
Atopic Dermatitis Vaccinia Network 
AE  
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CFU 
Colony Forming Units 
CLA 
Cutaneous Lymphocyte Antigen 
CMP 
Comprehensive Metabolic Panel 
CoNS 
Coagulase Negative Staphylococcal Species 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EASI 
Eczema Area and Severity Index 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FLG 
Filaggrin 
GCP 
Good Clinical Practice 
GD 
Gestational Day 
HILIC 
Hydrophilic Interaction Chromatography 
HIV 
Human Immunodeficiency Virus 


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IB 
Investigator Brochure 
IC 
Inhibitory Concentration 
ICH 
International Conference on Harmonization 
IGA 
Investigator Global Assessment 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISR 
Injection Site Reaction 
IUD 
Intrauterine Device 
IV 
Intravenous 
kDa 
Kilodalton 
LC 
Langerhans cell 
mAb 
Monoclonal Antibody 
mbQTL 
Microbiome Quantitative Trait Loci 
mITT 
Modified Intent-to-Treat 
MOP 
Manual of Procedures 
NBUVB 
Narrow Band Ultraviolet B 
NCI 
National Cancer Institute 
NESS 
Nottingham Eczema Severity Score 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
 
 
NP 
Nasal Polyposis 
NRS 
Numerical Rating Scale 
OHRP 
Office for Human Research Protections 
OLE 
Open-Label Extension 
OTU 
Operational Taxonomic Unit 
P. acnes 
Propionibacterium acnes 
PARC 
Pulmonary and Activation-Regulated Chemokine 
PBMC 
Peripheral Blood Mononuclear Cell 
PBS 
Phosphate Buffered Saline 
PCA 
Pyroglutamic Acid 
PCR 
Polymerase Chain Reaction 


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PHI 
Personal Health Identifiers 
PI 
[Site] Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PUVA 
Psoralen + Ultraviolet A 
PVDF 
Polyvinylidene Fluoride 
QTL 
Quantitative Trait Loci 
Q2W 
Every two weeks 
QW 
Once weekly 
RDBPC 
Randomized Double Blind Placebo Controlled 
RNA 
Ribonucleic Acid 
S. aureus 
Staphylococcus aureus 
SC 
Stratum Corneum 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAg 
Superantigen 
SAR 
Suspected Adverse Reaction 
SCORAD 
SCORing Atopic Dermatitis 
SD 
Standard deviation 
SNP 
Single Nucleotide Polymorphism 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TARC 
Thymus and Activation-Regulated Chemokine 
TDAR 
T-Cell Dependent Antibody Response 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TEWL 
Transepidermal Water Loss 
Th 
T Helper 
TJ 
Tight Junction 
TSB 
Tryptic Soy Broth 
UCA 
Urocanic Acid 
 
 
 
 
UVA1 
Ultraviolet A1 


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UVB 
Ultraviolet B 
γc 
Common Gamma Chain 
 
 
 


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1. Background and Rationale  
1.1. Background and Scientific Rationale 
Atopic dermatitis (AD) is the most common inflammatory skin disease, affecting 15 million Americans with a greater 
impact on quality of life than any other chronic skin condition (Bin et al, 2016). Despite this, until recently no Food and 
Drug Administration (FDA)-approved targeted systemic therapies were available for AD. Dupilumab (Dupixent) has 
recently been approved for the treatment of moderate-to-severe AD, with or without concomitant topical 
corticosteroids, in adult patients whose disease is not adequately controlled with prescribed topical therapies or for 
whom such treatments are not advisable. Dupilumab is a fully human monoclonal antibody that inhibits the signaling of 
T helper (Th)2 cytokines (Interleukin[IL]-4 and IL-13) resulting in rapid and significant clinical improvement in adults with 
moderate-to-severe AD (Simpson et al, 2016; Thaci et al, 2016; Beck et al, 2014). As such, dupilumab provides an 
unprecedented opportunity to further understand the relevance of Th2 inflammation on AD pathology, focusing on the 
microbial, epithelial, and immune compartments. To do this, we have designed a 6 week randomized double blind 
placebo controlled (RDBPC) trial with high density sampling of these compartments to characterize and quantify changes 
and their relationship to disease improvements, followed by a 10 week open-label extension of the study.  By integrating 
this multi-scale, high density data, we can model the complex interactions between the host and microbiome with and 
without Th2 blockade. 
A hallmark of AD is the increased type 2 immune response, that is triggered by a wide range of allergens, microbes, such 
as Staphylococcus aureus (S. aureus), and even epithelial proteins. This is a systemic disease as demonstrated by Type 2 
inflammation which is even present in non-lesional skin (Suarez-Farinas et al, 2011).  Furthermore, expansion of skin-
homing (CLA+) Th2 cells is observed in the peripheral blood of AD patients with severe disease (Czarnowicki et al, 2015). 
Lastly, serum markers of Th2 inflammation such as thymus and activation-regulated chemokine (TARC/CCL17) are much 
higher in AD than in other allergic disorders (Hijnen et al, 2004).  Another hallmark of AD is the increased susceptibility 
to skin colonization with S. aureus (Warner et al, 2009).  The final feature of the disease is skin barrier dysfunction which 
is even observed in non-lesional skin.  Below we highlight the evidence for the latter two features and summarize the 
evidence suggesting that they arise as a consequence of Th2 cytokines. 
1.1.1. Skin Colonization with S. aureus 
In the ADRN Registry study, we have found that 43% of AD participants have S. aureus that can be cultured from 
their skin in contrast to < 2% of healthy controls (Ong et al, 2016; Beck et al, 2008; Totté et al, 2016). PCR 
quantification of S. aureus highlights that virtually all AD participants have this pathogen on their skin surface 
(ADRN unpublished data).  This S. aureus abundance correlates strongly with skin barrier measurements such as 
transepidermal water loss (TEWL) (p=0.004) (data not shown) suggesting an interaction between microbiome 
and host. In 2012, the first microbiome analysis on a small number of AD subjects demonstrated an inverse 
relationship between the diversity of skin microbiota and intraindividual AD disease activity (Kong et al, 2012). 
Disease severity was associated with a relative increase in S. aureus and a decrease in commensals, including 
Propionibacterium acnes (P. acnes). Similarly, the ADRN Barrier study observed a reduction in P. acnes in AD 
participants who were culture positive for S. aureus (ADRN unpublished data), implicating commensals as critical 
for the normal skin biogeography (Shu et al, 2013).  In support of this idea, the 
 laboratory 
 has demonstrated that commensal bacteria, such as S. epidermidis and hominis produce 
antimicrobial molecules which restrict S. aureus survival (Lai et al, 2009; Lai et al, 2010; Cogen, Yamasaki, Muto 
et al, 2010; Cogen, Yamasaki, Sanchez et al, 2010; Nakatsuji et al, 2017).  Unfortunately, quantifying the relative 
(e.g. 16s RNA microbiome
) or even absolute amount of different bacterial species (e.g. 
qPCR of both pathogens and commensals – 
) is a first step in understanding AD skin 


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biography, but it does not tell us how these bacteria affect the host. For example, S. aureus strains differ in their 
secretion of virulence factors, which are important for amplifying inflammation and inducing class switching of B 
cells. Whether these toxins and virulence factors are produced can be suggested by the study of the bacterial 
genome (e.g. metagenome – 
) and direct toxin/virulence measurements (
 
). Metagenomic sequencing catalogs all the genes from uncultivated microbes directly from the site 
of interest. Metagenomics will be complemented by the direct measurement of S. aureus superantigens (SAgs), 
toxins, lipase, and proteases as has been developed in the laboratory of 
 (Vu et al, 2015).  In 
summary, type 2 immunity has been implicated as the etiology of the skin dysbiosis observed in AD patients.  In 
this protocol, we will employ complementary assays to give us an unprecedented qualitative and quantitative 
view of the skin bacterial flora to test whether Th2 blockade reduces S. aureus relative or absolute abundance, 
alters levels of and antimicrobial activity of commensals, and/or changes the toxigenic potential of S. aureus (as 
well as other bacteria).  
1.1.2. Skin Barrier Dysfunction 
The skin has two barrier structures, the stratum corneum (SC) and tight junctions (TJ). The SC is widely accepted 
to be dysfunctional based on: 1) alterations in SC lipids (Van Smeden and Bouwstra, 2016), 2) acquired or 
genetic defects in structural proteins such as filaggrin (FLG), loricrin, and other epidermal differentiation 
complex genes or 3) simply by scratching in response to intense itch (Matsui et al, 2015). Interestingly, in ADRN 
studies, FLG null mutations were not strongly implicated in European American AD participants’ susceptibility to 
S. aureus suggesting that other barrier defects and/or Th2 inflammation may be the explanations (Yoshida et al, 
2015; Rafaels et al, 2016). Preliminary lipidomic analysis of skin tape strips from ADRN AD participants identified 
a number of abnormalities (Berdyshev et al, 2017) which are largely recapitulated in keratinocytes stimulated 
with IL-4/IL-13, implicating type 2 immunity as the cause (Goleva et al, 2017). TJs are ring-like structures found 
below the SC, which function as a “gate” for paracellular transport, and are composed of transmembrane 
proteins including claudin family members (De Benedetto et al, 2011). ADRN studies demonstrated a remarkable 
defect in epidermal TJ integrity in AD non-lesional skin (De Benedetto et al, 2011). It is presumed that a leaky SC 
and TJ barrier promotes greater immunologic responsiveness to allergens and is responsible for the 
physiological abnormalities noted on the skin surface (e.g. reduced SC hydration, increased pH, enhanced 
TEWL). A number of groups have demonstrated that Th2 (but not Th17) cytokines adversely affect SC and TJ 
barrier functions (De Benedetto et al, 2015; Howell et al, 2009; Honzke et al, 2016; Yokouchi et al, 2015). These 
observations support our hypothesis that Th2 blockade, achieved with dupilumab treatment, will repair skin 
barrier function. In this protocol, we will monitor dupilumab effects on skin barrier by: 1) measuring 
physiological changes (TEWL – before and after tape stripping [e.g. SC integrity assay]), 2) lipidomics, 3) 
transcriptomics of epithelial barrier genes and 4) confocal images of TJ structures and their relationship to 
Langerhans Cells (LC) dendrites.  
In summary, it is clear that there is a dynamic interplay between the immune system, epithelial barrier function, 
and the skin bacterial flora, and these interactions are likely driving some, if not all, of the clinical features that 
we associate with AD.  We have proposed a study with a targeted systemic therapy that inhibits Th2 signaling to 
monitor the change in barrier function and skin flora in relationship to improvements in skin appearance and 
symptomatology to begin to address the relative importance of these different functions in disease severity.  


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1.2. Rationale for Selection of Investigational Product or Intervention 
1.2.1 
Dupilumab – Rationale 
Dupilumab is a fully human mAb directed against the IL-4 receptor alpha subunit (IL-4Rα), common to the Type 1 
and Type 2 receptors that mediate most of the biological functions of IL-4 and IL-13. It is the first biologic 
therapy FDA-approved for the treatment of adults with moderate-to-severe AD.   
1.2.2 
Efficacy and Safety 
Dupilumab treatment results in marked and rapid clinical improvement, with improvements observed in Eczema 
Area and Severity Index (EASI) scores by 2 weeks with greater than 80% improvement by 6 weeks (Simpson et al, 
2016; Thaci et al, 2016; Beck et al, 2014).  Dramatic and early reductions in pruritus, as measured by the 
numerical rating scale (NRS) and the 5-D pruritus scale, were also observed. The drug was well-tolerated with 
few serious adverse events attributable to dupilumab administration in AD trials (Simpson et al, 2016; Thaci et 
al, 2016; Beck et al, 2014). 
1.2.3 
Dupilumab Mechanistic Studies 
Several exploratory endpoints have been collected as part of Regeneron-sponsored studies and include serum 
biomarkers (indicative of type 2 immunity), skin S. aureus abundance (microbial DNA), PBMC immunoprofiling 
and skin transcriptome.  A pharmacodynamic response, as indicated by reduction in the Th2 biomarker, 
TARC/CCL17, could be observed as early as 1 week (Beck et al, 2014). None of the other readouts were 
performed before 4 weeks of dupilumab treatment. Skin transcriptome studies demonstrated that after 4 weeks 
of dupilumab treatment the lesional skin begins to approximate the non-lesional skin transcriptome (Hamilton 
et al, 2014).  In a different study, a significant reduction in S. aureus abundance was observed in lesional skin 
after 4 weeks (p<0.05), which was even more significant by 16 weeks of dupilumab treatment (p<0.01) 
(Guttman-Yassky et al, 2016).  Non-lesional swabs showed the same trend. This is consistent with observations 
made only in the Phase 2 studies where skin infections were reported more commonly in the placebo-treated 
group (24% vs 6%, respectively) (Beck et al, 2014).  Our protocol differs from the aforementioned studies as it 
will focus on frequent assessments of all relevant compartments (skin microbiome, barrier, and immunoprofile) 
with an emphasis on early time points (≤ 6 weeks); we will improve the sample processing ± assay methodology, 
will be the first to address effects on skin barrier function, will significantly enhance the depth and breadth of 
microbial analyses, and most of these measures will be performed in all study participants. This will provide a 
rich data-driven network to model and predict disease improvement 
 We will also take 
advantage of an open-label extension (providing 16 weeks and 10 weeks of continuous dupilumab treatment for 
participants randomized on entry to either active or placebo groups, respectively) to add to the disease severity 
modeling with a focus on intraindividual variation during dupilumab treatment. 
1.2.4 
Selection of Dupilumab over Alternative Systemic Biologics Targeting Th2 Cytokines 
Only two other systemic biologics targeting Th2 cytokines are in clinical development, namely lebrikizumab and 
tralokinumab. Both are directed against IL-13 and are at least a year behind dupilumab in clinical development. 
For this reason and because we hypothesize that blocking both IL-4 and IL-13 may be more effective, we have 
chosen dupilumab as the drug of choice to test the hypotheses outlined in this protocol. 
1.3. Preclinical Experience  
The following comes from the dupilumab Investigator’s Brochure 
  


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1.3.1. In Vitro Studies 
1.3.1.1. 
 
 
 
  
1.3.1.2. 
 
 
 
 
 
 
 
1.3.1.3. 
  
 
  
1.3.1.4. 
 
 
 
 
 
 
  
1.3.2. 
 
 
 
 
 
 
 
 
 


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1.3.2.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3.2.3. 
 
 
 
 
 
1.3.2.4. 
 
 
 
 
 
 
 
 
 
 
 
1.3.2.5. 
 
 
 
 
 
 
 


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1.4. Clinical Studies 
The following comes from the dupilumab package insert 
 
1.4.1. Clinical Pharmacology 
1.4.1.1. Mechanism of Action 
 
 
 
 
 
 
 
 
 
1.4.1.2. Pharmacodynamics 
 
 
 
 
 
 
 
 
 
1.4.1.3. Pharmacokinetics 
The pharmacokinetics of dupilumab 
 
1.4.1.3.1. Absorption 
 
 
 
 
 
 
 
 
  
 
 
1.4.1.3.2. Distribution 


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1.4.1.3.3. Elimination 
 
 
 
 
 
1.4.1.3.4. Dose Linearity 
 
 
 
1.4.1.3.5. Weight 
 
1.4.1.3.6. Age 
 
1.4.1.3.7. Immunogenicity 
 
 
 
1.4.1.3.8. Specific Populations 
 
 
 
  
 
 
 
1.4.1.3.9. Drug Interaction Studies 
 
 
 
 
 
 
 
 


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1.4.2. Clinical Trials Efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.2.1. Clinical Response at Week 16 (Trials 1, 2, and 3) 
 
 
 
 


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presented in Table 1.4.2.1b. 
 
 


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Table 1.4.2.1b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.3. Clinical Trials Safety 
 
 
 
 
 
 
 
 
 
 
1.4.3.1. Weeks 0 to 16 (Trials 1 to 4) 
 
 
 
 
 
 


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Table 1.4.3.1. 
 
 
 
1.4.3.2. Safety through Week 52 (Trial 3) 
 
 
 
 
 
 
 


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1.4.3.3. Specific Adverse Reactions 
1.4.3.3.1. 
  
 
 
 
 
 
 
1.4.3.3.2. 
 
 
 
 
 
 
 
 
1.4.3.3.3. 
 
 
 
 
1.4.3.3.4. 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.3.3.5. 
 
 
 
  
 
 


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2. Study Hypothesis/Objectives 
2.1. Hypothesis 
We hypothesize that dupilumab treatment will significantly alter the skin bacterial flora; specifically reducing abundance 
of S. aureus (lesionally and non-lesionally) as well as normalizing skin barrier function and these changes will be reflected 
in disease improvement. 
2.2. Primary Objective 
To assess the effect of dupilumab on S. aureus abundance on lesional skin as measured by microbial DNA 
2.3. Secondary Objective(s) 
1. To assess the effect of dupilumab on S. aureus abundance on non-lesional skin as measured by microbial DNA 
2. To assess the effect of dupilumab on epidermal barrier function in lesional and non-lesional skin 
3. To assess the effect of dupilumab on disease severity 
2.4. Exploratory Objective(s) 
1. To assess the effect of dupilumab on the microbiome and metagenome in lesional and non-lesional skin  
2. To assess the effect of dupilumab on the skin transcriptome in lesional and non-lesional skin 
 
participants only) 
3. To assess the effect of dupilumab on epidermal lipids in lesional and non-lesional skin  
4. To assess the effect of dupilumab on the expression of S. aureus superantigens, toxins, lipase, and proteases on 
lesional and non-lesional skin 
5. To assess the effect of dupilumab on non-lesional skin barrier structure and Langerhans cells (LC) by confocal 
imaging (
 participants only) 
6. To assess the effect of dupilumab on the function of the skin microbiome (i.e. ability of Coagulase-negative 
staphylococci isolates [CoNS] to kill S. aureus) in lesional and non-lesional skin   
7. To assess the effect of dupilumab on PBMC immunoprofiles  
8. To assess the effect of dupilumab on serum biomarkers (e.g.  Th2 biomarkers)   
9. To explore the association between genetic variation and (clinical and mechanistic) responsiveness to dupilumab 
10. To identify networks/pathways associated with responsiveness to dupilumab, quantified by disease severity, 
symptoms, and barrier function 
3. Study Design 
3.1. Description of Study Design  


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This is a multi-center, RDBPC study investigating the effect of 6 weeks of dupilumab treatment on quantitative and 
qualitative measures of cutaneous microbial community structure, skin barrier biology, skin transcriptome, and 
circulating T cell profiles in adults with moderate-to-severe AD, followed by a 10 week open-label extension of the study 
for all participants.  We have chosen a 6 week period for the RDBPC portion of the study based on findings from Phase 2 
and 3 studies that demonstrated that greater than 80% of the maximum improvement seen in EASI score was observed 
by that time point (Thaci et al, 2016; Simpson et al, 2016). Approximately 99 (66 active: 33 placebo) adult AD 
participants, 18 to 75 years of age, will be enrolled for this study.   
During the Screening Visit, participants will provide informed consent for study participation. Consented participants will 
then be assessed for study eligibility through the collection of medical history, including medication use and history of 
medical procedures, a physical exam, assessments of AD severity, a Comprehensive Metabolic Panel (CMP), a Complete 
Blood Count (CBC) with differential, and a pregnancy test for female participants of child-bearing potential.   
Participants who are eligible will return to clinic for their Treatment Initiation Visit (Day 0) and will be randomized 2:1 
active to placebo.  Participants will receive three doses of dupilumab or placebo based on their randomization 
assignment.  The first dose (600 mg loading dose or placebo) will be administered on Day 0 and the second and third 
doses (300 mg or placebo) on Day 14 and Day 28, respectively.  Participants will also return to clinic on Days 3, 7, and 21 
during the double-blind portion of the study.  Participants will begin the OLE at Day 42 and will receive dupilumab (600 
mg loading dose [two 300 mg injections] for those initially randomized to the placebo group and a 300 mg dose plus 
placebo injection for those initially randomized to the dupilumab group). Participants or their caregiver will administer 
one 300 mg dose of dupilumab at home on Day 56, Day 70, Day 84, and Day 98. If participants are unable or unwilling to 
self-administer or have a caregiver administer injections at home, they will be provided with the option of returning to 
the study clinic to have a staff member administer the injection. Participants will return to clinic on Days 77 and 112 
during the OLE portion of the study. During all visits (Day 0-Day 112), AEs, concomitant medications, and medical history 
will be assessed and physical exams including assessment of AD severity will be performed.  Blood, urine, skin swabs, 
skin tape strips, and skin biopsies, as applicable, will be collected, and barrier assessments will be performed per the 
Schedule of Events (Appendix A). Samples will be collected prior to dupilumab or placebo administration on Days 0, 14, 
28, and 42. After Day 112, a follow-up call (Day 182) will be made to assess for pregnancy, current medications, and AEs. 
If concerns arise between regularly scheduled visits, participants will be instructed to contact study personnel and may 
be asked to return to the study site for an “Unscheduled Visit.” Participants may be asked to return for Unscheduled 
Visits, as needed for the duration of the study, to provide additional blood, skin swabs, skin tape strips, or skin biopsies, 
as applicable, for further mechanistic and functional studies, or if samples are lost or destroyed, or if insufficient yields 
were obtained at a previous study visit. 
 
 


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Figure 3.1 Study Design Schematic 
 
3.2. Primary Endpoint(s)/Outcome(s) 
S. aureus abundance as measured by microbial DNA (femA qPCR) on lesional skin at Day 28 
3.3. Secondary Endpoint(s)/Outcome(s) 
1. S. aureus abundance as measured by microbial DNA (femA qPCR) on lesional skin at Days 0, 3, 7, 14, 21, 42, 77 
and 112 
2. S. aureus abundance as measured by microbial DNA (femA qPCR) on non-lesional skin at Days 0, 3, 7, 14, 21, 28, 
42, 77 and 112 
3. Basal (prior to tape stripping) transepidermal water loss (TEWL) of non-lesional and lesional skin at Days 0, 3, 7, 
14, 21, 28, 42, 77 and 112 
4. TEWL area under the curve of non-lesional skin at Days 0, 7, 14, 21, 28, 42, 77 and 112. TEWL will be assessed 
prior to tape stripping and repeated after 5, 10, and 15 tape strips.  
5. Change in TEWL per every 5 tape strips (i.e. slope) on non-lesional skin at Days 0, 7, 14, 21, 28, 42, 77 and 112 
6. Eczema Area and Severity Index [EASI], Investigator Global Assessment [IGA], and SCORing Atopic Dermatitis 
[SCORAD] at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112  
7. Pruritus numerical rating scale [NRS] at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112  
3.4. Exploratory Endpoint(s)/Outcome(s) 
1. Composition of bacterial taxa in lesional and non-lesional skin at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
2. Abundance of bacterial taxa in lesional and non-lesional skin at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112   
3. Gene expression in the skin transcriptome in non-lesional skin at Days 0 and 7, and in lesional skin at Days 0, 7, 
and 21 
4. Lipid profiles of non-lesional skin at Days 0, 7, 14, 21, 28, 42, 77 and 112 and of lesional skin at Days 0, 14, 28, 
and 112 
5. Expression of S. aureus superantigens, toxins, lipase, and proteases on lesional and non-lesional skin at Days 0, 
3, 7, 14, 21, 28, 42, 77 and 112 
Recruitment 
Screening 
Day 182 
Participant 
Completion4 
Day 0 
Treatment 
Initiation1,2 
Day 112End of 
Treatment1 
Day 42 
OLE 
Begins1,2 
1Clinic visit with sample collection (i.e. blood, skin swab, skin tape strip, skin biopsy) 
2In-clinic IP administration 
3At-home IP administration (participants may return to clinic for their injections if they choose) 
4Follow-up visit via phone 
Day 31 
Day 281,2 
Day 71 
Day 211 
Day 141,2 
Day 563 
Day 703 
Day 771 
Day 843 
Day 983 
RDBPC 
Follow-Up 
Open-Label 


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6. Confocal imaging of tight junctions (TJs) and relationship to LCs in the epidermis from non-lesional skin at Days 
0, 7 and 21 
7. Percent of coagulase-negative staphylococci [CoNS] isolates that kill S. aureus on lesional and non-lesional skin 
at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
8. PBMC immunoprofiling at Days 0, 14 and 28 
9. Levels of serum biomarkers (e.g. Th2 biomarkers and ADA) at Days 0, 7, 14, 21, 28, 42, 77 and 112 
10. The presence of single nucleotide polymorphisms (SNPs) 
3.5. Stratification, Randomization, and Blinding/Masking 
Randomization will be performed by the clinical sites using a validated interactive web response system (IWRS) created 
by the Statistical and Clinical Coordinating Center (SACCC) that automates the random assignment of treatment groups 
to study ID numbers. The randomization scheme will be reviewed by a statistician at the SACCC prior to implementation. 
Participants will be randomized using a 2:1 ratio of active (dupilumab) and control (placebo) participants. A stratified 
permuted block randomization algorithm will be used to maintain a balance between treatment arms with respect to 
clinical site and disease severity at Day 0 (EASI ≥ 21.1 or < 21.1).   
Randomization data will be kept strictly confidential, accessible only to authorized persons, until the time of unblinding. 
When all subject data through Day 112 is complete, the data files verified, and the protocol deviations determined, the 
investigational agent codes will be broken and made available for data analysis. 
The clinical site’s research pharmacy will dispense the study drug as per the randomization schedule provided by the 
SACCC. The unblinded pharmacist will confirm the expiration date, the dose, and randomization assignment. The 
injections will be administered by the blinded study physician or other qualified medical professional during the RDBPC 
portion of the study. Clinical research staff assessing clinical endpoints and participants will be blinded to treatment 
assignments for the RDBPC portion through the end of the trial. In order to maintain the blind for the RDBPC portion of 
the study, at the initiation of the OLE portion of the study, participants who were randomized to dupilumab for the 
RDBPC portion will receive one 300 mg injection of dupilumab and one placebo injection, while participants who were 
randomized to placebo will receive two 300 mg injections of dupilumab. Clinical research staff and participants will be 
aware of the treatment being received during the OLE portion of the study, as all participants will receive active 
treatment; neither the clinical research staff nor the participants will be told the original treatment assignment during 
the OLE portion of the study. Laboratory staff processing and analyzing samples will be blinded to participant treatment 
assignments during the RDBPC portion of the trial until all samples required for analysis are processed and raw data is 
available.  
3.6. Procedure for Unblinding/Unmasking 
If a clinically significant event occurs and knowledge of the treatment assignment is required, the study treatment may 
be unblinded. Unblinding must be approved by the Division of Allergy, Immunology, and Transplantation (DAIT)/National 
Institute of Allergy and Infectious Diseases (NIAID) Medical Monitor unless an immediate life-threatening condition has 
developed and the DAIT/NIAID Medical Monitor is not accessible.  In the event of an emergency, the investigator or 
designated qualified individual may obtain the participant’s blinded treatment assignment via the IWRS. Upon 
performance of a blind break, the IWRS will send out a blinded notification to alert Statistical and Clinical Coordinating 
Center and NIAID staff.  In the case of an accidental or emergency unblinding outside of IWRS, the site investigator will 
notify the DAIT/NIAID Medical Monitor and the SACCC team of the unblinding event by the next business day, following 
the unblinding. The unblinding will also be reported to the NIAID Asthma and Allergy Data and Safety Monitoring Board 
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A full account of the event will be recorded, including the date and time of the unblinding, the reason for the decision to 
unblind, the extent of the unblinding, the name of the individual who made the decision to unblind, and the names of 
the DAIT/NIAID Medical Monitor and others who were notified. The reasons for unblinding of a participant’s treatment 
will be included in the final study report. 
Unblinding the study will require written approval from NIAID.  No formal interim analysis is planned for this study.  In 
order to conduct analyses related to the scientific objectives, unblinding will occur after all participants have completed 
the Day 112 Visit and associated laboratory assays have been completed.  Refer to Section 13.5.1 for additional details. 
4. Selection of Participants and Clinical Sites/Laboratories 
4.1. Rationale for Study Population 
The purpose of this study is to understand the effect that Th2 blockade has on well-described pathophysiological 
features of AD (e.g. barrier, epidermal activation, dysbiosis, epidermal lipids, etc).  This study will be limited to male and 
female adult participants, ages 18-75 years, with moderate-to-severe AD.  Most human studies performed to date with 
dupilumab have been restricted to adults (≥ 18 years of age) and for this reason and the fact that we will be asking 
participants to undergo skin biopsies, which are not part of routine health care for a pediatric population, we have 
limited our studies to adults.  We have put an upper age limit on our study population because skin barrier 
function/structure deteriorates in elderly individuals, and we want to minimize the effect this confounding variable 
would have on our study interpretations. 
4.2. Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for enrollment as study participants: 
1. Must be able to understand and provide informed consent 
2. Male or female, 18-75 years inclusive at the Screening Visit 
3. Chronic AD, (according to the ADRN Standard Diagnostic Criteria), that has been present for at least 3 years 
before the Screening Visit for individuals aged 18-65 years old OR for at least 5 years before the Screening 
Visit for individuals aged 66-75 years old. Individuals aged 66-75 years of age must have documentation of a 
skin biopsy to rule out cutaneous T-cell lymphoma and other non-AD conditions present in the medical 
record. 
4. EASI score ≥12 at the Screening Visit and ≥16 at the Treatment Initiation Visit 
5. Investigator Global Assessment (IGA) score ≥3 (on the 0-4 IGA scale) at the Screening and Treatment 
Initiation Visits 
6. ≥10% body surface area of AD involvement at the Screening and Treatment Initiation Visits 
7. Must have active lesions (minimum of 3 of at least 4x4 cm2 each on the upper or lower extremities or trunk, 
excluding the palms of the hands, soles of the feet, buttock, navel, axilla, suprapubic area, and neck) at the 
Screening and Treatment Initiation Visits 
8. Documented recent history (within 6 months before the Screening Visit) of inadequate response to 
outpatient treatment with topical corticosteroids of medium to high potency (± topical calcineurin inhibitors 
as appropriate), or for whom topical treatments are otherwise inadvisable (e.g., because of important side 
effects or safety risks).  Acceptable documentation includes contemporaneous chart notes that record 
prescription of topical corticosteroids and/or topical calcineurin inhibitors, investigator documentation 
based on communication with patient’s treating physician, or medical history provided by the patient.  
9. Must agree to apply a stable dose of a topical emollient (moisturizer) at least twice daily for at least 7 days 
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10. Individuals with asthma must adhere to asthma controller medication(s) for the duration of the study 
including the open-label and follow-up portions 
11. Females of childbearing potential must have a negative pregnancy test at the Screening and Treatment 
Initiation Visits  
12. Females of reproductive potential* and sexually active must agree to use FDA approved methods of birth 
control for the duration of the study including the open-label and follow-up portions of the study. These 
include hormonal contraceptives, intrauterine device, double barrier contraception (i.e., condom plus 
diaphragm), or male partner with documented vasectomy.  
*Menopause is defined as at least 12 consecutive months without menses; if in question, a   
follicle stimulating hormone of ≥25 U/mL must be documented. Hysterectomy, bilateral oophorectomy, or 
bilateral tubal ligation must be documented, as applicable; if documented, women with these conditions are 
not required to use additional contraception. 
13. Males who are sexually active must agree to use an acceptable method of birth control (e.g. barrier methods 
with vaginal spermicide, surgical sterilization or surgically sterilized partner), or have a female partner 
practicing an approved birth control method for females as described in Inclusion Criterion #12. 
14. Willing and able to comply with all clinic visits and study-related procedures 
 
4.3. Exclusion Criteria  
Individuals who meet any of these criteria are not eligible for enrollment as study participants: 
1. Inability or unwillingness of an individual to give written informed consent or comply with study protocol 
2. Known systemic hypersensitivity to any of the excipients of the dupilumab or placebo study products 
3. Known or suspected immunosuppression, including history of invasive opportunistic infections (e.g., 
tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection 
resolution, or otherwise recurrent immune-compromised status, as judged by the investigator 
4. Known history of human immunodeficiency virus (HIV) infection 
5. 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 or active case of herpes 
keratitis; Sjogren’s Syndrome, Keratoconjunctivitis Sicca or Dry Eye Syndrome requiring daily use of 
supplemental lubrication; or individuals with ocular conditions that require the regular use of ocular 
corticosteroids or cyclosporine. 
6. Parasitic infection, except for vaginal trichomoniasis, within 12 months of the Treatment Initiation Visit, or 
high risk for contracting parasitic infections (e.g., living in or traveling to endemic areas)  
7. Presence of skin comorbidities that may interfere with study assessments 
8. History of malignancy within 5 years before the Treatment Initiation 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 or melanoma in situ 
9. History of non-malignant lymphoproliferative disorders 
10. History of alcohol or drug abuse within 2 years before the Screening Visit 
11. Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect the individual’s 
participation in the study. Examples include, but are not limited to, individuals with short life expectancy,  
uncontrolled diabetes (HbA1c ≥9%), cardiovascular conditions (e.g., stage III or IV cardiac failure according 
to the New York Heart Association classification), severe renal conditions (e.g.,  individuals on dialysis), 
hepato-biliary conditions (e.g., Child-Pugh class B or C), neurological conditions (e.g., demyelinating 
15. Able to understand and complete study-related questionnaires 


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diseases), active major autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, 
etc.), eosinophilic conditions (e.g. eosinophilic granulomatosis with polyangiitis), other severe 
endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic diseases. 
12. Any other medical or psychological condition including relevant laboratory abnormalities at screening that, 
in the opinion of the investigator, suggests 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 
individual’s participation unreliable, or may interfere with study assessments. This includes hypersensitivity 
to local anesthetics (e.g., lidocaine or Novocain), bleeding disorders, treatment with anticoagulants or other 
conditions that make the biopsy procedure inadvisable.  
13. Planned major surgical procedure during the screening period or study treatment (i.e. Screening through 
Day 112) 
14. Member of the investigational team or his/her immediate family 
15. Pregnant or breast-feeding women, or women planning to become pregnant or breastfeed during the study 
including the open-label and follow up portions of the study 
16. Individuals unwilling to use adequate birth control, if of reproductive potential and sexually active. Adequate 
birth control is defined as agreement to consistently practice an approved method of contraception for the 
duration of the study including the open-label and follow up portions of the study. Refer to Inclusion criteria 
#12 and #13.  
17. History of keloid formation 
18. History of serious life-threatening reaction to tape or adhesives 
19. Prior treatment with dupilumab  
20. Individuals with asthma who have required use of a systemic corticosteroid within 3 months prior to the 
Treatment Initiation Visit or who require a dose greater than 880 mcg/day of fluticasone propionate or 
equivalent inhaled corticosteroid to maintain asthma control 
21. Treatment with biologics as follows: 
x 
Any cell-depleting agents, including but not limited to rituximab, within 6 months before the 
Treatment Initiation Visit, or until lymphocyte and CD 19+ lymphocyte count returns to normal, 
whichever is longer 
x 
Infliximab, adalimumab, golimumab, certolizumab pegol, abatacept, etanercept, anakinra within 16 
weeks before the Treatment Initiation Visit for any indication 
x 
Other biologics within 5 half-lives (if known) or 16 weeks before the Treatment Initiation Visit, 
whichever is longer 
22. Treatment with a live (attenuated) vaccine within 12 weeks before the Treatment Initiation Visit or planning 
to receive a live vaccine during the study (through Day 182) 
23. Use of an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before 
the Treatment Initiation Visit 
24. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, 
antiprotozoals, or antifungals within 4 weeks before the Treatment Initiation Visit, or superficial skin 
infections within 1 week before the Treatment Initiation Visit 
25. The following treatments within 4 weeks before the Treatment Initiation Visit, or any condition that, in the 
opinion of the investigator, will likely require such treatment(s) during the screening period and study 
treatment (i.e., Screening through Day 112): 
x 
Systemic corticosteroids 


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x 
Immunosuppressive/immunomodulating drugs (e.g., cyclosporine, mycophenolate-mofetil, IFN-γ, 
Janus kinase inhibitors, azathioprine, or methotrexate) 
26. Use of phototherapy (such as narrow band ultraviolet B [NBUVB], ultraviolet B [UVB], ultraviolet A1 [UVA1], 
psoralen + UVA [PUVA]) or a tanning booth/parlor within 4 weeks of the Treatment Initiation Visit 
27. Treatment with bleach bath within 3 weeks before the Treatment Initiation Visit 
28. Use of a chlorinated hot tub within 3 weeks before the Treatment Initiation Visit 
29. Treatment with topical corticosteroids, phosphodiesterase inhibitors (crisaborole), or calcineurin inhibitors 
(tacrolimus or pimecrolimus) within 1 week before the Treatment Initiation Visit.  Low potency topical 
corticosteroids may be used just on the face up until 48 hours prior to the Treatment Initiation Visit. 
30. Initiation of treatment of AD with prescription moisturizers or moisturizers containing ceramide, hyaluronic 
acid, urea, or filaggrin during the screening period (participants may continue using stable doses of such 
moisturizers if initiated before the Screening Visit) 
31. Planned or anticipated use of any prohibited medications or procedures during the screening period and 
study treatment (i.e., Screening through Day 112). Refer to Section 7.3 for additional details. 
4.4. Selection of Clinical Sites/Labs  
This will be a multicenter study (
). All sites will be part of the ADRN. These sites have access 
to large adult AD populations, experience with clinical trials and performing required study procedures including skin 
biopsies, skin tape stripping, skin barrier assessments, AD severity scoring, blood/tissue processing, and biomaterials 
shipping.  
The laboratories processing and analyzing the samples for this study are discussed in Section 9. The proposed techniques 
for successful implementation and completion of the proposed studies have been established in preliminary studies at 
the respective laboratories.  
5. Known and Potential Risks and Benefits to Participants 
5.1. Risks of Investigational Product or Intervention as cited in the Package Insert 
 
 
 
 
 
  
 
 
 
 
  
 
 


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5.2. Risks of Investigational Product or Intervention Cited in Medical Literature 
Refer to Section 5.1 for reported risks. The medical literature has no additional information. 
5.3. Risks of Other Protocol Specified Medications 
Not applicable 
5.4. Risks of Study Procedures 
5.4.1 
Risks Associated with Stopping the Use of Protocol Prohibited Medications/Procedures 
Risks associated with stopping the use of protocol-prohibited medications/procedures may include worsening of 
the condition being treated and will be reported as such. In an effort to minimize these risks, participants with 
severe AD or severe asthma who may have difficulty tolerating periods without medication/procedure use will 
be excluded from participating, per study exclusion criteria. 
5.4.2. Risks Associated with Physical Exam 
There are no known risks associated with the physical exam.  
5.4.3. Risks Associated with Health Questionnaires 
There is a possibility that participants may find questions too personal. Participants may refuse to answer any 
questions that make them feel uncomfortable. There is also a possibility that a participant’s answers may be 
read by others; however, participants’ records are carefully protected so this is very unlikely. See Section 16.4 
for more information on confidentiality. 
5.4.4. Risks Associated with Blood Collection 
Risks associated with drawing blood include possible pain when the needle is inserted, as well as bleeding, 
bruising and/or infection at the puncture site.  Some people may experience lightheadedness, nausea, or 
fainting.  A topical anesthetic (e.g. topical lidocaine/prilocaine cream) may be placed on the skin before the 
blood draw to reduce the pain of the stick. Side effects from this cream (mainly skin rash) may occur. National 
Institutes of Health (NIH) guidelines for blood collection (amount and frequency based on age) will be followed. 
5.4.5. Risks Associated with Skin Swab Collection 
There are no significant risks associated with skin swab collection. 


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5.4.6  Risks Associated with Skin Barrier TEWL Measurement 
There are no known risks associated with this non-invasive skin measurement. 
5.4.7. Risks Associated with Skin Tape Strip Collection 
Risks associated with skin tape stripping, theoretically, include the rare possibility of an allergic reaction to the 
tape or a skin infection. Since the tape is removed immediately after application, the risk of an allergic reaction 
is extremely low. However, in previous and ongoing studies involving tape stripping, it has been noted that a 
very mild erythema may develop immediately after a series of tape strips on one localized area of skin, 
presumably due to the mild mechanical disturbance. The erythema is expected to resolve within 12 hours 
without sequelae. The risk of skin infection is extremely low since only superficial skin layers are removed. A 
bandage will be applied to the area of tape stripping to reduce the small likelihood of an infection. Some people 
may experience lightheadedness, nausea, or fainting. Possible bleeding and/or bruising may also occur at the 
area. Participants with a history of serious life-threatening reaction to tape or adhesives will be excluded from 
participating, per study exclusion criteria. 
5.4.8. Risks Associated with Skin Biopsies 
Risks of skin biopsy include pain and the possibility of an adverse reaction consisting of local swelling, bleeding, 
infection, and scar formation.  The pain associated with injection of a local anesthetic, such as lidocaine, is mild 
and transitory.  Allergic reactions to lidocaine are extremely rare and occur in less than 1 in 10,000 individuals 
who receive lidocaine. Reactions can be mild to life-threatening. Allergic reactions could result in hives, 
shortness of breath, an asthma attack, or anaphylactic shock.  Anaphylactic shock is the most severe form of an 
allergic reaction. It could lead to complete failure of the heart and circulation and could result in more health 
problems, or death.  However, anaphylactic shock is extremely rare and occurs in less than 30 in 100,000 
individuals who receive lidocaine.  Symptoms occur within minutes to 2 hours, but in rare instances may occur 
up to 4 hours later.  Individuals with asthma, eczema, or hay fever are at greater relative risk of experiencing 
anaphylaxis.  Occasionally, participants may experience swelling at the injection site.  Significant bleeding from 
the biopsy site(s) is rare and infrequent.  Infection of a biopsy site is unusual, but may occur.  A small scar may 
result at the biopsy site. Participants who receive skin biopsies will be given wound care instructions. 
Participants who have a lidocaine or Novocain allergy or those with a history of keloid formation will be 
excluded from participating, per study exclusion criteria. 
5.5. Potential Benefits 
There may or may not be any direct benefits for the participants who elect to enroll in this study.  Participants assigned 
to the dupilumab treatment arm during the double-blind portion of the study will receive a total of 16 weeks of 
treatment (6 weeks double-blind and 10 weeks open-label), and those assigned to the placebo arm will receive a total of 
10 weeks of dupilumab treatment during the OLE portion of the study. One potential benefit for participants is that their 
AD may improve and their itch may be reduced while on dupilumab; however, there is no guarantee that the product 
will help the participant’s condition and 33% of participants will receive placebo during the first 6 weeks of the study and 
not the active study drug.  The participant’s skin condition may even get worse by withholding his/her previous/regular 
AD treatment, or the participant could be in the placebo group and not receive active medication for the first 6 weeks of 
the study, in which case his/her AD may also flare. 
Although the results of this study may be of commercial value, it will be explained to participants that they will not have 
ownership of these results, and will not benefit financially from participation in this study, other than the nominal 
reimbursements provided for completing study procedures and visits.  The potential benefit to society is significant if it 


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improves our understanding of what affects AD disease severity and susceptibility to S. aureus colonization or virulence. 
Therefore, the expectation is that the results will benefit others in the future.  Information obtained from these studies 
will improve our understanding of the immune, epidermal, and barrier defects observed in AD participants.  
Comparisons of dupilumab- vs placebo-treated participants from Day 0 through Day 42 will clarify the relevance of IL-4 
and IL-13 in AD sub-phenotypes.  This is the first step to designing more rational therapeutic strategies to address this 
perplexing disorder characterized by propensity for S. aureus colonization, skin barrier defects, and T cell reactivity to 
microbes and allergens.  
6. Investigational Agent  
6.1 Investigational Agent 
The following information was taken from the dupilumab June 2019 package insert.  
6.1.1. Dupilumab 
6.1.1.1. Formulation, Packaging, and Labeling 
 
 
 
  
 
 
 
 
  
 
 
 
 
6.1.1.2. Dosage, Preparation, and Administration 
 
 
 
 
  
 
 
 
 
 
 


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6.1.2. Placebo 
6.1.2.1. Formulation, Packaging, and Labeling 
 
  
 
 
 
 
   
 
 
6.1.2.2. Dosage, Preparation, and Administration 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
6.2. 
Drug Accountability 


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Under Title 21 of the Code of Federal Regulations (21CFR §312.62), the investigator will maintain adequate records of 
the disposition of the investigational products, including the date and quantity of the drug/placebo received, to whom 
the drug/placebo was dispensed (participant-by-participant accounting), and a detailed accounting of any drug/placebo 
accidentally or deliberately destroyed.  Details of investigational product dispensation to each participating clinical site 
will be maintained at Eminent Services, Inc.  
Records for receipt, storage, use, and disposition will be maintained by the clinical site.  A drug/placebo-dispensing log 
will be kept current for each participant.  This log will contain the identification number of each participant and the date 
and quantity of drug/placebo dispensed. 
All records regarding the disposition of the investigational products will be available for inspection.  At the termination 
of the study, all unused product will be returned to Eminent for destruction. For more information on handling of the 
investigational product, please refer to the manual of procedures (MOP).  
6.3. 
Assessment of Participant Compliance with Investigational Agent 
Study product will be administered in the clinic through Day 42 by site personnel and thus is an observed compliance for 
the RDBPC portion of the study. Reminder calls will be provided for self-administered doses on Days 56, 70, 84, and 98, 
as outlined in the study MOP.  Compliance for the OLE will be based on participant self-report.  Compliance will be 
determined by the percentage of injections received. 
6.4. 
Toxicity Prevention and Management 
Dose modification for an individual participant is not allowed. Study drug may be prematurely discontinued as 
delineated in Section 6.5. If absolutely necessary (e.g., for treatment of intolerable AD symptoms or super-infection), a 
prohibited medication or procedure (as defined in Section 7.3) may be allowed at the discretion of the investigator (See 
Section 7.4). 
6.5. 
Premature Discontinuation of Investigational Agent 
Investigational products may be prematurely discontinued for any participant for any of the following reasons: 
x 
Anaphylactic reaction to study drug injection 
x 
Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or squamous or basal 
cell carcinoma of the skin 
x 
Evidence of pregnancy 
x 
Any infection that: 
o Requires parenteral treatment with an antibiotic, antifungal, antiviral, antiparasitic, or 
antiprotozoal agent 
o Requires oral treatment with such agents for longer than 2 weeks 
o Is opportunistic, such as tuberculosis and other infections whose nature or course may suggest 
an immune-compromised status 
x 
Severe worsening of AD, which in the opinion of the investigator requires stopping of the study 
medication 
x 
Evidence of severe and prolonged ISRs to study medication 
x 
Evidence of non-compliance to study protocol that in the opinion of the investigator requires 
discontinuation of study medication 
x 
Any serious AE that is possibly or definitely related to the investigational product  
 


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Investigational product may also be prematurely discontinued for any participant if the investigator believes that 
continuing use of the investigational product is no longer in the best interest of the participant. 
If a participant is prematurely discontinued from investigational product, but not withdrawn from the study, the 
participant will be asked and encouraged to complete any remaining study visits according to the Schedule of Events 
(Appendix A). 
7. 
Other Medications/Procedures 
7.1. 
Concomitant Medications 
Any treatment (including nutritional supplements) or procedure administered from the time of consent to the end of 
study visits is considered a concomitant medication/procedure. This includes permitted medications ongoing at the time 
of consent. 
7.1.1. Protocol-mandated 
Participants are required to apply a stable dose of a topical emollient at least twice daily for at least 7 days 
before the Treatment Initiation Visit.   Participants are prohibited from initiating treatment with prescription 
moisturizers or moisturizers containing ceramide, hyaluronic acid, urea, or filaggrin, but may continue using 
stable doses of such moisturizers if initiated before the Screening Visit.  
7.1.2. Other Permitted Concomitant Medications 
Other than the prohibited medications and procedures listed in Section 7.3, treatment with concomitant 
medications and procedures is permitted during the study.  This includes treatment with contraceptives, nasal 
and inhaled corticosteroids, and oral antihistamines. 
7.2. 
Prophylactic Medications 
Female participants of child-bearing potential must use an effective method of contraception (e.g. total abstinence, oral 
contraceptives, IUDs, barrier method with spermicide, surgical sterilization or surgically sterilized partner, Depo-Provera, 
Norplant, NuvaRing, or hormonal implants) for the duration of study participation including the open-label and follow up 
portions of the study.   
Pregnancy tests will be performed on female participants of child-bearing potential at the Screening, Treatment 
Initiation (Day 0), Day 14, Day 28, Day 42, and Day 77 Visits. These participants will also be asked during their other Clinic 
Visits and Follow-Up Phone Call as to whether they have tested positive to a pregnancy test since their last study visit.  
Male participants will be asked if a partner has tested positive to a pregnancy test at each Clinic Visit and Follow-Up 
Phone Call.  
All reported pregnancies, in female participants and the partners of male participants, will be followed as described in 
Section 12.6. 
7.3. 
Prohibited Medications/Procedures 
Treatment with the following concomitant medications and procedures is prohibited through Day 112. 
x 
Medications used for the treatment of AD or super-infection (these are considered rescue medications): 
o Topical calcineurin inhibitors (tacrolimus or pimecrolimus) 
o Topical phosphodiesterase inhibitors (crisaborole) 


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o Topical corticosteroids 
o Topical antibiotics 
o Initiation of prescription moisturizers or moisturizers containing ceramide, hyaluronic acid, urea, 
or filaggrin. Participants may continue using stable doses of such moisturizers if initiated before 
the Screening Visit.  
o Systemic treatment for AD with an immunosuppressive/immunomodulating agent (including, but 
not limited to, systemic corticosteroids, cyclosporine, mycophenolate-mofetil, azathioprine, 
methotrexate, IFN-γ, or other biologics) 
x 
Treatment with biologics including, but not limited to, the following: 
o Any cell-depleting agents (e.g.  rituximab) 
o Infliximab, adalimumab, golimumab, certolizumab pegol, abatacept, etanercept, or anakinra  
x 
Medications used for the treatment of asthma:  
o Systemic corticosteroids 
o Inhaled corticosteroids at a dose greater than 880 mcg/day of fluticasone propionate or 
equivalent  
x 
Systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals  
x 
Allergen immunotherapy (AIT), unless the participant has been on maintenance therapy for at least six 
months prior to the Treatment Initiation Visit. Participants on maintenance therapy for at least six 
months can continue AIT as long as no changes are made to dosing through Day 112. 
x 
Treatment with an investigational drug 
x 
Major elective surgical procedures 
x 
Procedures used for the treatment of AD (these are considered rescue procedures): 
o Phototherapy (such as NBUVB, UVB, UVA1, or PUVA) 
o Bleach baths 
x 
Use of a tanning booth/parlor 
In addition, participants will be asked to abstain from live (attenuated) vaccinations through the follow-up portion of the 
study (Day 182). 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: 
x 
BCG 
x 
Chickenpox (Varicella) 
x 
FluMist-Influenza 
x 
Intranasal influenza 
x 
Measles (Rubeola) 
x 
Measles-mumps-rubella (MMR) combination 
x 
Measles-mumps-rubella-varicella (MMRV) combination 
x 
Mumps 
x 
Oral polio (Sabin) 
x 
Oral typhoid 
x 
Rotavirus 
x 
Rubella 
x 
Smallpox (Vaccinia) 
x 
Varicella Zoster (shingles) 


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x 
Yellow fever 
7.4. 
Rescue Medications/Procedures  
If absolutely necessary (e.g. for treatment of intolerable AD symptoms or super-infection), a prohibited medication or 
procedure (as defined in Section 7.3) may be allowed at the discretion of the investigator. Participants who receive 
rescue treatment with a prohibited medication or procedure through Day 112 will be asked to continue with study 
treatment and procedures per the Schedule of Events (Appendix A) unless they meet Participant Stopping Rules (Section 
11.2).  
In the event of an infection or allergic reaction, best clinical practices will be followed for participant treatment. 
Infections will be treated with anti-bacterials based on the antibiotic sensitivity of the infection.  Allergic reactions to the 
topical anesthetic, lidocaine, tape strips, or study drug will be treated with antihistamine and/or epinephrine depending 
on the severity of the reaction. 
8. 
Study Procedures   
A summary of complete study procedures is included in the Schedule of Events (Appendix A). 
8.1. 
Recruitment  
Potential participants will be recruited using standardized questionnaires that collect contact information and medical 
history related to inclusion and exclusion criteria. Participants may be recruited by phone or in person. Once recruitment 
has been initiated, the participant will be assigned a unique participant identification (ID) number. Those who have no 
obvious characteristics making them ineligible for the study and who are interested in participating will be invited to 
clinic to complete the Screening Visit.  
8.2. 
Screening (Day -28 to Day -8) 
The purpose of the Screening Visit is to confirm eligibility to continue in the study. The study will be explained in lay 
terms to each potential participant. During the visit, written informed consent will be obtained from the participant 
prior to performing any study procedures.  
The following procedures, assessments, and laboratory measures will be conducted to determine participant eligibility:  
x 
Collection of demographics and contact information 
x 
Medical history and physical examination by a study physician or other qualified medical professional. The 
physical examination will include assessments of AD severity (EASI, IGA, SCORAD, and Pruritis NRS). 
x 
Confirm pregnancy status, including performing a urine pregnancy test for female participants of child-
bearing potential 
x 
Assessment of current medications 
x 
Vital signs, including temperature, blood pressure, heart rate, respiratory rate; and growth parameters, 
including height and weight 
x 
Blood collection; approximately 2 mL for a CBC with differential 
x 
Blood collection; approximately 4 mL for a CMP 
x 
Assessment of AEs 
Participants who do not meet inclusion and exclusion criteria due to assessment of their current 
medications/procedures will be asked whether they would be willing to come off their medications/procedures for a 


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washout period. Participants who do not wish to washout the prohibited medications/procedures will be identified as 
screen failures and will not continue in the study. 
Participants will be advised of situations that would put them at high risk for contracting a parasitic infection. 
Participants with asthma will be reminded that they should continue to take their asthma medications and will be 
counseled that they should only change their asthma medication in consultation with a physician.  
At the conclusion of the Screening Visit, participants who are eligible will be asked to return to clinic for their Treatment 
Initiation Visit. Participants will be instructed to apply a stable dose of emollient at least twice a day for at least 7 days 
prior to the Treatment Initiation Visit. Participants will be provided instructions regarding the use of emollients, 
including a reminder to not apply emollient 24 hours prior to the Treatment Initiation Visit. Participants will be asked to 
refrain from the use of prohibited medications/procedures as described in Section 7.3. Participants will be given an 
instructional hand card with restrictions on bathing/showering and use of chlorinated pools and hot tubs. Sexually active 
participants of child-bearing potential will be instructed to use an acceptable method of contraception as defined in 
Section 4.3.  
8.3. 
Treatment Initiation Visit (Day 0, to Occur within 28 Days of Screening) 
The purpose of the Treatment Initiation Visit (Day 0) is to initiate study treatment and conduct clinical and AE 
assessments. The following procedures, assessments, and laboratory measures will be conducted at the initial treatment 
visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, NESS, 
SCORAD, and Pruritus NRS) 
x 
Confirm pregnancy status of female participants of child-bearing potential and partners of male participants, 
including performing a urine pregnancy test for female participants of child-bearing potential 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 
x 
Randomization 
x 
Blood collection; approximately 20 mL for assessment of serum biomarkers (e.g., Th2 biomarkers and ADA) 
x 
Blood collection; approximately 40 mL for PBMC immunoprofiling 
x 
Blood collection; approximately 2 mL for DNA isolation if not previously collected for another ADRN or 
Atopic Dermatitis Vaccinia Network (ADVN) study 
x 
Photographs will be taken of the measured lesional and non-lesional sites for collection of skin swabs, tape 
strips, and biopsies. These photographs will be used to identify the areas at subsequent visits. 
x 
Skin swab collection; 3 lesional and 3 non-lesional swabs to be used to determine S. aureus abundance; S. 
aureus superantigen, toxin,  lipase, protease quantitation; metagenomics, microbiome 16S rRNA analysis; 
and skin microbiome functional assessment. 
x 
Skin barrier assessments (TEWL basal and after 5, 10, and 15 tape strips) 
x 
Skin tape strip collection; 1 set of 15 strips from non-lesional skin for lipidomics. These strips will be 
obtained as part of the TEWL barrier assessment.  
x 
Skin tape strip collection; 1 set of 5 strips from lesional skin for lipidomics 
x 
Skin biopsy collection; 1 x 3 mm non-lesional skin biopsy for confocal imaging 
 
x 
Skin biopsy collection; 1 x 2.5 mm lesional biopsy and 1 x 2.5 mm non-lesional biopsy for skin 
transcriptomics 
 


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x 
IP administration (loading dose); two subcutaneous injections of dupilumab (300 mg) or two subcutaneous 
injections of placebo based on treatment assignment at two different injection sites (injections will be 
administered in any of the four abdominal quadrants, thighs, or upper arms).   
x 
Assessment of AEs 
If a participant has not refrained from the use of prohibited medications/procedures (as described in Section 7.3) or 
followed instructions for bathing/showering, use of chlorinated pools and hot tubs, and use of emollients prior to this 
visit, the visit will be rescheduled. 
Clinic staff will educate participants and/or caregivers on administering study product beginning at the Day 0 Visit. 
Participants or their caregivers will be expected to complete supervised study product administration at a minimum of 
one visit if the participant or caregiver intends to administer injections at home during the OLE portion of the study. The 
investigator or other qualified staff must feel confident that the participant or their caregiver can administer study 
product per the study protocol before they will be provided with study product for home administration. 
At the conclusion of this visit, participants will be reminded to refrain from the use of prohibited 
medications/procedures as described in Section 7.3. Participants will be given instructions regarding restrictions on 
bathing/showering, use of chlorinated pools and hot tubs, and use of emollients, including instructions not to apply 
emollients to sampling areas 24 hours prior to study visits. Sexually active participants of child-bearing potential will be 
instructed to use an acceptable method of contraception as described in Section 4.3. Participants will be advised of 
situations that would put them at high risk for contracting a parasitic infection. 
Participants with asthma will be reminded that they should continue to take their asthma medications and will be 
counseled that they should only change their asthma medication in consultation with a physician.  A letter will be 
provided to alert the physician managing their asthma to contact the study physician if changes to the asthma 
medication regimen will be made. 
Participants will be provided with instructions on when to contact the research clinic should they experience any 
adverse events, including new onset of eye symptoms. This card will include symptoms of an allergic/anaphylactic 
reaction. Contact information for the study physician and the 24 hour on call physician will also be provided. The 
physician receiving the call will assess if the participant will need to be seen in clinic or if any further treatment is 
necessary. Alternatively, the participants will be instructed to take an emergency contact hand card with them should 
they seek medical care at another facility. The emergency contact hand card will include contact information for the 
research site and will state that the participant is currently in a clinical trial involving the administration of dupilumab, a 
fully human monoclonal antibody against the IL-4 receptor. 
8.4. 
Day 3 (± 1 Day) 
The purpose of the Day 3 Visit is to conduct clinical and AE assessments. The following procedures, assessments, and 
laboratory measures will be conducted at the Day 3 Visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, SCORAD, 
and Pruritus NRS) 
x 
Confirm pregnancy status of female participants of child-bearing potential and of partners of male 
participants 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 


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x 
Photographs will be taken of the measured lesional and non-lesional sites for skin swab collection. These 
sites should be the same areas that were selected and photographed during the Treatment Initiation Visit. 
The areas swabbed should be the same size as the areas swabbed during the Treatment Initiation Visit, even 
if the lesion is smaller.  Even if the lesion has cleared, the sample(s) should be labeled as “lesional.” 
x 
Skin swab collection; 3 lesional and 3 non-lesional swabs to be used to determine S. aureus abundance; S. 
aureus superantigen, toxin, lipase, and protease quantitation; metagenomics, microbiome 16S rRNA 
analysis; and skin microbiome functional assessment. 
x 
Skin barrier assessments (TEWL basal) 
x 
Assessment of AEs 
Assessments and sample collection will be completed for all participants regardless of whether they used prohibited 
medications/procedures or met sampling criteria. Protocol deviations will be recorded, as applicable.  
At the conclusion of this visit, participants will be reminded to refrain from the use of prohibited 
medications/procedures as described in Section 7.3. Participants will be given instructions regarding restrictions on 
bathing/showering, use of chlorinated pools and hot tubs, and use of emollients, including instructions not to apply 
emollients to sampling areas 24 hours prior to study visits. Sexually active participants of child-bearing potential will be 
instructed to use an acceptable method of contraception as described in Section 4.3. Participants will be advised of 
situations that would put them at high risk for contracting a parasitic infection. Participants with asthma will be 
reminded that they should continue to take their asthma medications and will be counseled that they should only 
change their asthma medication in consultation with a physician.  Participants will be reminded to contact the research 
clinic should they experience any adverse events, including new onset of eye symptoms. 
8.5. 
Day 7 (± 2 days) 
The purpose of the Day 7 Visit is to conduct clinical and AE assessments. The following procedures, assessments, and 
laboratory measures will be conducted at the Day 7 Visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, SCORAD, 
and Pruritus NRS) 
x 
Confirm pregnancy status of female participants of child-bearing potential and partners of male participants 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 
x 
Blood collection; approximately 20 mL for serum biomarkers (e.g., Th2 biomarkers and ADA) 
x 
Photographs will be taken of the measured lesional and non-lesional sites for collection of skin swabs, tape 
strips, and biopsies. These sites should be the same areas that were selected and photographed during the 
Treatment Initiation Visit. The areas swabbed should be the same size as the areas swabbed during the 
Treatment Initiation Visit, even if the lesion is smaller.  Even if the lesion has cleared, the sample(s) should 
be labeled as “lesional”. 
x 
Skin swab collection; 3 lesional and 3 non-lesional swabs to be used to determine S. aureus abundance; S. 
aureus superantigen, toxin, lipase, and protease quantitation; metagenomics, microbiome 16S rRNA 
analysis; and skin microbiome functional assessment. 
x 
Skin barrier assessments (TEWL basal and after 5, 10, and 15 tape strips) 
x 
Skin tape strip collection; 1 set of 15 strips from non-lesional skin for lipidomics. These strips will be 
obtained as part of the TEWL barrier assessment.  
x 
Skin biopsy collection; 1x 3 mm non-lesional skin biopsy for confocal imaging 
 


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x 
Skin biopsy collection; 1 x 2.5 mm lesional biopsy and 1 x 2.5 mm non-lesional biopsy for skin 
transcriptomics 
 
x 
 Assessment of AEs 
Assessments and sample collection will be completed for all participants regardless of whether they used prohibited 
medications/procedures or met sampling criteria. Protocol deviations will be recorded, as applicable.  
At the conclusion of this visit, participants will be reminded to refrain from the use of prohibited 
medications/procedures as described in Section 7.3. Participants will be given instructions regarding restrictions on 
bathing/showering, use of chlorinated pools and hot tubs, and use of emollients, including instructions not to apply 
emollients to sampling areas 24 hours prior to study visits. Sexually active participants of child-bearing potential will be 
instructed to use an acceptable method of contraception as described in Section 4.3. Participants will be advised of 
situations that would put them at high risk for contracting a parasitic infection. Participants with asthma will be 
reminded that they should continue to take their asthma medications and will be counseled that they should only 
change their asthma medication in consultation with a physician.  Participants will be reminded to contact the research 
clinic should they experience any adverse events, including new onset of eye symptoms. 
8.6. 
Day 14 (± 2 days) 
The purpose of the Day 14 Visit is to administer study treatment and conduct clinical and AE assessments. The following 
procedures, assessments, and laboratory measures will be conducted at the Day 14 Visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, SCORAD, 
and Pruritus NRS) 
x 
Confirm pregnancy status of females of child-bearing potential and partners of male participants, including 
performing a urine pregnancy test for female participants of child-bearing potential 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 
x 
Blood collection; approximately 20 mL for serum biomarkers (e.g., Th2 biomarkers and ADA) 
x 
Blood collection; approximately 40 mL for PBMC immunoprofiling 
x 
Photographs will be taken of the measured lesional and non-lesional sites for collection of skin swabs and 
tape strips. These sites should be the same areas that were selected and photographed during the 
Treatment Initiation Visit. The areas swabbed should be the same size as the areas swabbed during the 
Treatment Initiation Visit, even if the lesion is smaller.  Even if the lesion has cleared, the sample(s) should 
be labeled as “lesional”. 
x 
Skin swab collection; 3 lesional and 3 non-lesional swabs to be used to determine S. aureus abundance, S. 
aureus superantigen toxin, lipase, and protease quantitation; metagenomics, microbiome 16S rRNA analysis 
and skin microbiome functional assessment. 
x 
Skin barrier assessments (TEWL basal and after 5, 10, and 15 tape strips) 
x 
Skin tape strip collection; 1 set of 15 strips from non-lesional skin for lipidomics. These strips will be 
obtained as part of the TEWL barrier assessment.  
x 
Skin tape strip collection; 1 set of 5 strips from lesional skin for lipidomics 
x 
IP administration; one 300 mg dupilumab subcutaneous injection or one placebo injection in the abdomen, 
thigh, or upper arm. The selected injection site should be different from the sites used for the loading dose 
two weeks earlier.  
x 
Assessment of AEs 


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Assessments and sample collection will be completed for all participants regardless of whether they used prohibited 
medications/procedures or met sampling criteria. Protocol deviations will be recorded, as applicable.  
Clinic staff will educate participants and/or caregivers on administering study product at the Day 14 Visit. The participant 
or their caregiver may complete study product administration under the supervision of the investigator or other 
qualified staff at the Day 14 Visit. Participants or their caregivers will be expected to complete supervised study product 
administration at a minimum of one visit if the participant or caregiver intends to administer injections at home during 
the OLE portion of the study. The investigator or other qualified staff must feel confident that participants or their 
caregiver can administer study product per the study protocol before they will be provided with study product for home 
administration. 
At the conclusion of this visit, participants will be reminded to refrain from the use of prohibited 
medications/procedures as described in Section 7.3. Participants will be given instructions regarding restrictions on 
bathing/showering, use of chlorinated pools and hot tubs, and use of emollients, including instructions not to apply 
emollients to sampling areas 24 hours prior to study visits. Sexually active participants of child-bearing potential will be 
instructed to use an acceptable method of contraception as described in Section 4.3. Participants will be advised of 
situations that would put them at high risk for contracting a parasitic infection. Participants with asthma will be 
reminded that they should continue to take their asthma medications and will be counseled that they should only 
change their asthma medication in consultation with a physician.   
Participants will be provided with instructions on when to contact the research clinic should they experience any 
adverse events, including new onset of eye symptoms. This card will include symptoms of an allergic/anaphylactic 
reaction. Contact information for the study physician and the 24 hour on call physician will also be provided. The 
physician receiving the call will assess if the participant will need to be seen in clinic or if any further treatment is 
necessary. Alternatively, the participants will be instructed to take an emergency contact hand card with them should 
they seek medical care at another facility. The emergency contact hand card will include contact information for the 
research site and will state that the participant is currently in a clinical trial involving the administration of dupilumab, a 
fully human monoclonal antibody against the IL-4 receptor. 
8.7. 
Day 21 (± 2 days) 
The purpose of the Day 21 Visit is to conduct clinical and AE assessments. The following procedures, assessments, and 
laboratory measures will be conducted at the Day 21 Visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, SCORAD, 
and Pruritus NRS) 
x 
Confirm pregnancy status of female participants of child-bearing potential and partners of male participants 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 
x 
Blood collection; approximately 20 mL for serum biomarkers (e.g., Th2 biomarkers and ADA) 
x 
Photographs will be taken of the measured lesional and non-lesional sites for collection of skin swabs, tape 
strips, and biopsies. These sites should be the same areas that were selected and photographed during the 
Treatment Initiation Visit. The areas swabbed should be the same size as the areas swabbed during the 
Treatment Initiation Visit, even if the lesion is smaller.  Even if the lesion has cleared, the sample(s) should 
be labeled as “lesional”. 


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x 
Skin swab collection; 3 lesional and 3 non-lesional swabs to be used to determine S. aureus abundance, S. 
aureus superantigen, toxin, lipase, and protease quantitation; metagenomics, microbiome 16S rRNA analysis 
and skin microbiome functional assessment. 
x 
Skin barrier assessments (TEWL basal and after 5, 10, and 15 tape strips) 
x 
Skin tape strip collection; 1 set of 15 strips from non-lesional skin for lipidomics. These strips will be 
obtained as part of the TEWL barrier assessment.  
x 
Skin biopsy collection; 1 x 3 mm non-lesional skin biopsy for confocal imaging 
 
x 
Skin biopsy collection; 1 x 2.5 mm lesional biopsy for skin transcriptomics 
 
x 
Assessment of AEs 
Assessments and sample collection will be completed for all participants regardless of whether they used prohibited 
medications/procedures or met sampling criteria. Protocol deviations will be recorded, as applicable.  
At the conclusion of this visit, participants will be reminded to refrain from the use of prohibited 
medications/procedures as described in Section 7.3. Participants will be given instructions regarding restrictions on 
bathing/showering, use of chlorinated pools and hot tubs, and use of emollients, including instructions not to apply 
emollients to sampling areas 24 hours prior to study visits. Sexually active participants of child-bearing potential will be 
instructed to use an acceptable method of contraception as described in Section 4.3. Participants will be advised of 
situations that would put them at high risk for contracting a parasitic infection.  Participants with asthma will be 
reminded that they should continue to take their asthma medications and will be counseled that they should only 
change their asthma medication in consultation with a physician.   
 Participants will be reminded to contact the research clinic should they experience any adverse events, including new 
onset of eye symptoms. 
8.8. 
Day 28 (± 2 days) 
The purpose of the Day 28 Visit is to administer study treatment and conduct clinical and AE assessments. The following 
procedures, assessments, and laboratory measures will be conducted at the Day 28 Visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, SCORAD, 
and Pruritus NRS) 
x 
Confirm pregnancy status of females of child-bearing potential and partners of male participants, including 
performing a urine pregnancy test for female participants of child-bearing potential 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 
x 
Blood collection; approximately 20 mL for serum biomarkers (e.g., Th2 biomarkers and ADA) 
x 
Blood collection; approximately 40 mL for PBMC immunoprofiling 
x 
Photographs will be taken of the measured lesional and non-lesional sites for collection of skin swabs and 
tape strips. These sites should be the same areas that were selected and photographed during the 
Treatment Initiation Visit. The areas swabbed should be the same size as the areas swabbed during the 
Treatment Initiation Visit, even if the lesion is smaller.  Even if the lesion has cleared, the sample(s) should 
be labeled as “lesional.” 
x 
Skin swab collection; 3 lesional and 3 non-lesional swabs to be used to determine S. aureus abundance, S. 
aureus superantigen, toxin, lipase, and protease quantitation; metagenomics, microbiome 16S rRNA analysis 
and skin microbiome functional assessment. 
x 
Skin barrier assessments (TEWL basal and after 5, 10, and 15 tape strips) 


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x 
Skin tape strip collection; 1 set of 15 strips from non-lesional skin for lipidomics. These strips will be 
obtained as part of the TEWL barrier assessment.  
x 
Skin tape strip collection; 1 set of 5 strips from lesional skin for lipidomics 
x 
IP administration; one 300 mg dupilumab subcutaneous injection or one placebo injection in the abdomen, 
thigh, or upper arm. The selected injection site should be different from the site used for the previous dose.  
x 
Assessment of AEs 
Assessments and sample collection will be completed for all participants regardless of whether they used prohibited 
medications/procedures or met sampling criteria. Protocol deviations will be recorded, as applicable.  
Clinic staff will counsel participants and/or caregivers on administering study product at the Day 28 Visit. The participant 
or their caregiver may complete study product administration under the supervision of the investigator or other 
qualified staff at the Day 28 Visit. Participants or their caregiver will be expected to complete supervised study product 
administration at a minimum of one visit if the participant or caregiver intends to administer injections at home during 
the OLE portion of the study. The investigator or other qualified staff must feel confident that participants or their 
caregiver can administer study product per the study protocol before they will be provided with study product for home 
administration. 
At the conclusion of this visit, participants will be reminded to refrain from the use of prohibited 
medications/procedures as described in Section 7.3. Participants will be given instructions regarding restrictions on 
bathing/showering, use of chlorinated pools and hot tubs, and use of emollients, including instructions not to apply 
emollients to sampling areas 24 hours prior to study visits. Sexually active participants of child-bearing potential will be 
instructed to use an acceptable method of contraception as described in Section 4.3. Participants will be advised of 
situations that would put them at high risk for contracting a parasitic infection. Participants with asthma will be 
reminded that they should continue to take their asthma medications and will be counseled that they should only 
change their asthma medication in consultation with a physician.   
Participants will be provided with instructions on when to contact the research clinic should they experience any 
adverse events, including new onset of eye symptoms. This card will include symptoms of an allergic/anaphylactic 
reaction. Contact information for the study physician and the 24 hour on call physician will also be provided. The 
physician receiving the call will assess if the participant will need to be seen in clinic or if any further treatment is 
necessary. Alternatively, the participants will be instructed to take an emergency contact hand card with them should 
they seek medical care at another facility. The emergency contact hand card will include contact information for the 
research site and will state that the participant is currently in a clinical trial involving the administration of dupilumab, a 
fully human monoclonal antibody against the IL-4 receptor. 
8.9. 
Day 42 (± 2 days) 
The purpose of the Day 42 Visit is to conduct clinical and AE assessments and to begin the OLE. The following 
procedures, assessments, and laboratory measures will be conducted at the Day 42 Visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, SCORAD, 
and Pruritus NRS) 
x 
Confirm pregnancy status of female participants of child-bearing potential and partners of male participants, 
including performing a urine pregnancy test for female participants of child-bearing potential 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 


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x 
Blood collection; approximately 20 mL for serum biomarkers (e.g., Th2 biomarkers and ADA) 
x 
Photographs will be taken of the measured lesional and non-lesional sites for collection of skin swabs and 
tape strips. These sites should be the same areas that were selected and photographed during the 
Treatment Initiation Visit. The areas swabbed should be the same size as the areas swabbed during the 
Treatment Initiation Visit, even if the lesion is smaller.  Even if the lesion has cleared, the sample(s) should 
be labeled as “lesional”. 
x 
Skin swab collection; 3 lesional and 3 non-lesional swabs to be used to determine S. aureus abundance, S. 
aureus superantigen, toxin, lipase, and protease quantitation; metagenomics, microbiome 16S rRNA analysis 
and skin microbiome functional assessment. 
x 
Skin barrier assessments (TEWL basal and after 5, 10, and 15 tape strips) 
x 
Skin tape strip collection; 1 set of 15 strips from non-lesional skin for lipidomics. These strips will be 
obtained as part of the TEWL barrier assessment.  
x 
IP administration; In order to maintain the blind, participants who were randomized to dupilumab for the 
RDBPC portion will receive one 300 mg injection of dupilumab and one placebo injection, while participants 
who were randomized to placebo will receive two 300 mg injections of dupilumab. The two injections will be 
administered at different sites in the abdomen, thighs, or upper arms.  The selected injection sites should 
not be the same as the injection site selected for the previous dose.  
x 
Assessment of AEs 
Assessments and sample collection will be completed for all participants regardless of whether they used prohibited 
medications/procedures or met sampling criteria. Protocol deviations will be recorded, as applicable.  
Clinic staff will educate participants and/or caregivers on administering study product. The participant or their caregiver 
must complete study product administration under the supervision of the investigator or other qualified staff at this visit 
if the participant intends to complete injections at home during the OLE portion of the study. The investigator or other 
qualified staff must feel confident that participants or their caregiver can administer study product per the study 
protocol before they will be provided with study product for home administration. Participants who intend to complete 
injections at home will be provided with two doses of dupilumab for self-administration at home on Days 56 and 70. The 
participant may alternatively choose to return to the clinic to have their Day 56 and Day 70 doses administered. 
At the conclusion of this visit, participants will be reminded to refrain from the use of prohibited 
medications/procedures as described in Section 7.3. Participants will be given instructions regarding restrictions on 
bathing/showering, use of chlorinated pools and hot tubs, and use of emollients, including instructions not to apply 
emollients to sampling areas 24 hours prior to study visits. Sexually active participants of child-bearing potential will be 
instructed to use an acceptable method of contraception as described in Section 4.3. Participants will be advised of 
situations that would put them at high risk for contracting a parasitic infection. Participants with asthma will be 
reminded that they should continue to take their asthma medications and will be counseled that they should only 
change their asthma medication in consultation with a physician.   
Participants will be provided with instructions on when to contact the research clinic should they experience any 
adverse events, including new onset of eye symptoms. This card will include symptoms of an allergic/anaphylactic 
reaction. Contact information for the study physician and the 24 hour on call physician will also be provided. The 
physician receiving the call will assess if the participant will need to be seen in clinic or if any further treatment is 
necessary. Alternatively, the participants will be instructed to take an emergency contact hand card with them should 
they seek medical care at another facility. The emergency contact hand card will include contact information for the 


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research site and will state that the participant is currently in a clinical trial involving the administration of dupilumab, a 
fully human monoclonal antibody against the IL-4 receptor. 
8.10. 
Day 56 (± 7 days) Home IP Injection  
Participant or caretaker will administer 300 mg of dupilumab subcutaneously in the abdomen, thigh, or upper arm. The 
selected injection site should not be the same as the injection sites selected for the previous dose. If a participant is not 
comfortable self-administering injections and does not have a caretaker willing to administer injections, the participant 
may return to the study clinic to have their injection administered. IP injections should occur at minimum 7 days apart. If 
a participant misses a dose it should be administered within 7 days from the missed dose. If the missed dose is not 
administered within 7 days, the participant will be instructed to wait until their next scheduled dose based on their 
original dosing schedule. 
8.11. 
Day 70 (± 7 days) Home IP Injection 
Participant or caretaker will administer 300 mg of dupilumab subcutaneously in the abdomen, thigh, or upper arm. The 
selected injection site should not be the same as the injection site selected for the previous dose. If a participant is not 
comfortable self-administering injections and does not have a caretaker willing to administer injections, the participant 
may return to the study clinic to have their injection administered. IP injections should occur at minimum 7 days apart. If 
a participant misses a dose it should be administered within 7 days from the missed dose. If the missed dose is not 
administered within 7 days, the participant will be instructed to wait until their next scheduled dose based on their 
original dosing schedule. 
 
8.12. 
Day 77 (± 2 days) 
The purpose of the Day 77 Visit is to conduct clinical and AE assessments. The following procedures, assessments, and 
laboratory measures will be conducted at the Day 77 Visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, SCORAD, 
and Pruritus NRS) 
x 
Confirm pregnancy status of female participants of child-bearing potential and partners of male participants, 
including performing a urine pregnancy test for female participants of child-bearing potential 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 
x 
Blood collection; approximately 20 mL for serum biomarkers (e.g., Th2 biomarkers and ADA) 
x 
Photographs will be taken of the measured lesional and non-lesional sites for collection of skin swabs and 
tape strips. These sites should be the same areas that were selected and photographed during the 
Treatment Initiation Visit. The areas swabbed should be the same size as the areas swabbed during the 
Treatment Initiation Visit, even if the lesion is smaller.  Even if the lesion has cleared, the sample(s) should 
be labeled as “lesional”. 
x 
Skin swab collection; 3 lesional and 3 non-lesional swabs to be used to determine S. aureus abundance, S. 
aureus superantigen, toxin, lipase, and protease quantitation; metagenomics, microbiome 16S rRNA analysis 
and skin microbiome functional assessment. 
x 
Skin barrier assessments (TEWL basal and after 5, 10, and 15 tape strips) 
x 
Skin tape strip collection; 1 set of 15 strips from non-lesional skin for lipidomics. These strips will be 
obtained as part of the TEWL barrier assessment.  
x 
Assessment of AEs 


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Assessments and sample collection will be completed for all participants regardless of whether they used prohibited 
medications/procedures or met sampling criteria. Protocol deviations will be recorded, as applicable.  
At the conclusion of this visit, participants who intend to complete injections at home will be provided with two doses of 
dupilumab for self-administration at home on Days 84 and 98. The participant may alternatively choose to return to the 
clinic to have their Day 84 and Day 98 doses administered. Participants will be reminded to refrain from the use of 
prohibited medications/procedures as described in Section 7.3. Participants will be given instructions regarding 
restrictions on bathing/showering, use of chlorinated pools and hot tubs, and use of emollients, including instructions 
not to apply emollients to sampling areas 24 hours prior to study visits. Sexually active participants of child-bearing 
potential will be instructed to use an acceptable method of contraception as described in Section 4.3. Participants will 
be advised of situations that would put them at high risk for contracting a parasitic infection. Participants with asthma 
will be reminded that they should continue to take their asthma medications and will be counseled that they should only 
change their asthma medication in consultation with a physician.  Participants will be reminded to contact the research 
clinic should they experience any adverse events, including new onset of eye symptoms. 
8.13. 
Day 84 (± 7 days) Home IP Injection  
Participant or caretaker will administer 300 mg of dupilumab subcutaneously in the abdomen, thigh, or upper arm. The 
selected injection site should not be the same as the injection site selected for the previous dose. If a participant is not 
comfortable self-administering injections and does not have a caretaker willing to administer injections, the participant 
may return to the study clinic to have their injection administered. IP injections should occur at minimum 7 days apart. If 
a participant misses a dose it should be administered within 7 days from the missed dose. If the missed dose is not 
administered within 7 days, the participant will be instructed to wait until their next scheduled dose based on their 
original dosing schedule. 
8.14. 
Day 98 (± 7 days) Home IP Injection 
Participant or caretaker will administer 300 mg of dupilumab subcutaneously in the abdomen, thigh, or upper arm. The 
selected injection site should not be the same as the injection site selected for the previous dose. If a participant is not 
comfortable self-administering injections and does not have a caretaker willing to administer injections, the participant 
may return to the study clinic to have their injection administered. IP injections should occur at minimum 7 days apart. If 
a participant misses a dose it should be administered within 7 days from the missed dose. If the missed dose is not 
administered within 7 days, the participant will be instructed to wait until their next scheduled dose based on their 
original dosing schedule. 
8.15. 
Day 112 (± 2 days) 
The purpose of the Day 112 Visit is to conduct clinical and AE assessments. The following procedures, assessments, and 
laboratory measures will be conducted at the Day 112 Visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, SCORAD, 
and Pruritus NRS) 
x 
Confirm pregnancy status of female participants of child-bearing potential and partners of male participants, 
including performing a urine pregnancy test for female participants of child-bearing potential 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 
x 
Blood collection; approximately 20 mL for serum biomarkers (e.g., Th2 biomarkers and ADA) 
x 
Photographs will be taken of the measured lesional and non-lesional sites for collection of skin swabs and 
tape strips. These sites should be the same areas that were selected and photographed during the 


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Treatment Initiation Visit. The areas swabbed should be the same size as the areas swabbed during the 
Treatment Initiation Visit, even if the lesion is smaller.  Even if the lesion has cleared, the sample(s) should 
be labeled as “lesional”. 
x 
Skin swab collection; 3 lesional and 3 non-lesional swabs to be used to determine S. aureus abundance, S. 
aureus superantigen, toxin, lipase, and protease quantitation; metagenomics, microbiome 16S rRNA analysis 
and skin microbiome functional assessment. 
x 
Skin barrier assessments (TEWL basal and after 5, 10, and 15 tape strips) 
x 
Skin tape strip collection; 1 set of 15 strips from non-lesional skin for lipidomics. These strips will be 
obtained as part of the TEWL barrier assessment.  
x 
Skin tape strip collection; 1 set of 5 strips from lesional skin for lipidomics 
x 
Assessment of AEs 
Assessments and sample collection will be completed for all participants regardless of whether they used prohibited 
medications/procedures or met sampling criteria. Protocol deviations will be recorded, as applicable.  
At the conclusion of this visit, participants will be allowed to resume use of prohibited medications/procedures as 
described in Section 7.3. Participants will be asked to continue to abstain from live (attenuated) vaccinations. They will 
be allowed to resume bathing/showering, use of chlorinated pools and hot tubs, and emollients without restrictions. 
Participants will be referred back to their primary care physician for their AD management. Sexually active participants 
of child-bearing potential will be instructed to use an acceptable method of contraception as described in Section 4.3.  
Participants with asthma will be reminded that they should continue to take their asthma medications and will be 
counseled that they should only change their asthma medication in consultation with a physician. A letter will be 
provided to alert the physician managing their asthma that their patient is no longer participating in the clinical trial.  
Participants will be provided with an instructional hand card including post-treatment reminders. 
8.16. 
Day 182 Follow-Up Phone Call (± 5 days) 
The purpose of the Day 182 Follow-Up Phone Call is to complete participant follow-up including assessment of 
concomitant medications, AEs, and pregnancy status. This call will be brief, and female participants of child-bearing 
potential will be asked if they have tested positive to a pregnancy test since their last visit. Male participants will be 
asked if their partner has tested positive to a pregnancy test since their last visit. Sexually active participants of child-
bearing potential will be asked about birth control compliance and will be allowed to discontinue using an acceptable 
method of contraception as mandated by the protocol at the conclusion of this visit, should they elect to do so. 
Participants will be allowed to receive live (attenuated) vaccinations, as needed, after the conclusion of the Day 182 
Follow-Up Phone Call. Participants with asthma will be reminded that they should continue to take their asthma 
medications and will be counseled that they should only change their asthma medication in consultation with a 
physician. 
8.17. 
Unscheduled Visits  
If disease activity increases or other concerns arise between regularly scheduled visits, participants should be instructed 
to contact study personnel and may be asked to return to the study site for an “Unscheduled Visit.” Participants may 
also be asked to return to the clinic for Unscheduled Visits, as needed, to provide additional blood, skin swabs, skin tape 
strips, and/or skin biopsies for further mechanistic and functional studies, or if samples are lost or destroyed, or if 
insufficient yields were obtained at a previous study visit.  
 


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Any of the following procedures, assessments, and laboratory measures may be conducted at the Unscheduled Visit: 
x 
Interim medical history and physical examination, including assessments of AD severity (EASI, IGA, SCORAD, 
and Pruritus NRS) 
x 
Confirm pregnancy status of female participants of child-bearing potential and partners of male participants, 
including performing a urine pregnancy test for female participants of child-bearing potential per 
investigator discretion 
x 
Assessment of concomitant medications 
x 
Vital signs, including temperature, blood pressure, heart rate, and respiratory rate 
x 
Blood collection, up to 68 total mL, as applicable 
x 
Photographs will be taken of the measured lesional and non-lesional sites for collection of skin samples, as 
applicable 
x 
Skin swab collection, up to 6 total swabs, as applicable 
x 
Skin tape strip collection, up to 15 non-lesional and 5 lesional tape strips, as applicable 
x 
Skin biopsy collection, up to 2 total biopsies (1 x 3 mm non-lesional biopsy at 
, 1 x 2.5 mm lesional 
biopsy and/or 1 x 2.5 mm non-lesional biopsy at 
s), as applicable 
x 
IP Administration, as applicable 
x 
IP Distribution, as applicable 
x 
Assessment of AEs 
At the conclusion of this visit, participants will be reminded to refrain from the use of prohibited 
medications/procedures as described in Section 7.3. Participants will be given instructions regarding restrictions on 
bathing/showering, use of chlorinated pools and hot tubs, and use of emollients, including instructions not to apply 
emollients to sampling areas 24 hours prior to study visits. Sexually active participants of child-bearing potential will be 
instructed to use an acceptable method of contraception as described in Section 4.3. Participants with asthma will be 
reminded that they should continue to take their asthma medications and will be counseled that they should only 
change their asthma medication in consultation with a physician. Participants will be reminded to contact the research 
clinic should they experience any adverse events, including new onset of eye symptoms. 
8.18. 
Visit Windows 
Study visits should take place within the time limits specified above. The designated visit windows (i.e., ± n days) for 
each scheduled visit are also indicated on the Schedule of Events (Appendix A). 
9. 
Mechanistic Assays 
This section describes the proposed methodologies for this study. The techniques are state-of-the-art at the time of the 
writing of this protocol. Even so, the techniques will be updated and/or changed should there be additional technical 
breakthroughs in this area of research. The same methodologies/techniques will be utilized for all samples of a given 
type to ensure standardization and reduce variability.  Details of the laboratory processes are described in Standard 
Operating Procedures (SOPs) maintained by each laboratory.  
9.1. 
Measurement of S. aureus Abundance  
Measurement of S. aureus abundance will be performed by the 
 laboratory at 
. Skin microbiota 
will be collected by skin swabs from pre-measured areas on lesional and non-lesional skin.  The swabs will be placed in 
cryotubes with sterile phosphate buffered saline (PBS) and stored at -80°C. Total DNA will be extracted from the 
suspended microbiota using a DNA isolation kit and a bead beater homogenizer for mechanical lysis. Genomic DNA will 
be quantitated by 
 and used for measurement of S. aureus abundance (as well as 16S 


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rRNA and metagenome analysis of the skin microbiome – refer to Section 9.3). 
DNA extracted from skin swabs will be assayed by qPCR to quantitate the abundance of S. aureus at each collection site. 
Quantitation will be done using the S. aureus gene target (femA) in a multiplex 
gene expression assay. A 
minimum of three technical replicates will be used for each participant sample. A standard curve of the femA PCR product 
will be used to quantify the S. aureus copy number or abundance.  
9.2. 
Measurement of S. aureus Superantigens, Toxins, Lipase, and Proteases 
Measurement of S. aureus superantigens, toxins, lipase and proteases will be performed by the 
 laboratory at 
 Skin swabs will be frozen and batch shipped to the 
laboratory. As part of the workflow for 
the measurement of S. aureus superantigens and toxins from skin swabs, staphylococci will be quantified by Colony-
forming units (CFUs) of both S. aureus and coagulase-negative staphylococci by serial plate counts on mannitol salt agar. 
Yellow colonies will be tested by slide catalase and coagulase tests for verification as S. aureus. Red colonies will be 
verified as coagulase-negative by the same 2 tests. CoNS will be selected, inoculated into media, frozen, and shipped to 
the 
laboratory. Premoistened skin swabs have approximately 0.1 mL liquid volume when wet. The swabs will be 
placed in 1.9 mL of saline for serial dilution. The lower limit of detection by this assay is 1 colony in the first 0.2 mL 
volume.  
Proteins will be measured directly from swabs (0.6 total mL of the original 2 mL sample from above). Superantigens 
(staphylococcal enterotoxins A-G [excluding F which is now called TSST-1]), TSST-1, and enterotoxin-like superantigens 
H-X), cytotoxins (α, β, γ, δ, ε, and PSM-alpha3), lipase, and staphylococcal serine and cysteine proteases will be 
measured by Western Immunoblot. The Schlievert laboratory has on hand all required polyclonal hyperimmune 
antibodies to the native superantigens, cytotoxins, and lipase, and will have antibodies to the 2 major proteases by 
September 2019. For each sample, 20 μL for assessment of each superantigen, cytotoxin, lipase, cysteine protease, and 
serine protease will be spotted directly and dried onto polyvinylidene fluoride (PVDF) membranes. At the same time, 3 
serial, 10-fold dilutions of highly purified control superantigen, cytotoxin, lipase, and proteases will be treated similarly 
(the lower limit of detection of these toxins is approximately 75 pg). The PVDF membranes will be blocked with bovine 
serum albumin, reacted with 1/100 diluted primary antibodies, washed to remove unbound primary antibodies, reacted 
with 1/100 diluted conjugated antibodies against rabbit IgG (Li-Core IRDye 680 LT Goat Anti-Rabbit), washed again, and 
then developed. Reactions will be analyzed by NIH program Image J after scanning into the Odyssey CLx LI-COR 
instrument. A standard curve will be set up with the three dilutions of purified superantigens and cytotoxins. The 
reactivity of the saline samples will be compared for quantification. 
9.3. 
Analysis of the Skin Microbiome 
Analysis of the microbiome samples will be performed by the 
 laboratory at 
. Skin swab samples obtained from 
non-lesional and lesional skin sites will be collected and stored at -80°C pending S. aureus abundance (see Section 9.1), 
16S rRNA, and metagenome analysis.  
9.3.1. Microbiome Assessment by 16S rRNA 
Lesional and non-lesional skin swabs will be collected at all time points prior to and throughout dupilumab or 
placebo treatment. DNA extracted from skin swabs will be assayed by sequencing the V1-V3 16S rRNA 
hypervariable region to assess composition and diversity of the atopic dermatitis microbiome prior to and during 
treatment with dupilumab or placebo. The V1-V3 region will be amplified with PHusion High-Fidelity DNA 
Polymerase (New England Biolabs) using dual-indexed bar-coded primers (Fadrosh et al, 2014). Amplified products 
will be purified and normalized on 
 and pooled for 300 bp paired-end 
sequencing on an Illumina MiSeq. Quality and quantity of the libraries will be evaluated using an Agilent 


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BioAnalyzer. This approach routinely yields high quality sequence data, with ~40K reads per sample and assembly 
of 250-300 bp overlapping amplicons from the paired-end reads for each sample (Merkley et al, 2015). 
9.3.2. Metagenomic Analysis of Microbiome 
Metagenome analysis of skin samples collected prior to and during dupilumab or placebo treatment will identify 
genomic-level functional features of the microbiome. Metagenome libraries will be constructed using Illumina 
Nextera XT (Illumina) and sequenced on an Illumina HiSeq2500 using standard protocols for 125 bp paired-end 
sequencing. Samples will be multiplexed to provide a minimum of 80M mappable reads/sample. Based on ongoing 
metagenome analysis of atopic dermatitis samples, we anticipate that ~20% of the 80M reads will represent non-
human or bacterial DNA. This will result in ~16M high-quality bacterial reads for metagenome analysis.  
9.4. 
Functional Assessment of Coagulase Negative Staphylococcal Species (CoNS) Isolates for Antimicrobial Activity 
Functional assessments for antimicrobial activity will be performed by the 
 laboratory at 
 CoNS will be 
isolated from each swab sample by the Schlievert laboratory. CoNS strains will be stored at -80oC for future analysis.  
Up to 84 individual colonies of CoNS will be randomly selected from each sample and transferred to TSB (400 μL) in a 96-
well cluster tube for analysis.  For analysis, each assay plate will contain internal controls of a non-antimicrobial strain of 
S. epidermidis (ATCC1457) as negative control, a known antimicrobial strain of Staphylococcus hominis producing Sh-
lantibiotics as positive control, and blank wells without bacteria.  CoNS clones will be expanded in a 96-well cluster tube 
at 37oC overnight with shaking at 250 rpm.  Bacterial growth will be evaluated by measuring OD600 and only CoNS 
grown to (OD600>0.6) will be used for the following analysis.  This will be performed by removing bacteria by 
centrifugation followed by sterile filtration by a 96-well filter plate with 0.22 μm PVDF membrane 
  The 
antimicrobial activity in each sterile filtered media (100 μL) will then be evaluated by mixing with fresh TSB (10 μL) 
containing 1×104 CFUs of S. aureus (ATCC35556). Antimicrobial CoNS strains will be defined as those that suppress S. 
aureus growth after 22 hours to less than 50% (I50) of average growth seen in negative controls.  The frequency of 
antimicrobial CoNS will be determined to total CoNS numbers subjected to the assay. CoNS isolates may then be 
processed for species identification by metagenomic sequencing. 
9.5. 
Assessment of Lipid Components  
Skin tape strip samples obtained from non-lesional and lesional skin sites will be collected and stored pending analysis. 
 
The analyses of lipids including filaggrin breakdown products (urocanic acid [UCA] and pyroglutamic acid [PCA]) will be 
conducted at the 
 laboratory at 
 Tape strips will be stored at -80°C until 
processed. Both lipids and UCA and PCA will be extracted from the skin tape strips and quantified using mass 
spectrometry. This protocol includes collecting biological skin specimens from skin tape strips, followed by a two-step 
modified Bligh and Dyer extraction with careful collection of both water-methanol and chloroform layers with a 
preservation of protein denaturants in the interphase for protein estimation. Biological material from skin tape strips #4 
and #5 will be combined and processed. The material from skin tape strips will be removed by scraping in 
methanol/water (1:9, v/v) solution. The entire suspension will be subjected to chloroform/methanol extraction that 
allows extraction and separation of chloroform-soluble lipids and polar components. Protein denaturates will be 
digested overnight using 1N NaOH at 37°C; then protein content will be determined using BSA standards subjected to 
the same digestion procedure. The chloroform phase will be concentrated by a stream of nitrogen and redissolved in 
methanol for a subsequent liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of lipids. Separately, 
the water-methanol phase with polar components will be evaporated by a stream of nitrogen and redissolved in 
acetonitrile:water for a subsequent LC-MS/MS analysis.  Each batch of skin tape strips will be accompanied by 
processing three blank tape strips to correct for background noise in each subsequent analysis. 


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Chloroform-soluble components (lipids) and water-soluble compounds (polar analytes, i.e. UCA and PCA) will be 
analyzed using reverse-phase chromatography or hydrophilic interaction chromatography (HILIC) and electrospray 
ionization tandem mass spectrometry (ESI-LC-MS/MS) on a Sciex 6500 QTRAP instrument interfaced with a Shimadzu 
Nexera X2 UHPLC system using developed targeted methods for the exact quantitation of analytes. Lipids will be 
separated on an Ascentis Express RP-amide column using gradient elution from System A (methanol:water:formic acid 
65:35:0.5, with or without 5 mM ammonium formate) to System B (methanol:chloroform:water:formic acid 
90:10:0.5:0.5, with or without 5 mM ammonium formate). UCA and PCA will be separated on a Waters Acquity UPLC 
BEH Amide column using gradient elution from System A (acetonitrile) to System B (methanol:water:formic acid, with 5 
mM ammonium formate).  Quantitation will be achieved by creating standard curves of responses of variable amounts 
of analytes versus fixed amounts of the internal standards. When the exact analyte is not available, quantitation 
parameters will be taken from the closest analog with the best possible approximation. To quantify UCA and PCA, 100 ng 
U-13C, 15N-proline will be added during the initial steps of sample processing. For quantitation of different groups of 
lipids, the following internal standards will be used: C13:0-lysophosphatidylcholine, N-12:0-sphingomyelin, D7-
sphingosine, N-16:0-D7-sphingosine (D7-ceramide), and D7-cholesterol.  
9.6. 
Confocal Imaging of Skin Biopsies 
Confocal imaging will be performed by the 
 laboratory at 
 Immediately after the non-lesional skin biopsy is 
obtained, the epidermis will be lifted from the dermis by a short incubation in dispase. For 2D imaging, fixed epidermal 
sheets will be stained for epidermal barrier proteins and innate immune receptors as well as markers of Langerhans cells 
(LC)/dendritic cells (DC) and markers of LC/DC activation as we have done previously for other ADRN studies (Kuo et al, 
2013).  We will use a laser scanning confocal microscope at the URMC Confocal Microscopy Core. For 3D data visualization, 
processing, and analysis, we will utilize 
 software in order to more objectively capture 
the magnitude and localization of TJ molecules and innate receptors and their spatial relationship to LC/DC dendrites. 
9.7. 
Skin Transcriptomics 
Skin transcriptomic assays will be performed by the 
 laboratory at 
 RNA-Seq transcriptomics of the skin before 
and during treatment will identify host transcriptional responses to dupilumab or placebo. Total RNA will be extracted 
from whole 2.5 mm skin biopsy samples using 
 
according to the manufacturer’s instructions. RNA will be quantitated by 
 RNA 
integrity will be assessed on an Agilent BioAnalyzer. RNA-Seq libraries will be prepared using the 
 
 The double-stranded, tagged cDNA libraries will be 
purified using Agencourt AMPure Beads. Quality and quantity of the libraries will be evaluated using an Agilent 
BioAnalyzer. Sequencing will be performed on an Illumina HiSeq2500 using standard protocols for 100 bp paired-end 
sequencing. Samples will be multiplexed to provide a minimum of 20M mappable reads/sample for skin RNA. This 
approach will enable us to generate libraries from low-input RNA samples.  
9.8. 
PBMC Immunoprofiling 
Blood samples obtained for PBMC immunoprofiling will be collected and stored pending analysis. 
 
PBMC immunoprofiling will be performed by the 
 laboratory at 
 PBMC analysis of resting and activated 
populations will provide information on immune changes induced by IL-4 and IL-13 blockade by dupilumab.  These changes 
may paradoxically include short-term increases in circulating Th2 and skin-homing T cells, as these cells are released from 
skin sites of inflammation, and/or inhibited from entering the skin. This data should be complementary to the 
transcriptomic analysis of skin biopsies.  Longer-term immune changes may correlate with alterations in the microbiome, 
particularly the levels of S. aureus. 


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Peripheral blood samples will be collected at each clinical research site and shipped at room temperature to arrive at 
 within 24 hours.  PBMCs will be prepared and cryopreserved.  When all samples have been collected, the PBMC 
samples will be thawed and analyzed in batches, with all samples from a participant analyzed within the same batch to 
maximize the precision of intra-participant comparisons.  Eighteen-color phenotyping panels will be used to identify 
resting leukocyte populations, as well as T cell responses to antigens and myeloid responses to TLR ligands.   The panels 
will include analysis of T cell cytokines associated with Th2, Th17, and skin responses (IL-4, IL-13, IL-17, IL-22), as well as 
skin-homing subsets and myeloid response markers. Our new SWIFTreg registration program will be used to align samples 
between assay days to minimize any batch effects between different days.   
9.9. 
Analysis of Serum Biomarkers  
Serum biomarkers will be analyzed at a central laboratory, which will be determined for each biomarker. Th2 biomarkers 
to be assessed may include, but are not limited to, the following: thymus and activation-regulated chemokine 
(TARC/CCL17), pulmonary and activation-regulated chemokine (PARC/CCL18), total serum immunoglobulin E (IgE), and 
antigen-specific IgE. Serum may be used to measure ADA levels and other pharmacokinetic and pharmacodynamic 
studies.  
9.10. 
Genotyping 
Blood samples will be shipped to the Barnes lab at the 
 for DNA isolation.  Isolated DNA samples 
will be pre-tested using an Illumina® Veracode TM 384-SNP barcode panel or a similar platform. The ancestry-
informative markers-focused panel provides confirmation of the participant’s gender, detects mendelian inconsistencies 
and duplicates in the sample set, assesses sample performance and produces a genetic barcode that allows samples to 
be tracked from production to data release. Samples that do not pass the barcode quality control will be excluded from 
further genetic studies. Extracted DNA samples may be genotyped on commercially available genome-wide association 
studies (GWAS) SNP chips, such as 
   
10. Biospecimen Storage 
During the consent process, participants will be asked to give permission for long-term storage and future use of 
samples for research in the fields of AD and immunology.  The following biospecimens will be stored: 
o Serum  
o PBMCs 
o DNA, if collected 
o Skin tape strip samples and any derivatives  
o Skin biopsies and any derivatives 
o Skin swabs and any derivatives 
Instructions for sample preparation, handling, storage, and shipping are included in the MOP. Principal Investigators 
(PIs) will be responsible for being aware of and observing all the regulations for classification, packaging and labeling, 
permits or authorizations, and personnel training for shipment of biological and hazardous materials required for the 
conduct of this study. 
11. Criteria for Participant and Study Completion and Premature Study Termination 
11.1. 
Participant Completion 
Participant participation will be defined as complete at the conclusion of the Day 182 Follow-Up Phone Call. 


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11.2. 
Participant Stopping Rules and Withdrawal Criteria 
Participants may be prematurely terminated from the study for the following reasons: 
1. The participant elects to withdraw consent from all future study activities, including follow-up 
2. The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts to reestablish 
contact with the participant have failed). The ADRN standard definition of “lost to follow-up,” as defined in 
the MOP, will be used.  
3. The participant dies 
4. The participant becomes pregnant 
5. The Investigator no longer believes participation is in the best interest of the participant 
6. Medical condition for which continued participation, in the opinion of the Investigator, would pose a risk to 
the participant or would be likely to confound interpretation of the results  
7. The participant has an anaphylactic reaction to study drug injection 
8. The participant is diagnosed with a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin 
9. The participant acquires any opportunistic infection, such as tuberculosis and other infections whose nature 
or course may suggest an immune-compromised status 
10. The participant shows evidence of non-compliance to study protocol that in the opinion of the investigator 
requires discontinuation 
11.3. 
Participant Replacement 
Participants who were randomized and who withdraw or are withdrawn prior to the completion of the Day 182 Follow-
Up Phone Call will not be replaced.  
11.4. 
Follow-up After Early Study Withdrawal 
If a participant is withdrawn from the study for any reason, the participant will be asked to complete a final visit by 
phone to assess any AEs and concomitant medications since their last visit.  This visit will occur 30 days after withdrawal 
for any participant who withdraws before they receive study treatment and will occur 84 days after withdrawal if they 
have received study treatment (dupilumab or placebo). Any participant with an ongoing AE/SAE at the time of this 
contact will continue to be followed until the event is resolved with or without sequelae or until the AE stabilizes or until 
30 days following this contact, whichever occurs first. Monitoring of a pregnant participant or consented partner of a 
male participant shall continue until the conclusion of the pregnancy.    
11.5. 
Study Stopping Rules 
Study enrollment will be suspended pending DAIT NIAID and NIAID Allergy and Asthma DSMB expedited review of all 
pertinent data if any of the following occur: 
x 
1 death, or life-threatening adverse event, that is possibly related to dupilumab 
x 
A grade 3 or higher adverse event that is possibly related to dupilumab in two or more participants 
The study may not be resumed until all pertinent information is discussed with DAIT NIAID, NIAID Allergy and Asthma 
DSMB, and the central IRB, and all parties concur with the resumption of the study. Local IRBs will be informed of the 
study stoppage and the DSMB/Central IRB’s decision on resumption of the study.  
The study may be terminated by DAIT/NIAID or the NIAID Allergy and Asthma DSMB upon review of any observations, 
events, or new information that merits such action.  


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12. Safety Monitoring and Reporting 
12.1. 
Overview 
This section defines the types of safety data that will be collected under this protocol and outlines the procedures for 
appropriately collecting, grading, recording, and reporting those data. AEs that are classified as serious according to the 
definition of health authorities must be reported promptly (per Section 12.5) to the sponsor DAIT/NIAID.  Appropriate 
notifications will also be made to site PIs, and IRBs.  
Information in this section complies with International Conference on Harmonization (ICH) Guideline E2A: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, ICH Guideline E-6: Guideline for Good Clinical 
Practice (GCP), 21CFR Parts 312 and 320, and applies the standards set forth in the National Cancer Institute (NCI), 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03: http://ctep.cancer.gov/reporting/ctc.html. 
12.2. 
Definitions 
12.2.1. Adverse Event (AE) 
Any untoward or unfavorable medical occurrence associated with the subject’s participation in the          
research, whether or not considered related to the subject’s participation in the research (modified from the 
definition of AEs in the most current ICH E-6 Guidelines for Good Clinical Practice) (from Office of Human 
Research Protections (OHRP) "Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to 
Subjects or Others and Adverse Events (1/15/07)" http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2). 
The investigator must report adverse events regardless of relationship to study therapy regimen or study 
mandated procedures. 
 
For this study, an AE will include any untoward or unfavorable medical occurrence associated with:   
x 
Dupilumab or Placebo regimen:  An AE occurring after treatment initiation and within 84 days after 
the last dose of dupilumab or placebo  
x 
Study mandated procedures:  
o Blood Draw 
The following events related to the blood draw procedure will be considered AEs if they occur within 
48 hours of the blood draw: 
x 
Fainting / Vasovagal Events 
x 
Bruising at the puncture site larger than 2 cm in diameter 
x 
Bleeding from the puncture site lasting more than 30 minutes 
x 
Swelling at puncture site larger than 2 cm 
x 
Allergic reaction to topical anesthetic that requires use of rescue medications, detailed in 
Section 7.4  
o Tape Stripping 
The following events related to the skin tape strip collection procedure will be considered AEs if they 
occur within 48 hours of the tape stripping: 


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x 
Fainting / Vasovagal Events 
x 
Bruising at the tape stripping site larger than 2 cm in diameter 
x 
Bleeding from the tape stripping site lasting more than 30 minutes 
x 
Redness or swelling at the tape stripping site larger than 3 cm 
x 
Fever (> 100.4°F) x two readings separated by more than 10 hours 
x 
Allergic reaction to skin tape strips that requires use of rescue medications, detailed in 
Section 7.4  
Purulent drainage from a tape stripping site within 2 weeks of the procedure will also be considered 
an AE. 
o 
Skin Biopsy 
The following events related to the skin biopsies will be considered AEs if they occur within 48 hours 
of the skin biopsies: 
x 
Fainting / Vasovagal Events 
x 
Bleeding at skin biopsy site lasting more than 6 hours 
x 
Redness or swelling at biopsy site larger than 2 cm in diameter 
x 
Fever (> 100.4°F) x two readings separated by more than 10 hours 
x 
Allergic reaction to lidocaine that requires use of rescue medications, detailed in Section 7.4 
Rescue Medications 
Purulent drainage from a skin biopsy site within 2 weeks of the procedure will also be considered an 
AE. 
12.2.1.1. Suspected Adverse Reaction (SAR)  
Any AE for which there is a reasonable possibility that the study drug caused the AE. For the purposes of 
safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between 
the product and the AE. A SAR implies a lesser degree of certainty about causality than adverse reaction, 
which means any AE caused by a drug (21 CFR 312.32(a)). 
12.2.2. Unexpected Adverse Event  
An AE or SAR is considered “unexpected” if it is not listed in the package insert or is not listed at the specificity, 
severity, or rate of occurrence that has been observed. 
12.2.3.  Serious Adverse Event (SAE) 
An AE or SAR is considered “serious” if, in the view of either the investigator or DAIT/NIAID Medical Monitor, it 
results in any of the following outcomes (21 CFR 312.32(a)):  
1. Death 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either the 
investigator or DAIT/NIAID Medical Monitor, its occurrence places the participant at immediate risk of 
death. It does not include an AE or SAR that, had it occurred in a more severe form, might have caused 
death.  
3. Inpatient hospitalization or prolongation of an existing hospitalization 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5. Congenital anomaly or birth defect 


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6. Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant 
and may require medical or surgical intervention to prevent one of the outcomes listed above. 
Elective hospitalizations are not to be reported as an SAE unless hospitalization is prolonged due to 
complications.  
 
12.3. 
Grading and Attribution of Adverse Events 
12.3.1. Grading Criteria 
The study sites will grade the severity of AEs experienced by the study participants according to the criteria set 
forth in the NCI- CTCAE Version 4.03. This document (referred to herein as the NCI-CTCAE manual) provides a 
common language to describe levels of severity, to analyze and interpret data, and to articulate the clinical 
significance of all AEs. The NCI-CTCAE manual has been reviewed by the study investigators and sponsor and has 
been deemed appropriate for the participant population to be studied in this protocol.  
AEs will be graded on a scale from 1 to 5 according to the following standards in the NCI-CTCAE manual: 
Grade 1 = mild 
Grade 2 = moderate 
Grade 3 = severe 
Grade 4 = life-threatening 
Grade 5 = death 
Events grade 1 or higher will be recorded on the appropriate AE electronic case report form (eCRF) for this 
study. 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, but not limited to, a 
radiograph, an ultrasound, an electrocardiogram etc.), a treatment-emergent AE is defined as an increase in 
grade from baseline or from the last post-baseline value that doesn’t meet grading criteria. Changes in grade 
from screening to treatment initiation at Day 0 will also be recorded as AEs, but are not treatment-emergent. If 
a specific event or result from a given clinical or laboratory evaluation is not included in the NCI-CTCAE manual, 
then an abnormal result would be considered an AE if changes in therapy or monitoring are implemented as a 
result of the event/result. 
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE web site: 
http://ctep.cancer.gov/reporting/ctc.html. 
12.3.2. 
Attribution Definitions 
The relationship, or attribution, of an AE to the study drug or study procedure(s) will initially be determined by 
the site investigator and recorded on the appropriate AE eCRF.  Final determination of attribution for safety 
reporting will be determined by the DAIT/NIAID Medical Monitor.  The relationship of an AE to study therapy 
regimen or procedures will be determined using the descriptors and definitions provided in Table 12.3.2. 
 


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Table 12.3.2. Attribution of Adverse Events 
Code 
Descriptor 
Relationship (to investigational products or study 
procedures:  blood draw, skin tape stripping, skin 
biopsy) 
NOT RELATED CATEGORY 
1 
Not 
Related 
The AE is clearly not related:  there is insufficient 
evidence to suggest a causal relationship. 
 RELATED CATEGORIES 
2 
Possible 
The AE has a reasonable possibility to be related; 
there is evidence to suggest a causal relationship. 
3 
Related 
The AE is clearly related. 
 
12.4. 
Collection and Recording of Adverse Events 
12.4.1. Collection Period 
AEs will be collected from the time of consent until a participant completes study participation; or until 84 days 
after he/she prematurely withdraws (without withdrawing consent) or is withdrawn from the study if the 
participant received study treatment (dupilumab or placebo); or until 30 days after he/she prematurely 
withdraws (without withdrawing consent) or is withdrawn from the study if withdrawn prior to study treatment. 
12.4.2. Collecting Adverse Events 
AEs (including SAEs) may be discovered through any of these methods: 
x 
Observing the participant 
x 
Interviewing the participant in an objective manner [e.g., using structured questioning] 
x 
Receiving an unsolicited complaint from the participant 
x 
Receiving a call from the participant outside of their regular study visits; instructions for contacting the 
clinic will be provided on an instructional hand card 
x 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an AE, 
as defined in Section 12.3 
12.4.3. Recording Adverse Events 
Throughout the study, the investigator will record AEs and SAEs as described previously (Section 12.2) on the 
appropriate AE/SAE eCRF regardless of the relationship to study therapy regimen or study procedure. 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or the AE/SAE stabilizes, or 
until the end of study participation, or until 30 days after the participant’s final follow-up contact, whichever 
occurs first. Monitoring of a pregnant participant or consented partner of a male participant shall continue until 
the conclusion of the pregnancy.    
 


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12.5. 
Reporting of Serious Adverse Events and Adverse Events 
12.5.1. Reporting of Serious Adverse Events to DAIT/NIAID  
This section describes the responsibilities of the site investigator to report SAEs to DAIT/NIAID and the SACCC via 
the SAE eCRF. Timely reporting of AEs is required by 21 CFR and ICH E6 guidelines.  
Site investigators will report all SAEs (see Section 12.2.3), regardless of relationship or expectedness within 24 
hours of discovering the event. 
For SAEs, all requested information on the SAE eCRF will be provided.  However, unavailable details of the event 
will not delay submission of the known information.  Initial SAE eCRFs should include as much information as 
possible, but at a minimum must include the following:  
x 
AE term  
x 
Relationship to investigational product  
x 
Relationship to study procedure  
x 
Reason why the event is serious  
x 
Supplementary CRF pages that are current at the time of SAE reporting: medical history, concomitant 
medications, demographics, investigational product administration  
 
As additional details become available, the SAE eCRF should be updated and submitted. Every time the SAE eCRF 
is submitted, it should be electronically signed by the investigator or sub-investigator.  
For additional information regarding SAE reporting, contact Rho Product Safety:  
Rho Product Safety  
12.5.2. Reporting to Health Authority 
 
Not Applicable 
12.5.3. Reporting of Adverse Events to the Central IRB 
All investigators shall report AEs and SAEs, in a timely fashion to their local and central IRB in accordance with 
applicable regulations and guidelines.  
12.6. 
Pregnancy Reporting 
The investigator shall be informed of any pregnancy in a female study participant or the partner of a male study 
participant immediately upon becoming aware of the event. Study treatment will be discontinued for the pregnant 
participant.  A male participant whose partner becomes pregnant will be allowed to continue study treatment. The 
investigator shall counsel the female participant or male participant with a pregnant partner and discuss the risks of 
continuing with the pregnancy and the possible effects on the fetus. Monitoring of the pregnant participant or 
consented partner of a male participant shall continue until the conclusion of the pregnancy.    
The investigator shall report to the SACCC all pregnancies within 24 hours of becoming aware of the event using the 
Pregnancy eCRF.  The SACCC will report all pregnancies to DAIT/NIAID. All pregnancies in female participants and 


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consented partners of male participants identified during the study shall be followed to conclusion, and the outcome of 
each must be reported.  The Pregnancy eCRF shall be updated and submitted to the SACCC when details about the 
outcome are available.   
Should pregnancy complications result in a congenital abnormality, birth defect, miscarriage, or medically indicated 
abortion - an SAE must be submitted to the SACCC using the SAE reporting procedures described in Section 12.5.   
12.7. 
Reporting of Other Safety Information 
An investigator shall promptly notify their local and central IRB, in accordance with applicable regulations and 
guidelines, as well as the SACCC and DAIT/NIAID via email when an “unanticipated problem involving risks to subjects or 
others” is identified, which is not otherwise reportable as an adverse event. 
12.8. 
Review of Safety Information 
12.8.1. Medical Monitor Review 
The DAIT/NIAID Medical Monitor shall receive monthly reports from the SACCC compiling new and accumulating 
information on AEs, SAEs, and pregnancies recorded by the clinical sites on appropriate eCRFs. 
In addition, the DAIT/NIAID Medical Monitor shall review and make decisions on the disposition of the SAE and 
pregnancy reports received by the SACCC (See Sections 12.5.1 and 12.6).   
12.8.2. DSMB Review  
The SACCC will provide the NIAID Allergy and Asthma DSMB with a listing of all AEs and SAEs on an ongoing basis 
(at least annually).   
12.8.2.1. Planned DSMB Reviews  
The NIAID Allergy and Asthma DSMB shall review safety data at least yearly during planned DSMB Review 
Meetings. Data for the planned safety reviews will include, at a minimum, a listing of all reported AEs and 
SAEs.   
12.8.2.2. Ad hoc DSMB Reviews  
In addition to the pre-scheduled data reviews and planned safety monitoring, the NIAID Allergy and 
Asthma DSMB may be called upon for ad hoc reviews when an event occurs that is of sufficient concern to 
the DAIT/NIAID Medical Monitor and/or the protocol chair to warrant DSMB review. The DSMB will be 
notified within 24-48 hours by the NIAID Medical Monitor and will promptly review any event that 
potentially impacts safety at the request of the protocol chair or DAIT/NIAID or any occurrence that meets 
the definition of the Participant Study Stopping Rules or Study Stopping Rules defined in Sections 11.2 and 
11.5.  
After review of the data, the DSMB will make recommendations regarding study conduct and/or 
continuation. 
12.8.2.2.1. Temporary Suspension of Enrollment for ad hoc DSMB Safety Review  
A temporary halt in enrollment will be implemented if an ad hoc DSMB safety review is required.  
New participants will not be consented for study participation during the enrollment halt. 
Participants already on therapy will continue dupilumab or placebo treatment. Participants screened 
but not yet randomized will not be allowed to continue with the Day 0 Treatment Initiation Visit. All 
participants not randomized within 12 days of the Screening Visit must rescreen.  


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13. Statistical Considerations and Analytical Plan 
13.1. 
Overview  
The primary research objective of this study is to assess the effect of dupilumab on S. aureus abundance on lesional skin 
as measured by microbial DNA. This objective will be addressed using a multicenter trial, involving a 6 week RDBPC 
portion followed by a 10 week OLE, investigating the effect of dupilumab treatment on quantitative and qualitative 
measures of cutaneous microbial community structure, skin barrier biology, and circulating T cell profiles for adult 
participants ages 18-75 years with chronic moderate-to-severe AD.  
13.2. 
Endpoints/Outcomes 
The primary endpoint is S. aureus abundance as measured by microbial DNA (femA qPCR) on lesional skin at Day 28.  
Secondary endpoints include: 
1. S. aureus abundance as measured by microbial DNA (femA qPCR) on lesional skin at Days 0, 3, 7, 14, 21, 42, 
77 and 112 
2. S. aureus abundance as measured by microbial DNA (femA qPCR) on non-lesional skin at Days 0, 3, 7, 14, 21, 
28, 42, 77 and 112 
3. Basal (prior to tape stripping) TEWL of non-lesional and lesional skin at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
4. TEWL area under the curve of non-lesional skin at Days 0, 7, 14, 21, 28, 42, 77 and 112. TEWL will be assessed 
prior to tape stripping and repeated after 5, 10, and 15 tape strips.   
5. Change in TEWL per every 5 tape strips (i.e. slope) on non-lesional skin at Days 0, 7, 14, 21, 28, 42, 77 and 112 
6. EASI, IGA, and SCORAD at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
7. Pruritus NRS at Days 0, 3, 7, 14, 21, 28, 42, 77 and 112 
13.3. 
Measures to Minimize Bias  
To minimize bias, randomization will be performed by the clinical sites using a SACCC validated system that automates 
the random assignment of treatment groups to study ID numbers. The randomization scheme will be reviewed by a 
statistician at the SACCC prior to implementation. Participants will be randomized using a 2:1 ratio of active (dupilumab) 
and control (placebo) participants. A stratified permuted block randomization algorithm will be used to maintain a 
balance between treatment arms with respect to clinical site and disease severity at Day 0 (EASI ≥ 21.1 or < 21.1).   
13.4. 
Analysis Plan 
13.4.1. Analysis Populations 
The following groups of participants will define samples for endpoint analysis: 
x 
Modified intent-to-treat (mITT) sample: All participants who are randomized and have S. aureus 
abundance measured at Day 0 and Day 28. Participants will be analyzed according to the treatment arm 
to which they were randomized, regardless of the medication they actually received. 
x 
Safety sample: All participants who are randomized and receive at least one dose of study treatment. 
Participants will be analyzed according to the medication they actually received, regardless of the 
treatment arm to which they were randomized. Non-treatment emergent adverse events (e.g., any 
adverse event that occurs before the first injection) will be summarized in all participants who are 
enrolled, while treatment emergent adverse events (e.g., any adverse event that occurs on or after the 
first injection) will be summarized in the safety sample.  


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x 
Per-protocol (PP) sample: All participants who are randomized, receive the correct medication and 
dosage to which they were randomized, do not have a major protocol deviation, do not miss any 
scheduled injections, have not used any of the medications/procedures listed in Section 7.3 with the 
exception of topical calcineurin inhibitors (tacrolimus or pimecrolimus), topical corticosteroids, topical 
phosphodiesterase inhibitors (crisaborole) and topical antibiotics if applied to areas of the skin not being 
sampled, and have met sampling criteria. 
13.4.2. Primary Analysis of Primary Endpoint(s)/Outcome(s)   
The primary analysis will compare S. aureus abundance between treatment arms at Day 28 using an ANCOVA 
model applied to the modified intent-to-treat sample. Prior to analysis, a log-10 transformation will be applied 
to S. aureus abundance. If any participant to be included in the analysis has a value of zero, the participant’s 
value will be adjusted by adding a value of 1 prior to transformation. To account for the study design induced by 
the randomization scheme, the model will also include fixed effects for clinical site and disease severity at Day 0, 
as measured by EASI ≥ 21.1 or < 21.1. To increase statistical efficiency, the model will also adjust for skin swab 
collection site and S. aureus abundance at Day 0. Such a model will allow us to estimate the adjusted geometric 
mean ratio of the abundance of S. aureus at Day 28 (and corresponding 95% confidence interval) between the 
dupilumab and placebo arms. A two-sided significance level of 0.05 will be used for this analysis.  
13.4.3. Supportive Analyses of the Primary Endpoint(s)/Outcome(s)  
Analyses for the primary endpoint may be supported by several analyses.  
To evaluate the distributional assumptions made in the primary ANCOVA model, a permutation test will be used 
as a supplementary analysis of the primary analysis (Manly, 1997).   
The primary analysis will be replicated using S. aureus abundance as measured by microbial DNA (femA qPCR) on 
lesional skin at Day 28. 
Rather than exclude participants who are randomized but do not have S. aureus abundance measured at Day 0 
and Day 28 (as defined by the mITT sample), a multiple imputation technique will be employed to impute the 
missing primary endpoint of S. aureus abundance at Day 0 or Day 28. The ANCOVA model specified in Section 
13.4.2 will be run on each imputed dataset, and results will then be pooled to estimate one geometric mean 
ratio and corresponding 95% CI. 
The ANCOVA model specified in Section 13.4.2 will be adjusted to include clinical site as a random effect, rather 
than a fixed effect.    
To test if the effect of dupilumab on S. aureus abundance at Day 28 is modified by particular sub-groups, 
separate ANCOVA models will be developed to test the two-way interaction between treatment arm and 
variables defining the sub-groups of interest. Sub-groups that will be investigated include: 
o Clinical site 
o Disease severity at Day 0, as measured by EASI ≥ 21.1 or < 21.1 
o Disease severity at Day 0, as measured above and below the median value of TARC  
13.4.4. Analyses of Secondary and Other Endpoint(s)/Outcome(s) 
Generalized linear mixed models will be used to model the following endpoints at multiple time points: S. aureus 
on lesional and non-lesional skin (as measured by femA qPCR), basal TEWL on lesional and non-lesional skin, 


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TEWL AUC on non-lesional skin, change in TEWL on non-lesional skin, and disease severity, as measured by EASI 
(as well as percent change over time in EASI and EASI50), IGA (as well as percent change over time in IGA), 
SCORAD (as well as percent change over time in SCORAD) and Pruritus NRS (as well as percent change over time 
in Pruritis NRS). All models will be adjusted for clinical site, skin collection site, and disease severity at Day 0 as 
measured by EASI ≥ 21.1 or < 21.1 (for endpoints other than EASI). Data transformations (e.g., Box-Cox or 
arcsine square root) will be undertaken if the data deviate markedly from the normal distribution. For endpoints 
measured on both lesional and non-lesional skin, models will include a random effect for participant to account 
for correlation between lesional and non-lesional samples within the same participant. Likewise, skin collection 
site will also be considered as a random effect for endpoints collected on both lesional and non-lesional skin.  
Analyses for the secondary endpoints may be supported by several analyses. For instance, to compare the cross-
sectional and longitudinal effects of S. aureus abundance on disease severity between treatment arms, a 
generalized linear mixed model similar to that described in Chapter 15.4 of Fitzmaurice et al (2004) will be used. 
By including an interaction between treatment arm and S. aureus abundance at Day 0, as well as an interaction 
between treatment arm and the change in S. aureus abundance over time, this model will allow us to 
simultaneously estimate the effect of S. aureus abundance at Day 0 on disease severity at Day 0 in the 
dupilumab and placebo arms separately, as well as the change in S. aureus abundance over time on the change 
in disease severity over time in the dupilumab and placebo arms separately.  The model will also be adjusted for 
clinical site, skin collection site, and disease severity at Day 0, as measured by EASI ≥ 21.1 or < 21.1 (for 
endpoints other than EASI).         
13.4.5. Analyses of Exploratory Endpoint(s)/Outcome(s) 
13.4.5.1. Skin Microbiome 
13.4.5.1.1. 16S rRNA Analysis 
Analysis of 16S rRNA microbiome data will identify changes in community composition and diversity 
at lesional and non-lesional skin sites prior to and throughout dupilumab or placebo treatment. The 
16S rRNA bacterial sequence reads will first be assessed for quality and then analyzed using 
phylogenetic and Operational Taxonomic Unit (OTU) (Zhang et al, 2007) methods in QIIME (Caporaso 
et al, 2012). QIIME will be used to de-multiplex the barcoded reads and preprocess for quality. 
Chimera detection and removal will be performed de novo using UCHIME (Edgar et al, 2011). To 
identify OTUs, USearch 5.2 will be used to cluster the remaining reads based on percent identity, with 
a threshold of 97% in order to maximize taxonomic specificity (Edgar et al, 2010). Taxonomic 
assignments will be made to the resulting OTUs based on the seed of each cluster, using the RDP 
classifier with the GreenGenes database of reference sequences and their known taxonomic 
assignments (DeSantis et al, 2006). Within each sample type, individuals will be clustered based on 
constituent phyla using the hclust function of R, which performs hierarchical clustering iteratively, 
using the Lance-Williams dissimilarity update formula and computing complete distances. Bacterial 
diversity within each sample (alpha diversity) will be computed as the Shannon Index. Bacterial 
diversity between samples (beta diversity) will be computed as the Bray-Curtis dissimilarity index. 
Dissimilarity between lesional and non-lesional skin sites in each participant and treatment point will 
be assessed to correlate shifts in abundance of S. aureus and other members of the AD microbiome 
in response to dupilumab or placebo. In order to account for the correlation present in this 
experiment, we will analyze changes in S. aureus abundance using generalized linear mixed models. 
Between-group differences in overall microbiota composition will be visualized using unsupervised 


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machine learning methods, such as non-metric multidimensional scaling and principal components 
analysis. 
13.4.5.1.2. Metagenomics 
Comprehensive functional analysis of the AD microbiome will identify genomic level variation and 
changes in bacterial functions associated with dupilumab treatment. Sequence data will be processed 
for quality reads and those that map to human sequence. Taxonomic assignments will be made using 
reference based methods, including Bowtie (Langmead and Salzberg, 2012) and Pathoscope (Francis 
et al, 2013) with the Human Microbiome Project database of reference genomes. Functional gene 
groups will be characterized using the KEGG Orthology gene pathway (KO) (Abubucker et al, 2012; 
Kanehisa and Goto, 2000). Corresponding gene abundance will be calculated using the HMP Unified 
Metabolic Analysis Network (HUMAnN) (Abubucker et al, 2012). 
13.4.5.2. Skin Transcriptome 
RNAseq reads will go through standard pre-processing procedures. We will align the short reads to the 
human reference genome using TopHat. Using Samtools, we will remove reads with low quality score or 
potential PCR duplicates. We will utilize the Cufflinks (Langmead and Salzberg, 2012; Kim et al, 2013; 
Trapnell et al, 2010) suite of software programs for discovery of differentially expressed genes between 
groups and novel splice variants. We will perform standard differential expression analysis, conditional 
quantile normalization correcting for GC content bias and employ surrogate variable approaches to 
identify, quantify, and account for potential artifacts in transcript level estimates (Hansen et al 2012; Leek 
et al, 2010; Leek and Storey, 2007). Functional enrichment will be performed using over-representation 
statistic and gene-set enrichment methods to find transcription factors (from TRANSFAC and JASPER) and 
molecular processes and pathways (from KEGG and GO databases) associated with dupilumab treatment 
(Yaari et al, 2013). 
13.4.5.3. Epidermal Lipids  
For each time point, we will compare lipid profiles between dupilumab and placebo arms as previously 
described (Janssens et al, 2012). A generalized linear mixed model, similar to that described in Section 
13.4.4, will be used to investigate the effect of dupilumab on lipid profiles over time. 
13.4.5.4. S. aureus Superantigens, Toxins, Lipase, and Proteases 
We will compare the expression of each S. aureus superantigen (SAg), toxin, lipase, and  protease over 
time between dupilumab and placebo arms using a generalized linear mixed model, similar to that 
described in Section 13.4.4. For the analysis, each endpoint will be considered in two ways: with 
continuous expression as the outcome, as well as a binary indicator for presence/absence as the outcome.  
13.4.5.5. Functional Assessment of CoNS Antimicrobial Activity Data 
The frequency of commensal Staphylococcus species producing antimicrobial activity, as measured by the 
number of colonies with antimicrobial activity against S. aureus per sample, between dupilumab and 
placebo will be compared using a generalized linear mixed model, similar to that described in Section 
13.4.4. 
13.4.5.6. PBMC Immunoprofiles 
Flow cytometry analysis will be performed on PBMCs, using phenotyping panels to identify resting 
leukocyte populations, as well as T cell responses to antigens and myeloid responses to TLR ligands.     


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The flow data will be analyzed manually to conform with previous data, and also, with greater resolution, 
by algorithmic analysis by SWIFT (Naim et al, 2014; Mosmann et al, 2014).  Algorithmic methods can often 
exceed the capabilities of manual methods (Aghaeepour et al, 2013), particularly in high dimensions.   An 
extension of the main SWIFT algorithm, competitive template assignment (Rebhahn et al, 2016), further 
increases the resolution of SWIFT.  This procedure was used in a blind analysis of PBMC samples from a 
dupilumab clinical trial, and successfully predicted the dupilumab group versus the placebo group, based 
on the differences between day 1 and day 29.  In the ADRN Barrier study, the SWIFT competitive method 
identified multiple differences between non-atopic versus AD S. aureus- subjects, and also between AD S. 
aureus- and AD S. aureus+ subjects.   
This initial analysis will be used to identify cell sub-populations and markers that distinguish the treatment 
groups.  This can be a strong analysis, e.g., in a large systems biology analysis of vaccination, the flow data 
was the most discriminatory (Tsang et al, 2014). Refer to Section 13.4.5.8 regarding additional analysis of 
flow data.  
13.4.5.7. Serum Biomarkers 
We will compare serum biomarkers (Th2 biomarkers and ADA) over time between dupilumab and placebo 
arms using generalized linear mixed models, similar to that described in Section 13.4.4.  
13.4.5.8. Systems Biology 
The RNA-Seq data of host and microbiome will be integrated using statistical learning methods and 
graphical models (Thakar et al, 2013; Raghavan et al, 2007; Thakar and Albert, 2010; Campbell et al, 2011) 
to evaluate effects of host-pathogen interactions on microbial relative abundance, absolute S. aureus 
abundance, expression of S. aureus superantigens, toxins, lipase, proteases, AD severity, barrier function, 
and immune pathway activation upon dupilumab treatment. We have developed and used approaches to 
find co-regulated gene modules from transcriptomic data that are correlated with serum levels of the Th2 
biomarker, TARC (Qian et al, 2014; Raghavan et al, 2007; Katanic et al, 2016). Furthermore, gene module 
approaches have been developed to adjust for confounder effects using multivariate regression to infer 
associations between host-pathogen networks and clinical parameters. We will also use machine learning 
algorithms, such as support vector machines and random forest, to find gene signatures that can 
discriminate between the dupilumab and placebo treatment groups in the RDBPC portion of this study (i.e. 
first 6 weeks) (Piepenbrink et al, 2016; Rebhahn et al 2016). To investigate the relationships between the 
gene-signatures and lipidomics specific to dupilumab treatment, we will extract features from lipidomics 
data and will integrate those with annotations using pathways databases. Thus, the host-pathogen 
networks will reveal molecular processes associated with AD severity, skin barrier function, and ultimately, 
dupilumab responsiveness.  
We may complement the rich RNA expression and lipidomics data with high-resolution flow cytometry 
analysis (Refer to Section 13.4.5.6).   The flow data will be combined with data on clinical responses, gene 
expression, lipidomics, and bacterial population changes in an integrated analysis of patterns that 
correlate with response and microbiome changes.  The RDBPC portion as well as the OLE of the study will 
allow subject-specific functional analysis of the mechanistic readouts allowing us to identify signatures of 
intra-individual variation observed with fluctuation in clinical response (EASI, SCORAD, and NRS) in 
response to dupilumab treatment. Using both portions of this clinical study, we will identify associations 
between circulating immune cell populations (clusters), tissue gene-signatures, biogeography, and skin 
barrier functions including lipidomics that correlate with dupilumab responsiveness. 


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If genetic data are available, we will perform an exploratory, unbiased scan for quantitative trait loci (QTL) 
within each of the omics data types using genotype data generated using the MEGA chip imputed up to a 
reference panel (i.e., The 1000 Genomes Project) using conventional pipelines. We will consider both cis-
QTLs and trans-eQTLs (defined at +/- 1Mb of gene start/stop) for eQTLs and microbiome QTLs (mbQTL) 
where the quantitative omics level can be linearly assigned to a gene window, but perform tests agnostic 
to a gene window for the mbQTLs. We will address the multiple comparisons problem and label QTLs as 
significant at FDR thresholds=5%. 
13.4.6. Descriptive Analyses  
Descriptive analyses will be reported separately for the dupilumab and placebo arms in the mITT, safety, and PP 
samples. Continuous baseline measures will be reported using a mean (or geometric mean) with 95% confidence 
interval or median with first and third quartiles, as appropriate. Categorical baseline and demographic 
characteristics and study disposition will be reported as frequencies and proportions. 
13.5. 
Interim Analyses  
13.5.1. Interim Analysis of Efficacy Data 
No formal interim analysis of efficacy data will be performed for this study. However, statistical analyses of 
scientific objectives, to include all data through Day 112, are planned to occur as soon as applicable data 
collection is complete. The study database through Day 112 will be monitored and cleaned per the Data 
Management Plan. Data-entry for all study visits through Day 112 will be locked in order to begin analyses. Data-
entry will remain open for safety data collected after Day 112, and this data will be analyzed once all study visits 
have been completed. Further details will be specified in the Statistical Analysis Plan. 
13.5.2. Interim Analysis of Safety Data 
The NIAID Allergy and Asthma DSMB will receive periodic safety reports on enrolled participants. However, no 
formal interim analysis of safety data will be conducted.  
13.5.3. Futility Analysis 
No formal futility analysis will be performed for this study. 
13.6. 
Statistical Hypotheses  
All primary and secondary objectives will be based on two-sided superiority tests. For instance, the null and alternative 
hypotheses for the primary objective are: 
Null hypothesis: S. aureus abundance at Day 28 in the dupilumab arm is equal to S. aureus abundance at Day 28 in the 
placebo arm.  
Alternative hypothesis: S. aureus abundance at Day 28 in the dupilumab arm is not equal to S. aureus abundance at Day 
28 in the placebo arm. 
Other secondary objectives have similar null and alternative hypotheses to the above. 
13.7. 
Sample Size Considerations  
The sample size for this trial is based on the primary endpoint of S. aureus abundance at Day 28. Based on previous data 
provided by 
 (Guttman-Yassky et al, 2016), the median (coefficient of variation) of S. aureus abundance at Day 
28 after randomization was 108.9 (1.2) CFU/area and 1296.1 (2.2) CFU/area in the dupilumab and placebo arms, 


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respectively, corresponding to a ratio between the dupilumab and placebo arms of 0.08. Conservatively assuming that 
the coefficient of variation in each arm is 2.2 and the ratio of the medians will be an acceptable estimate for the 
geometric mean ratio between the two arms, a total sample size of 84 (56 in the dupilumab arm and 28 in the placebo 
arm) will allow us to detect a 0.36 geometric mean ratio of S. aureus abundance between dupilumab and placebo arms 
with at least 90% power via a two-sample pooled t-test of a mean ratio with lognormal data. The
 study also 
showed that the percent change in EASI at 4 weeks was -63% (SD=29%) and the percent change in pruritus NRS at 4 
weeks was -45% (SD=28%) in the dupilumab arm while in the placebo arm, the percent change in EASI at 4 weeks was 
3% (SD=53%) and the percent change in pruritus NRS at 4 weeks was 7% (SD=79%). Assuming similar effects are seen in 
our study, this sample size will also allow us to detect these effect sizes with >99% and 91% power, respectively. 
Assuming 15% of participants will not have S. aureus abundance available at Day 0 or Day 28 due to dropout or missing 
data, 99 participants will be randomized (66 in the dupilumab arm and 33 in the placebo arm) to ensure the sample size 
of 84 participants is met.   
14. Identification and Access to Source Data 
14.1. 
Source Data 
Source documents and source data are considered to be the original documentation where participant information, visit 
consultations, examinations, and other information are recorded.   Documentation of source data is necessary for the 
reconstruction, evaluation, and validation of clinical findings, observations and other activities during a clinical trial.    
14.2. 
Access to Source Data 
The site investigators and site staff will make all source data available to DAIT/NIAID and authorized representatives of 
DAIT/NIAID. Authorized representatives as noted above are bound to maintain the strict confidentiality of medical and 
research information that may be linked to identified individuals. 
15. Protocol Deviations 
15.1. 
Protocol Deviation Definitions 
Protocol Deviation – The investigators and site staff will conduct the study in accordance to the protocol; no deviations 
from the protocol are permitted.  Any change, divergence, or departure from the study design or procedures constitutes 
a protocol deviation.  As a result of any deviation, corrective actions will be developed by the site and implemented 
promptly. 
 
Major Protocol Deviation (Protocol Violation) - A Protocol Violation is a major deviation from the IRB approved protocol 
that may affect the participant’s rights, safety, or well-being and/or the completeness, accuracy, and reliability of the 
study data.  In addition, protocol violations include willful or knowing breaches of human subject protection regulations, 
or policies, any action that is inconsistent with the NIH Human Research Protection Program’s research, medical, and 
ethical principles, and a serious or continuing noncompliance with federal, state, local, or institutional human subject 
protection regulations, policies, or procedures. Examples of Major Protocol Deviations are described in the MOP.  
 
Non-Major Protocol Deviation - A non-major protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that does not have a major impact on the participant’s rights, safety, or 
well-being, or the completeness, accuracy, and reliability of the study data. 


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15.2. 
Reporting and Managing Protocol Deviations 
The study site PI has the responsibility to identify, document, and report protocol deviations as directed by DAIT/NIAID.  
However, protocol deviations may also be identified during site monitoring visits or during other forms of study conduct 
review.  
Upon determination that a protocol deviation has occurred, the study staff will a) notify the site PI, b) notify the SACCC 
and c) will complete a Protocol Deviation form. The protocol deviation form will document at minimum the date the 
deviation occurred, the date it was identified, a description of the event, whether the deviation resulted in an SAE/AE, PI 
signature, IRB report requirement, and documentation of a corrective action plan. DAIT/NIAID may request discussion 
with the site PI to determine the effect of the protocol deviation on the study participant and his/her further study 
participation, the effect of the protocol deviation on the overall study, and corrective actions. The PI will sign the paper 
source Protocol Deviation CRF, electronically sign Major Deviations in the electronic data capture (EDC), and submit the 
deviation to the central IRB, and local IRB/EC per IRB regulations.  Major protocol deviations will be reported to the 
NIAID Allergy and Asthma DSMB by the DAIT/NIAID Medical Monitor at the medical monitor’s discretion.  
16. Ethical Considerations and Compliance with Good Clinical Practice 
16.1. 
Quality Control and Quality Assurance 
The investigator is required to keep accurate records to ensure that the conduct of the study is fully documented. The 
investigator is required to ensure that all CRFs are completed for every participant entered in the trial. 
The sponsor is responsible for regular inspection of the conduct of the trial, for verifying adherence to the protocol, and 
for confirming the completeness, consistency, and accuracy of all documented data. 
The CRFs will be completed online via a web-based EDC system that has been validated and is compliant with Part 11 
Title 21 of the Code of Federal Regulations. Study staff at the site will enter information into the eCRFs, and the data will 
be stored remotely at a central database. Data quality will be ensured through the EDC system’s continuous monitoring 
of data and real-time detection and correction of errors. All elements of data entry (i.e., time, date, verbatim text, and 
the name of the person performing the data entry) will be recorded in an electronic audit trail to allow all changes in the 
database to be monitored and maintained in accordance with federal regulations. 
16.2. 
Statement of Compliance 
This clinical study will be conducted using GCP, as delineated in Guidance for Industry: E6 Good Clinical Practice 
Consolidated Guidance, and according to the criteria specified in this study protocol.  Before study initiation, the 
protocol and the informed consent documents will be reviewed and approved by the central IRB. Any amendments to 
the protocol or to the consent materials will also be approved by the central IRB before they are implemented. 
16.3. 
Informed Consent Process 
The consent process will provide information about the study to a prospective participant and will allow adequate time 
for review and discussion prior to his/her decision.  The PI listed on the Investigator of Record or a designee will review 
the consent and answer questions.  Consent designees must be listed on the site delegation of responsibilities log, 
complete consenting certification, and have demonstrated knowledge of the protocol and study procedures. The 
prospective participant will be told that being in the trial is voluntary and that he or she may withdraw from the study at 
any time, for any reason.  The participant will read, sign, and date a consent form before undergoing any study 
procedures.  Consent materials will be presented in the participant’s primary language. A copy of the signed consent 
form will be given to the participant. 


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The consent process will be ongoing. The consent form will be revised when important new safety information is 
available, the protocol is amended, and/or new information becomes available that may affect participation in the 
study.  
In the event that the partner of a male participant becomes pregnant, she will be invited to the research clinic to be 
consented into the study for pregnancy follow-up only. The consent process will be completed as outlined above. 
Documentation of the consent process must be entered on a source document. 
 
16.4. 
Privacy and Confidentiality 
Following the Health Insurance Portability and Accountability Act guidelines, a participant’s privacy and confidentiality 
will be maintained throughout the study.  Each participant will be assigned a unique identification number and these 
numbers rather than names will be used to collect, store, and report participant information. All biological samples will 
be labeled with the identification number. Data reported in medical journals or scientific meetings will be presented in 
aggregate for participants as a whole. No individual participant will be identified in any way. Site personnel will not 
transmit documents containing personal health identifiers (PHI) to the study sponsor or their representatives.  
17. Publication Policy 
The ADRN Publications Policy will apply to presentations and publications of the results of this trial. 


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Allergy Clin Immunol. 2013; 131(2): 266-278. 
 
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Mosmann TR, Naim I, Rebhahn J, Datta S, Cavenaugh JS, Weaver JM, Sharma G. “SWIFT-scalable clustering for 
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Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T, Shafiq F, Kotol PF, Bouslimani A, Melnik AV, Latif H, Kim JN, 
Lockhart A, Artis K, David G, Taylor P, Streib J, Dorrestein PC, Grier A, Gill SR, Zengler K, Hata TR, Leung DY, Gallo RL. 
“Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic 
dermatitis.” Sci Transl Med. 2017; 9(378). 
Ong PY, Leung DYM. “Bacterial and viral infections in atopic dermatitis: a comprehensive review.” Clin Rev Allergy 
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Piepenbrink MS, Samuel M, Zheng B, Carter B, Fucile C, Bunce C, Kiebala M, Khan AA, Thakar J, Maggirwar SB, Morse D, 
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Qian F, Thakar J, Yuan X, Nolan M, Murray KO, Lee WT, Wong SJ, Meng H, Fikrig E, Kleinstein SH, Montgomery RR. 
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Rafaels NM, Lockhart A, Babineau D, Artis K, David G, Yoshida T, Boguniewicz M, Ong PY, De Benedetto A, Hanifin JM, 
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175(4):687-95. 
 
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Signatures Observed in the Nonlesional Skin from European American Atopic Dermatitis Subjects Who Are Colonized 
with Staphylococcus aureus.” J Allergy Clin Immunol. 2016; 137(2) Suppl:AB183. 
 
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filaggrin mutations and Staphylococcus aureus skin colonization in European American atopic dermatitis subjects.” 
Society for Investigational Dermatology Annual Meeting. 2015 May 6-9; Atlanta, Georgia. 
 
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human cytomegalovirus transcriptome." J Virol. 2007; 81(20): 11267-11281. 
 
 
 


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Appendix A: Schedule of Events 
Study Portion 
RDBPC 
Open-Label 
Follow
-Up 
 
Study Visit 
Recruitment 
Screening 
Visit 
Treatment 
Initiation 
(Day 0) 
Day 3 
Day 7 
Day 14 
Day 21 
Day 28 
Day 42 
Day 56 Home 
IP Injection 
Day 70 Home 
IP Injection 
Day 77 
Day 84 Home 
IP Injection 
Day 98 Home 
IP Injection 
Day 112 
Day 182 
Follow-Up 
Phone Call 
Unscheduled 
Visit1 
Visit Window 
 
Day -28 to 
Day -8 
Day 0 
Day 3 ± 12 
Day 7 ± 22 
Day 14 ± 2 
Day 21 ± 2 
Day 28 ± 2 
Day 42 ± 2 
Day 56 ± 73 
Day 70 ± 73 
Day 77 ± 2 
Day 84 ± 73 
Day 98 ± 73 
Day 112 ± 2 
Day 182 ± 5 
 
Study Procedures/Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
Medical History 
 
X 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
 
 
X4 
 
 
X4 
 
X4 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
Pregnancy Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
Pregnancy Test5 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
X 
Vital Signs/Growth Parameters6 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
Physical Exam 
 
X 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
 
 
X4 
 
 
X4 
 
X4 
AD Severity Assessments7 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
Blood Sample Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/differential 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Comprehensive Metabolic Panel 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
DNA8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
      Serum Biomarkers 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
  PBMC Immunoprofiling 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
Skin Sampling Location Photographs 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
Skin Swab Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S. aureus Abundance (Les, NL) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
Metagenomics (Les, NL) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
Microbiome 16S rRNA analysis (Les, 
NL)  
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 


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Study Portion 
RDBPC 
Open-Label 
Follow
-Up 
 
Study Visit 
Recruitment 
Screening 
Visit 
Treatment 
Initiation 
(Day 0) 
Day 3 
Day 7 
Day 14 
Day 21 
Day 28 
Day 42 
Day 56 Home 
IP Injection 
Day 70 Home 
IP Injection 
Day 77 
Day 84 Home 
IP Injection 
Day 98 Home 
IP Injection 
Day 112 
Day 182 
Follow-Up 
Phone Call 
Unscheduled 
Visit1 
Superantigen, Toxin, Lipase, and 
Protease Quantitation (Les, NL) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
Microbiome Functional Assessment9 
(Les, NL) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
Skin Tape Stripping 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipidomics 10 (Les11, NL) 
 
 
X11 
 
X 
X11 
X 
X11 
X 
 
 
X 
 
 
X11 
 
X 
Barrier Assessments12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Basal TEWL (Les, NL) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
TEWL Area Under the Curve (NL) 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
TEWL Slope of the Curve (NL) 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
Skin Biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confocal Imaging (NL)13 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
Skin Transcriptomics14  (Les, NL15)  
 
 
X15 
 
X15 
 
X 
 
 
 
 
 
 
 
 
 
X 
IP Administration 
 
 
X16 
 
 
X17 
 
X17 
X18 
X19 
X19 
 
X19 
X19 
 
 
X 
IP Distribution20 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
1. 
If medical concerns arise between regularly scheduled visits, participants will be instructed to contact study personnel and may be asked to return to the clinical site for an Unscheduled Visit. 
Participants also may be asked to complete an Unscheduled Visit for additional blood, skin swab, skin tape strip, or skin biopsy collection, as applicable, if samples are lost or destroyed, or insufficient 
yields were obtained during a previous visit or for further mechanistic and functional studies.  
2. 
The Day 3 and Day 7 Visits should be scheduled a minimum of 2 days apart. 
3. 
IP injections should occur at minimum 7 days apart. If a participant misses a dose it should be administered within 7 days from the missed dose. If the missed dose is not administered within 7 days, the 
participant will be instructed to wait until their next scheduled dose based on their original dosing schedule. 
4. 
An abbreviated medical history and physical exam will be conducted at Days 0, 3, 7, 14, 21, 28, 42, 77, 112, and Unscheduled Visits. 
5. 
A urine pregnancy test will be completed for all female participants of child bearing potential. 
6. 
Temperature, blood pressure, heart rate, and respiratory rate will be measured. Growth parameters to include height and weight will only be measured at the Screening Visit. 
7. 
AD disease severity will be assessed using the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Nottingham Eczema Severity Score (NESS) (Treatment Initiation Visit only), 
SCORing Atopic Dermatitis (SCORAD), and pruritus Numerical Rating Scale (NRS). 
8. 
DNA will only be collected from participants who did not have blood collected in a previous ADRN or ADVN study. 
9. 
Samples for functional assessment of antimicrobial activity will be stored for future analysis. 
10. All participants will have tape strips for lipidomics collected from non-lesional sites (1 set of 15/visit) at Days 0, 7, 14, 21, 28, 42, 77, and 112. 
11. Tape strips for lipidomics from lesional sites (1 set of 5 strips) will only be collected at Days 0, 14, 28, and 112. 


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12. Tape strips for barrier assessments will only be collected from non-lesional sites. These strips will be used for the non-lesional lipidomics analysis. 
13. Non-lesional skin biopsies (1x3 mm biopsy/visit) for confocal imaging will only be collected from participants at the 
 clinical site. 
14. Non-lesional and lesional skin biopsies (1x2.5 mm biopsy each/visit) for skin transcriptomics analysis will only be collected from participants at 
 sites. 
15. Non-lesional biopsies for skin transcriptomics will only be collected at Days 0 and 7. 
16. Two 300 mg dupilumab or placebo subcutaneous injections (loading dose) will be administered in the abdomen, thighs, or upper arms. The two injections should be administered in different locations 
(e.g. 2 different abdominal quadrants). 
17. One 300 mg dupilumab or placebo subcutaneous injection will be administered in the abdomen, thigh, or upper arm.  The injection site should be rotated with each dose so the same area is not injected 
twice in a row. 
18. Participants or their caregiver must administer the Day 42 injection(s) in the clinic at the Day 42 Visit if they intend to administer injections at home during the OLE. Study staff will confirm the 
participant and/or their caregiver is capable of administering injections at home during the OLE portion of the study. Participants originally randomized to the dupilumab group will receive one 300 mg 
dupilumab and one placebo subcutaneous injection. Participants originally randomized to the placebo group will receive a 600 mg loading dose (two 300 mg dupilumab subcutaneous injections). 
19. The Day 56, 70, 84, and 98 IP injections (300 mg dupilumab) will be administered by the participant or their caregiver at home or at the study clinic if the participant is uncomfortable or unable to 
administer injections at home. The injection site should be rotated with each dose so the same area is not injected twice in a row. 
20. IP will be distributed to participants on Day 42 for the Day 56 and 70 doses and on Day 77 for the Day 84 and 98 doses if they choose to administer injections at home. 
 

ICF_003.pdf: 
National Institute of Allergy and Infectious Diseases (NIAID)/Protocol ADRN-09 
  
 
IRB Approved Informed Consent Form 
 
  
 
 
 
  
WIRB Approved Version 3.0 29 August 2019  
 
Page 1 of 18 
  
 
MEMORANDUM via email 
 
To: ClinicalTrials.gov Protocol Registration and Results System (PRS) 
  
 
 
 
 
 
 
 
Subject: ClinicalTrials.gov Record (ClinicalTrials.gov Identifier: NCT03389893) titled, 
Effect of Dupilumab (Anti-IL4Rα) on the Host-Microbe Interface in Atopic 
Dermatitis, Dupilumab Study (ADRN-09)  
 
 
 
Submitted for posting is an IRB approved informed consent form version of ADRN-09 (Version 
3.0, August 29, 2019). 
 
 


National Institute of Allergy and Infectious Diseases (NIAID)/Protocol ADRN-09 
  
 
IRB Approved Informed Consent Form 
 
  
 
 
 
  
WIRB Approved Version 3.0 29 August 2019  
 
Page 2 of 18 
 
TITLE:  
Effect of Dupilumab (anti-IL4Rα) on the Host-Microbe Interface in Atopic 
Dermatitis 
 
PROTOCOL NO.: 
ADRN 09 
WIRB® Protocol #20172480 
 
SPONSOR: 
National Institute of Allergy and Infectious Diseases (NIAID) 
 
INVESTIGATOR: 
Name 
Address 
City, State  Zip 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Name 
Number (24 hour number required) 
 
 
YOUR PARTICIPATION IS VOLUNTARY 
We will explain this research study to you. You may ask as many questions as you need. 
• 
Taking part in this study is your decision. 
• 
You may change your mind at any time. 
• 
You will be given a signed copy of this consent form for your records.  
 
You are being asked to participate in this study because you have moderate-to-severe atopic dermatitis (AD for 
short, and also called eczema), and you currently have active areas (lesions) on your skin.  
 
INTRODUCTION/BACKGROUND 
AD is a disease with dry, scaly, itchy skin. People with AD often have problems with repeat bacterial and viral skin 
infections. These repeat infections are often caused by a specific bacteria known as, Staph aureus, or just Staph.  
 
People with chronic AD often use long-term topical or oral treatments to help control their disease symptoms. 
Using these medications over long periods of time can have side effects on the body. For this reason, new 
treatment options are being researched, especially for patients whose symptoms are not controlled by existing 
medications.  
 
Dupilumab is a new treatment recently approved by the Food and Drug Administration (FDA). It is for the 
treatment of moderate-to-severe AD in adults whose AD symptoms are not well-controlled with topical 
medications. 
 
PURPOSE OF THE STUDY 
The purpose of this study is to determine how dupilumab affects the amount of bacteria on the skin, the skin’s 
water loss, and the immune system.  
 


National Institute of Allergy and Infectious Diseases (NIAID)/Protocol ADRN-09 
  
 
IRB Approved Informed Consent Form 
 
  
 
 
 
  
WIRB Approved Version 3.0 29 August 2019  
 
Page 3 of 18 
STUDY COMPONENTS 
This study is funded and sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), through the 
Atopic Dermatitis Research Network (ADRN). 
 
This study will enroll 99 participants, 18 to 75 years of age. Participants will be enrolled from up to 16 centers 
across the United States. All participants will have chronic moderate-to-severe AD. 
 
This study has two main portions. In the first portion of the study, you will be randomly assigned, like flipping a 
coin, to receive either the active study medication or the placebo (a placebo does not contain active study 
medication). Neither you nor your study doctor and team, will know which treatment you are receiving. During this 
portion, 2 out of 3 participants will receive dupilumab, the active study medication, and 1 out of 3 participants will 
receive placebo. You will not be able to choose which treatment you receive. The first portion of this study will last 
for 6 weeks. During this first portion of the study, you will receive your treatment by injection, just under the skin 
every other week (three doses). Two injections (loading dose) will be given on the first day of treatment; the rest 
of your doses during this portion of the study will only require one injection.  
 
The second portion of the study will last for 10 weeks. During the second portion of the study, all participants will 
receive dupilumab, the study medication. This portion is called an open-label extension, because everyone will 
know that you are receiving dupilumab and no one will be receiving the placebo. Dupilumab will be given every 
other week for five doses. On the first day of the open-label portion of the study, two injections will be given in the 
clinic (loading dose). The rest of the doses will only require one injection and may be given at home by you or a 
caregiver that you choose. Your study doctor will teach you and/or your caregiver how to inject the study medicine 
during the first portion of the study. It is given just like diabetics give themselves insulin at home, with a tiny 
needle into a pinched up part of your skin. If you are not comfortable administering injections to yourself at home 
you will have the option to return to [Site name] to have the study doctor or another qualified medical staff 
member perform the injection for you. 
 
Your participation in the study will last about six to seven months. The study will require 10 visits to [Site Name] 
and 1 telephone visit. If you are using certain medications/therapies at your first clinic visit, you may be asked to 
return for another clinic visit after you have stopped using those medications/therapies. The study doctor will 
review the medications/therapies you are currently using to decide if they are safe to stop using while participating 
in the study. You must agree to stop using any prohibited medications/therapies while participating in the study. 
 
If you agree to participate in the study, you will be asked to avoid showering within 24 hours of your clinic visits. 
You will also be asked to avoid using hot tubs during your participation in the study and to avoid using chlorinated 
swimming pools within 24 hours of your clinic visits. The study staff will provide you with a card that lists these 
reminders for you to take home. 
 
If you are of reproductive potential and sexually active, you will be asked to use birth control during this study 
because of unknown risks to your unborn child. Acceptable methods of birth control for females include hormonal 
contraceptives, intrauterine device, double barrier contraception (i.e., condom plus diaphragm), surgical 
sterilization or surgically sterilized partner. Acceptable methods of birth control for males include barrier methods 
with vaginal spermicide, surgical sterilization or surgically sterilized partner, or having a female partner practicing 
an approved birth control method for females, as described previously. If you do become pregnant or you are a 
male participant and your partner becomes pregnant during the study, we ask that you report the pregnancy to 
the study staff. If you are a male and you and your partner conceive a child, you may continue your participation in 
the study; we will ask you, and your partner if she agrees, to provide information regarding the pregnancy and the 
birth and health of your child. If you are a female and you become pregnant, you may no longer participate in the 
study; you will however be asked to provide information regarding your pregnancy and the birth and health of 
your child. This information about pregnancy, birth, and child health is important because it helps researchers 
better understand potential effects of dupilumab on pregnant women and their fetuses. You may provide this 


National Institute of Allergy and Infectious Diseases (NIAID)/Protocol ADRN-09 
  
 
IRB Approved Informed Consent Form 
 
  
 
 
 
  
WIRB Approved Version 3.0 29 August 2019  
 
Page 4 of 18 
information yourself, or give permission to your health care provider or obstetrician to give it directly to your study 
doctor. 
 
If you agree to provide this information, you will be contacted until two weeks after your child’s birth. You will be 
asked to report any medical problems that you (if you are a female), your partner (if you are a male), or your baby 
experience during this time to your study doctor. If you decide at any time that you would no longer like to provide 
information regarding the pregnancy and the birth and health of your child, you may withdraw your consent. 
 
You (if you are a female) or your partner (if you are a male) and your child will not be asked to undergo any tests 
besides those that your health care provider, obstetrician, or pediatrician would normally perform in providing 
care during pregnancy, or taking care of your newborn child. If your study doctor believes that additional tests are 
needed to ensure the safety of you (female), your partner (male), and your child, you will be notified, and you will 
have the right to agree to or refuse these additional tests. 
 
The following procedures will occur during the screening, treatment, and follow-up portions of this study: 
 
Screening Visit 
Your initial visit to the center will take about 2 hours to complete. During the visit, the following will occur: 
• 
Consent: We will explain the study to you. You will be given time to read the consent form and ask 
questions. Once all of your questions are answered you will sign the consent form, if you want to 
participate in the study. 
• 
Questionnaires: If you consent, then you will answer some questions about your contact information. The 
study team will then ask you some questions to determine whether you are eligible for this study. The 
questionnaires are not tests. There are no right or wrong answers to the questions. If you do not 
understand certain questions, you may ask the study staff members for more information.  
• 
Physical Exam: You will receive a physical exam by a study doctor or another qualified staff member. The 
purpose of the exam is to make sure that you meet the health requirements for the study. During the 
exam, a member of the study staff will ask you questions about your health and your AD. 
• 
Medication/Therapy Use Review: A member of the study staff will ask about the medications you have 
recently taken and therapies you have used. The use of certain medications/therapies may mean that 
your study visit will need to be rescheduled. You can come back for your visit after you come off those 
certain medicines/therapies for a set amount of time, which is called a “washout” period. If you are 
unwilling or unable to washout of certain medications/therapies, you will not be eligible to participate in 
the study.  
• 
Pregnancy Test: If you are a female participant of child-bearing potential, you will be asked to give a small 
sample of urine for a pregnancy test. Results of the pregnancy test will be given to you. If your pregnancy 
test is positive, you will not be allowed to participate in the study.  
• 
Vital Signs and Growth Parameters: A member of the study staff will check your vital signs (blood 
pressure, heart rate, breathing rate, and temperature), height, and weight.  


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• 
Blood Collection: About half of a tablespoon of blood will be collected. All of the blood can usually be 
collected in 1 needle stick. Your blood samples will be labeled with a number only, and not your name. 
Several types of tests will be performed on your blood. One test, called a complete blood count, or CBC, 
gives important information about the kinds and numbers of cells in the blood, especially red blood cells, 
white blood cells, and platelets. Another test, called a complete metabolic panel, or CMP, provides your 
study doctor with information on your metabolism and the health of your kidneys and liver. These tests 
will help to determine if you are eligible to participate in the study. You will receive the results of these 
two tests.  
• 
Moisturizer Use: If you are eligible for the study, you will be asked to use a moisturizer at least twice a 
day for at least 7 days before your next visit. The study team will tell you which moisturizers can be used.  
 
Treatment Initiation Visit 
After you finish the Screening Visit, if you are eligible, you will be asked to complete the Treatment Initiation Visit 
procedures. The Treatment Initiation Visit will occur 8-28 days after the Screening Visit, when you have finished 
the 7 days of moisturizer use. This visit will take about 2.5 hours to complete. During the visit, the following will 
occur: 
• 
Questionnaires 
• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Pregnancy Test  
• 
Vital Signs 
• 
Adverse event assessment 
• 
Blood collection: About 4 tablespoons of blood will be collected. All of the blood can usually be collected 
in 1 needle stick. Your blood samples will be labeled with a number only, and not your name. Several 
types of research tests will be performed on your blood throughout this study. Blood tests will be done to 
look at your blood before and after you take the study medicine to see how the treatment affects your 
immune system’s response. Additional tests will look at markers in your blood related to the severity of 
your AD. We will not give you the results of these blood tests, which are for research and not for 
diagnostic purposes. Blood will be collected to see how your genes and other inherited traits affect your 
response to the study medicine. If you provided blood for genetic studies under a previous ADRN or ADVN 
study and agreed that your samples or data could be used for future studies, additional blood will not 
need to be collected for these genetic studies. We will not give you the results for your genetic tests 
which are exploratory and not for diagnostic purposes.  
• 
Skin Swab Collection: Skin swab samples will be collected from your arm, leg or trunk. These samples will 
be collected by rolling a sterile swab over the skin. The procedure will take about a minute and does not 
hurt. Up to 6 skin swabs will be collected during your study visit. The swabs will be used to look at bacteria 
on your skin. Your skin swabs that are collected before you receive any medication or placebo will be 
compared to your skin swabs that are collected after you take the study medication/placebo. We will not 
give you the results of these tests which are for research and not for diagnostic purposes.  
• 
Skin Tape Stripping: Skin tape strip samples will be collected from your arm, leg or trunk. If you have a 
history of serious or life threatening reactions to latex, tape, or adhesives, please tell the study team as 
you will not be eligible for the study. Up to 20 tape strip samples will be collected during your study visit. 
To collect these samples, your skin will be held tight and the tape strip applied. Light pressure will be 
applied, and then the tape strip will be slowly removed. The first 5 tape strips will be collected from a 
single lesional location. The remaining 15 strips will be taken from a single non-lesional location that is 
next to the lesional location. A different tape strip will be used each time. Skin tape strips will be used to 
determine the composition of your skin. Your skin tape strips that are collected before you receive any 
medication or placebo will be compared to your skin tape strips that are collected after you receive 
medication or placebo. We will not give you the results of these tests which are for research and not for 
diagnostic purposes. This procedure may be slightly uncomfortable due to the irritation to the skin from 


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the tape strips being applied and removed many times in the same place.  
• 
Skin Barrier Assessments: Study staff will use a machine, called an Aquaflux, to measure water loss from 
your skin. The procedure will involve the study staff placing a small probe on your skin for a few seconds. 
This procedure does not hurt. The study staff will take measurements with the Aquaflux machine before 
and during skin tape stripping. We will not give you the results of the skin barrier assessment test, which 
is for research and not for diagnostic purposes. 
• 
Skin Biopsy Collection: If you are allergic to numbing medications such as Lidocaine or Novocain or have a 
history of keloid-like scars (keloids are extra scar tissue that can appear after your skin is injured or 
becomes swollen, they usually appear as lumpy skin with a smooth surface), you will not be eligible to 
participate in the study. [URMC One piece of your skin up to 3 mm in diameter or the size of 3 pin heads, 
will be collected. Non-URMC Up to 2 pieces of your skin, up to 2.5 mm in diameter or the size of ~3 pin 
heads, will be collected]. Biopsy sample(s) will be taken from your arm, leg or trunk. The area will first be 
cleaned and numbed by injecting a numbing medicine through a tiny needle. Next the biopsies will be 
taken with an instrument called a sterile biopsy punch, which is tube-shaped. The instrument is rotated 
downward through the skin using a twirling motion. The procedure is quick and does not hurt since the 
skin is numbed first. The biopsy site(s) will need to be kept dry for the first 24-48 hours after the 
procedure. The study staff will provide you with instructions on caring for the biopsy site(s) at home. Skin 
biopsy samples will be used to look at how your skin responds to the study medication or the placebo. 
Your skin biopsies that are collected before you receive any medication or placebo will be compared to 
your skin biopsies that are collected after you receive medication or placebo. 
• 
Photographs of collection sites: Photographs will be taken of the sites where the skin swabs, tape strips, 
and biopsies will be collected. This will allow the study staff to identify the collection sites at later visits. 
Your face will not be included in any photos that are taken so you cannot be identified.  
• 
Injection of study medication or placebo: The injection of the study medication/placebo will be given 
subcutaneously (just under your skin, and not in your muscle). You will be randomly assigned to receive 
either the study medication or placebo. There will be a 2-in-3 chance that you will receive study 
medication and a 1-in-3 chance you will receive a placebo. Neither you nor the study staff will know which 
group you are assigned to. Two subcutaneous injections of either the study medication or placebo will be 
injected into either the skin of your belly, thighs, or upper arms by the study doctor or another qualified 
medical staff member. This procedure may be slightly uncomfortable due to the needle stick. The study 
staff will teach you or your caregiver how to inject the study medicine so that you can inject it at home 
during the open-label portion of the study, if you choose to do so. 
 
Day 3 Visit 
You will be asked to return to the clinic about 3 days after you begin your treatment. The Day 3 Visit will take 
about 1.5 hours to complete. During this visit, the following will occur:  
• 
Questionnaires 
• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Confirmation of Pregnancy Status  
• 
Vital Signs 
• 
Skin Swab Collection, up to 6 skin swabs 
• 
Skin Barrier Assessment 
• 
Photographs 
• 
Adverse event assessment 
 
Day 7 (Week 1) Visit 
You will be asked to return to the clinic about 7 days after you begin your treatment. The Day 7 Visit will take 
about 2.5 hours to complete. During this visit, the following will occur: 
• 
Questionnaires 


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• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Confirmation of Pregnancy Status  
• 
Vital Signs 
• 
Adverse event assessment 
• 
Blood Collection, about one and a half tablespoons for research tests. We will not give you the results of 
these blood tests, which are for research and not for diagnostic purposes. 
• 
Skin Swab Collection, up to 6 skin swabs 
• 
Skin Tape Stripping, up to 15 non-lesional skin tape strips 
• 
Skin Barrier Assessment before and after tape stripping  
• 
Skin Biopsy Collection, [URMC 1 skin biopsy non-URMC up to 2 skin biopsies] 
• 
Photographs 
 
Day 14 (Week 2) Visit 
You will be asked to return to the clinic about 14 days after you begin your treatment. The Day 14 Visit will take 
about 2.5 hours to complete. During this visit, the following will occur: 
• 
Questionnaires 
• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Pregnancy Test 
• 
Vital Signs 
• 
Adverse Event assessment 
• 
Blood Collection, about 4 tablespoons for research tests. We will not give you the results of these blood 
tests, which are for research and not for diagnostic purposes. 
• 
Skin Swab Collection, up to 6 swabs 
• 
Skin Tape Stripping, up to 15 non-lesional and 5 lesional skin tape strips 
• 
Skin Barrier Assessment before and after tape stripping 
• 
Photographs  
• 
Injection of study medication or placebo (1 injection) 
o 
The study staff will teach you or your caregiver how to inject the study medicine so that you can 
inject it at home during the open-label portion of the study, if you choose to do so. At this visit 
you may choose to give the injection yourself, or have your caregiver give the injection, under 
the supervision of a qualified staff member. 
 
Day 21 (Week 3) Visit 
You will be asked to return to the clinic about 21 days after you begin your treatment. The Day 21 Visit will take 
about 2.5 hours to complete. During this visit, the following will occur: 
• 
Questionnaires 
• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Confirmation of Pregnancy Status  
• 
Vital Signs 
• 
Adverse Event Assessment 
• 
Blood Collection, about one and a half tablespoons for research tests. We will not give you the results of 
these blood tests, which are for research and not for diagnostic purposes. 
• 
Skin Swab Collection, up to 6 swabs 
• 
Skin Tape Stripping, up to 15 non-lesional skin tape strips 
• 
Skin Barrier Assessments before and after tape stripping 
• 
Skin Biopsy Collection, [URMC 1 skin biopsy non-URMC up to 2 skin biopsies]  


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• 
Photographs 
 
Day 28 (Week 4) Visit 
You will be asked to return to the clinic about 28 days after you begin your treatment. The Day 28 Visit will take 
about 2.5 hours to complete. During this visit, the following will occur: 
• 
Questionnaires 
• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Pregnancy Test 
• 
Vital Signs 
• 
Adverse Event assessment 
• 
Blood Collection, about 4 tablespoons for research tests. We will not give you the results of these blood 
tests, which are for research and not for diagnostic purposes. 
• 
Skin Swab Collection, up to 6 swabs 
• 
Skin Tape Stripping, up to 15 non-lesional and 5 lesional skin tape strips 
• 
Skin Barrier Assessments before and after tape stripping 
• 
Photographs 
• 
Injection of study medication or placebo (1 injection) 
o 
The study staff will teach you or your caregiver how to inject the study medicine so that you can 
inject it at home during the open-label portion of the study, if you choose to do so. At this visit 
you may choose to give the injection yourself, or have your caregiver give the injection, under 
the supervision of a qualified staff member. 
 
Day 42 (Week 6) Visit 
You will be asked to return to the clinic about 42 days after you begin your treatment. The Day 42 Visit will take 
about 2 hours to complete. During this visit, the following will occur: 
• 
Questionnaires 
• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Pregnancy Test 
• 
Vital Signs 
• 
Adverse Event assessment 
• 
Blood Collection, about one and a half tablespoons for research tests. We will not give you the results of 
these blood tests, which are for research and not for diagnostic purposes. 
• 
Skin Swab Collection, up to 6 swabs 
• 
Skin Tape Stripping, up to 15 non-lesional skin tape strips 
• 
Skin Barrier Assessments before and after tape stripping 
• 
Photographs 
• 
Two injections of study medication or placebo. Participants who were previously receiving the placebo 
will receive two injections of the study medication. Participants who were previously receiving the study 
medication will receive one injection of the study medication and one injection of placebo. This will help 
make sure you and your study team do not know which treatment you were receiving during the first 
portion of the study.  
o 
The study staff will teach you or your caregiver how to inject the study medicine so that you can 
inject it at home during the open-label portion of the study. The study staff will ask you or your 
caregiver to give your injection at this visit, so that they can ensure you are able to safely 
complete injections at home during the open-label extension portion of the study, if you choose 
to do so. 
• 
If you choose to administer study medication at home, you will be provided with two doses of study 
medication to take home for administration on Days 56 and 70. 


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Day 56 (Week 8) Home Study Medication Injection 
You or your caretaker will give one injection of study medication. If you are not comfortable administering 
injections to yourself at home, you will have the option to return to [Site name] to have the study doctor or 
another qualified medical staff member perform the injection for you. 
 
Day 70 (Week 10) Home Study Medication Injection 
You or your caretaker will give one injection of study medication. If you are not comfortable administering 
injections to yourself at home, you will have the option to return to [Site name] to have the study doctor or 
another qualified medical staff member perform the injection for you. 
 
Day 77 (Week 11) Visit 
You will be asked to return to the clinic about 77 days after you begin treatment for the first portion of the study 
(35 days after you begin the open-label portion of the study). The Day 77 Visit will take about 2 hours to complete. 
During this visit, the following will occur:  
• 
Questionnaires 
• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Pregnancy Test 
• 
Vital Signs 
• 
Adverse Event Assessment 
• 
Blood collection, about one and a half tablespoons for research tests. We will not give you the results of 
these blood tests, which are for research and not for diagnostic purposes. 
• 
Skin Swab Collection, up to 6 skin swabs 
• 
Skin Tape Stripping, up to 15 non-lesional skin tape strips 
• 
Skin Barrier Assessments before and after tape stripping 
• 
Photographs 
• 
If you choose to administer study medication at home, you will be provided with two doses of study 
medication to take home for administration on Days 84 and 98. 
 
Day 84 (Week 12) Home Study Medication Injection 
You or your caretaker will give one injection of study medication. If you are not comfortable administering 
injections to yourself at home, you will have the option to return to [Site name] to have the study doctor or 
another qualified medical staff member perform the injection for you. 
 
Day 98 (Week 14) Home Study Medication Injection 
You or your caretaker will give one injection of study medication. If you are not comfortable administering 
injections to yourself at home, you will have the option to return to [Site name] to have the study doctor or 
another qualified medical staff member perform the injection for you. 
 
Day 112 (Week 16) Visit 
You will be asked to return to the clinic about 112 days after you begin treatment in the first portion of the study 
(10 weeks after you begin your open label treatment). The Day 112 Visit will take about 2 hours to complete. 
During this visit, the following will occur:  
• 
Questionnaires 
• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Pregnancy Test 
• 
Vital Signs 
• 
Adverse Event Assessment 


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• 
Blood collection, about one and a half tablespoons for research tests. We will not give you the results of 
these blood tests, which are for research and not for diagnostic purposes. 
• 
Skin Swab Collection, up to 6 skin swabs 
• 
Skin Tape Stripping, up to 15 non-lesional and 5 lesional skin tape strips 
• 
Skin Barrier Assessments before and after tape stripping 
• 
Photographs 
 
Day 182 (Week 26) Follow-Up Phone Call 
A study staff member will call you about 182 days after you begin treatment (12 weeks after you receive your last 
dose of study medication). The call will take about 30 minutes. You will be asked about your AD, any new 
symptoms you have experienced since your last clinic visit, and any medications/therapies you have used since 
your last visit. You will be asked if you have consistently used birth control and if you have tested positive to a 
pregnancy test since your last visit if you are a female participant. You will be asked if your partner has tested 
positive to a pregnancy test since your last clinic visit if you are a male. If you have asthma, you will be reminded 
not to change your asthma medications without approval from your doctor. 
 
Unscheduled Visit 
You may be asked to return for an Unscheduled Visit as needed, if your AD worsens or other concerns arise 
between regularly scheduled visits. The site staff may also ask you to return to the clinic to provide additional 
samples for more detailed testing, or if samples were lost or destroyed, or if the amounts of samples collected at a 
previous visit were not enough to complete the testing. The type and amount of each sample may vary at each 
Unscheduled Visit, and will be explained prior to your clinic visit. 
 
If an Unscheduled Visit occurs, the following procedures will occur: 
• 
Questionnaires 
• 
Physical Exam 
• 
Medication/Therapy Use Review 
• 
Pregnancy Test, per investigator discretion 
• 
Vitals  
 
The following items may occur based on the reason for your Unscheduled Visit: 
• 
Skin Barrier Assessments 
• 
Blood Collection: Up to 4 tablespoons of blood may be collected 
• 
Skin Tape Stripping: Up to 15 non-lesional and 5 lesional skin tape strips may be collected  
• 
Skin Swab Collection: Up to 6 skin swabs may be collected 
• 
Skin Biopsy Collection: [URMC 1 skin biopsy may be collected non-URMC Up to 2 skin biopsies may be 
collected] 
 
RISKS and DISCOMFORTS 
Procedures in this research study may involve risks that are not possible to predict. You will be informed of any 
new risks that may be identified during the study. Below is a description of the risks we know about for each 
procedure. Please ask your study doctor or the research staff to explain any procedures or risks that you do not 
understand. 
 
Questionnaires 
You may find that some of the questions are too personal. You do not have to answer any questions that make you 
feel uncomfortable. There is also a possibility that your answers may be read by others outside of the study. Your 
participant identification number, not your name, is put on the questionnaires.  
 
Physical Exam 


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There are no known risks for the physical exam. 
 
Stopping Medication/Therapy Use 
Stopping medications/therapies during this study may cause your AD to get worse.  
 
Pregnancy Test 
There are no known risks for the pregnancy test. 
 
Vital Signs and Growth Parameters 
There are no known risks for having your vital signs and growth parameters checked. 
 
Skin Barrier Assessments 
There are no known risks for the skin barrier assessments.  
 
Blood Collection 
The risks of having blood taken may include pain, bleeding, or bruising. Lightheadedness and fainting rarely occur. 
A numbing agent may be placed on the skin before the blood draw to numb the area and reduce the pain of the 
stick. Side effects of the numbing agent (mainly skin rash) are unlikely, but may occur. 
 
Skin Swab Collection 
There are no known risks for the skin swab collection.  
 
Skin Tape Stripping 
Skin tape stripping may cause mild redness and irritation of the skin where the tape was applied. Redness and 
irritation should disappear after about 12 hours. There is a small risk of infection at the tape stripping site. There is 
also a possible risk of rare allergic reactions to the tape. If you have a history of serious or life-threatening allergic 
reactions to tape, or adhesives, you will not be able to participate in the study.  
 
Skin Biopsy Collection 
The risks of a skin biopsy include pain and the possibility of swelling, bleeding, and infection. A tiny scar may form 
at the biopsy site. In very rare instances, injection of the lidocaine to numb the skin can cause allergic reactions, 
which can be mild to life-threatening. These can range from hives, itching, swelling of the throat, mouth, or lips, 
difficulty breathing or significant drop in blood pressure. If you are allergic to lidocaine or have a history of keloid-
like scars, you will not be eligible to participate in the study. 
 
Injection of Study Medication and/or Placebo 
The most common risks (occurring in greater than or equal to 1% of participants) associated with injection of the 
study treatment are: 
• 
Injection site reactions including 
o 
Pain 
o 
Tenderness 
o 
Bruising 
o 
Swelling 
o 
Redness 
o 
Rash 
o 
Hives 
o 
Itch 
o 
Inflammation (swelling) 
• 
Eye conditions including: 
o 
Conjunctivitis (redness and swelling of the outermost layer of the white part of the eye and the 
inner surface of the eyelid) 


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o 
Blepharitis (inflammation or swelling of the eyelid) 
o 
Keratitis (inflammation or irritation of the cornea covering the iris and pupil) 
o 
Eye pruritus (itching) 
o 
Dry eye 
• 
Oral herpes and other herpes simplex infections 
 
Rare risks (occurring in less than 1% of participants) include hypersensitivity and cardiovascular thromboembolic 
events. For AD patients, increased eosinophil count (eosinophils are a type of white blood cell that are linked to 
inflammation) is also rare although it is found to be more common in patients with asthma and chronic 
rhinosinusitis.  
 
Hypersensitivity is a condition in which your body’s immune system over-reacts to receiving the study treatment. 
Hypersensitivity may result in serum sickness (an allergic response from your body) or serum sickness-like reaction 
with fever, rash, and joint symptoms. Hypersensitivity may result in an allergic reaction. Allergic reactions can be 
mild to life-threatening. These can range from hives; itching; swelling of the throat, mouth, or lips; difficulty 
breathing or significant drop in blood pressure. Sometimes life-threatening allergic reactions are called 
anaphylaxis. If you have a history of serious or life-threatening allergic reactions (anaphylaxis) to any of the 
ingredients in the study medication or placebo, you will not be able to participate in the study. 
 
Some people on study treatment may have an increase in the number of eosinophils in their blood. The increase in 
eosinophils is temporary.  
 
Cardiovascular thromboembolic events are events such as heart attack and stroke. These events are caused by a 
blood clot which blocks blood flow through an artery in the heart or brain. 
 
If you have asthma you will be asked to continue taking your current asthma treatment medications as prescribed 
by your doctor. Stopping or decreasing your asthma medications while on study treatment could cause you to have 
an asthma attack.  
 
It is not known whether the immune response to a parasite infection is affected by study treatment, but this is a 
possible risk. The study team will explain to you the types of situations that could put you at high risk for getting a 
parasite infection.  
 
Genetic Studies 
As part of this study, we will be collecting genetic information about you and the resulting data will be sent to the 
National Institutes of Health (NIH) repository (a repository is a place where data and/or specimens are stored, 
maintained and shared for future use). Genetic data will be shared with other researchers at many institutions 
through a central repository kept at the National Center for Biotechnology Information at the National Institutes of 
Health. Because data is shared, other researchers may use the data to study other diseases or conditions.  
 
The data from this study will be coded and traditional identifiers (name, birth date, initials, etc.) will be removed. 
Your study doctor may keep the key to the code that links your name to the data. However, the National Institutes 
of Health will never receive this code or any other information that could identify you. The clinical sites involved in 
this study will not be told what types of research will be done with the data that is sent to the repository.  
 
Any researcher who uses the data will follow rules on confidentiality restrictions. Even though we will remove 
traditional identifying information (name, birth date, initials, etc.), there is a very small chance this information 
could accidentally become known to you, the study doctor, or others.  
 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it illegal for health 
insurance companies, group health plans, and most employers to discriminate against you based on your genetic 


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information. Be aware that this Federal law does not protect you against genetic discrimination by companies that 
sell life insurance, disability insurance, or long-term care insurance. GINA also does not protect you against 
discrimination if you have already been diagnosed with the genetic disease being tested.  
 
Although we have made every effort to protect your identity, there is a small risk of loss of confidentiality. If the 
results of these studies of your genetic makeup were to be accidentally released, it might be possible that the 
information we will gather about you as part of this study could become available to an insurer or an employer, or 
a relative, or someone else outside the study. Even though there are discrimination protections in both state and 
Federal law, there is still a small chance that you could be harmed if a release occurred. 
 
POTENTIAL BENEFITS 
If you agree to take part in this study, there may be no direct medical benefit to you. Your AD may or may not 
improve while in this study. There is a possibility that your disease symptoms will improve while you are receiving 
the study medication. Given 33% of participants will receive placebo during the first portion of the study, and you 
will be asked to withhold your current AD management medications, your disease may get worse. The information 
learned from this study may someday benefit the future treatment and care of people with AD. 
 
ALTERNATIVES TO PARTICIPATION 
There are other options available for you if you decide not to enroll in this study. You may receive treatment from 
a doctor without participating in this study. Your doctor may prescribe dupilumab for you since it is an FDA 
approved medication that is available to the public. You may choose to enroll in another study. You do not have to 
participate in this study in order to receive treatment at [Site Name]. 
 
VOLUNTARY WITHDRAWAL FROM STUDY 
You may decide not to take part in the study or to leave the study at any time. If you decide not to participate, or 
to leave the study, there is no penalty or loss of benefits in your routine medical care or any other benefit(s) that 
you would otherwise receive.  
 
If you leave the study prior to completion, we may ask you to complete a final assessment by phone. This phone 
call will be to confirm that any ongoing signs and symptoms related to your participation in the study are resolved. 
Study staff will be able to answer any questions you may have about your AD.  
 
If you decide to leave the study or if you decide you do not want us to keep your contact information, you can call 
[Number] to remove your information from our list. You can also write to us at [Site Address] to let us know that 
you want to leave the study. 
 
REASONS WHY YOU MAY BE TAKEN OFF STUDY WITHOUT YOUR CONSENT 
You may be removed from the study without your consent at any time. Reasons why you may be removed from 
the study include, but are not limited to, the following: 
• 
The study doctor feels it is not in your best interest to continue in this study.  
• 
You are unable to complete required study procedures. This may be due to the development of a new 
disease, becoming pregnant, or starting treatment(s) not allowed for study participants. 
• 
The study is stopped by [Site Name], the National Institute of Allergy and Infectious Diseases, or other 
health authorities. 
• 
You do not comply with study procedures or follow study rules.  
 
COSTS TO THE PARTICIPANT (YOU) 
There will be no charge to you or your health insurance company for any costs for the study medication or 
placebo. There will be no cost to you or your health insurance company for costs which are directly related to this 
study’s procedures:  
• Blood draw 


National Institute of Allergy and Infectious Diseases (NIAID)/Protocol ADRN-09 
  
 
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• Skin Swab Collection 
• Skin Tape Stripping 
• Skin Barrier Assessments 
• Skin Biopsy Collection 
 
The normal costs related to your AD care during the course of the study will be up to you and/or your insurer: 
• Physician visits outside of study visits 
• Emergency room or urgent care visits 
• Hospitalizations 
 
PAYMENTS (REIMBURSEMENT) 
You will be compensated for the time and effort that you put into this study. 
 
You will receive $35 for completing questionnaires, the physical exam, and pregnancy testing (if applicable) at each 
visit. You will receive $25 (per visit) if you complete the blood collection, $10 (per visit) if you complete the skin 
swab collection (up to 6 skin swabs), $25 (per visit) if you complete the skin tape strip collection (up to 20 tape 
strips), and $15 (per visit) if you complete the skin barrier assessments. You will receive $50 (per visit) per skin 
biopsy. Refer to the Table below for payments for each study visit.  
 
 
Screening 
Treatment 
Initiation 
Day 
3 
Day 
 7 
Day 
 14 
Day 
21 
Day 
28 
Day 
42 
Day 
77 
Day 
112 
Day 
182 
Unscheduled 
Visit 
Questionnaires, 
physical exam, 
pregnancy 
testing (as 
applicable), 
vital signs 
$35 
$35 
$35 
$35 
$35 
$35 
$35 
$35 
$35 
$35 
 
$35 
Blood 
Collection 
$25 
$25 
 
$25 
$25 
$25 
$25 
$25 
$25 
$25 
 
$25 
Skin Swab 
Collection 
 
$10 
$10 
$10 
$10 
$10 
$10 
$10 
$10 
$10 
 
$10 
Skin Tape Strip 
Collection 
 
$25 
 
$25 
$25 
$25 
$25 
$25 
$25 
$25 
 
$25 
Skin Barrier 
Assessments 
 
$15 
$15 
$15 
$15 
$15 
$15 
$15 
$15 
$15 
 
$15 
[URMC Skin 
Biopsy 
Collection] 
 
$50 
 
$50 
 
$50 
 
 
 
 
 
$50 
[non-URMC 
Skin Biopsy 
Collection] 
 
$50/bx* 
 
$50/
bx* 
 
$50/
bx 
 
 
 
 
 
$50/bx* 
Study Drug 
Injection 
 
$25 
 
 
$25 
 
$25 
$25 
 
 
 
 
Phone Call 
 
 
 
 
 
 
 
 
 
 
$10 
 
[URMC Total] 
$60 
$185 
$60 
$160 
$13
5 
$160 
$13
5 
$135 
$110 
$110 
$10 
Up to $160 
[non-URMC 
Total] 
$60 
$235 
$60 
$210 
$13
5 
$210 
$13
5 
$135 
$110 
$110 
$10 
Up to $210 
 
*Up to 2 biopsies (bx) will be collected at this visit 


National Institute of Allergy and Infectious Diseases (NIAID)/Protocol ADRN-09 
  
 
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If you are asked to return for an Unscheduled Visit to provide additional blood, skin swabs, skin tape strips, or skin 
biopsies, you will be compensated per sample. If you are requested to provide multiple sample types at the 
Unscheduled Visit, you will be compensated for each sample you provide. The table above outlines the 
compensation you will receive per sample.  
 
In the event you are asked to return to clinic for an Unscheduled Visit due to experiencing increased disease 
activity, adverse reactions to the study medication or placebo, or other concerns, you will receive $35 for each 
visit.  
 
If you choose to, or are asked to, leave the study before it is finished, you will only be compensated for the 
activities you complete. 
 
It is important to know that payment for participation in a study may be taxable income.  
 
RESEARCH-RELATED INJURY 
If you are injured or become ill because of taking part in this study, it is important to tell your study doctor [PI 
Name]. Emergency medical treatment will be available to you, through [Site Name]. You or your health insurance 
provider will be billed for the payment for any treatment you require as a result of a study-related injury. No other 
form of reimbursement is available. [Site Name] and the National Institutes of Health, including the Division of 
Allergy, Immunology, and Transplantation do not have programs to pay if you are hurt or have other bad results 
that are not the fault of the study doctors. You may contact [name] at [Number] for more information or to report 
study-related injuries.  
 
In case of injury resulting from this study, you will not lose any legal rights by signing this form. 
 
CONFIDENTIALITY  
Your medical and research records will be confidential to the extent permitted by law. Efforts will be made to keep 
your personal information private. However, we cannot guarantee complete confidentiality. You will be identified 
by a code, and personal information from your records will not be released without your written permission. You 
will not be identified in any publication or in the sharing of your data about this study.  
 
Your records may be reviewed by the United States agency financially sponsoring the research (the National Institute of 
Allergy and Infectious Diseases). This includes National Institute of Allergy and Infectious Diseases representatives, 
agents, employees, contractors, and other persons assisting in conducting, monitoring or analyzing the study. This 
includes the study monitors from Rho, Inc., [insert local IRB, if applicable], Western Institutional Review Board, Principal 
Investigator, the U.S. Food and Drug Administration (FDA), and research staff at [Site Name]. Your records may also be 
looked at by companies that are providing support for this study; this includes Regeneron Pharmaceuticals, Inc., Sanofi, 
LLC., and their affiliates. All of these people are required to keep your identity and information confidential. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time. Data may also be entered into other databanks; however, no 
information will be included that can identify you.  
 
CERTIFICATE OF CONFIDENTIALITY 
We will do everything we can to keep others from learning about your participation in this study. To help us 
protect your privacy, we have obtained a Certificate of Confidentiality from the United States Department of 
Health and Human Services (DHHS). 
 


National Institute of Allergy and Infectious Diseases (NIAID)/Protocol ADRN-09 
  
 
IRB Approved Informed Consent Form 
 
  
 
 
 
  
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With this Certificate, we cannot be forced (for example by court order or subpoena) to disclose information that 
may identify you in any federal, state, local, civil, criminal, legislative, administrative, or other proceedings. The 
researchers will use the Certificate to resist any demands for information that would identify you, except to 
prevent serious harm to you or others, and as explained below.  
 
You should understand that a Certificate of Confidentiality does not prevent you, or a member of your family, from 
voluntarily releasing information about yourself, or your involvement in this study. 
 
If an insurer or employer learns about your participation, and obtains your consent to receive research 
information, then we may not use the Certificate of Confidentiality to withhold this information. This means that 
you and your family must also actively protect your own privacy.  
 
A Certificate of Confidentiality does not represent an endorsement of the research study by the Department of 
Health and Human Services or the National Institutes of Health. 
 
PROBLEMS OR QUESTIONS 
 
 I can call  
 At  
 If I have questions or concerns about 
 
[PI Name] 
Phone:  [Phone number] 
General study questions 
 
[24 hour number] Research-related injuries or emergencies 
 
Any research-related concerns or complaints 
 
 
Western Institutional Review Board® Phone: 1-800-562-4789 
Rights of a research participant 
(WIRB®) 
or 360-252-2500 
Any research-related questions, concerns or 
complaints 
Address: 1019 39th Avenue SE 
 
If investigator/study contact cannot be reached 
Suite 120 
If I want to speak with someone other than 
Puyallup Washington 98374-2115 
Investigator, Study Contact or research staff  
E-mail: Help@wirb.com 
 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about appointment times. 
However, you may contact WIRB if the research staff cannot be reached or if you wish to talk to someone other 
than the research staff.  
 
STORAGE OF SAMPLES and/or INFORMATION FOR FUTURE USE  
We are asking your permission to store and share your unused blood, skin swabs, skin tape strips, and skin biopsies 
collected during the course of this study. This will include any secondary samples created from them. Storing and 
sharing your unused samples will mean they are available for use in future research studies. Stored samples may 
be used for tests not currently planned and new scientific discoveries may lead to new tests. Future studies may 
help researchers learn more about AD or other immunological diseases.  
 
Your blood serum samples may also be shared with companies that are providing support for this study; this 
includes Regeneron Pharmaceuticals, Inc., Sanofi, LLC., and their affiliates. 
 


National Institute of Allergy and Infectious Diseases (NIAID)/Protocol ADRN-09 
  
 
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The results of tests performed on stored samples or reports resulting from the analysis of your samples will not be 
given to you or your doctor, and they will not be put in your medical record. They will not identify you in traditional 
ways (name, birth date, initials, etc.) and will not affect your routine medical care. 
 
There is no anticipated potential benefit to you from the collection, storage, and sharing of your samples. The 
purpose of storage and sharing data is to make information available for use in health research. Collecting, storing, 
sharing information and making it available to other researchers for other studies may help people in the future. 
Although your stored research samples will not be sold, the information obtained from the research performed on 
your samples may in the future lead to the development of commercial products. You will not receive any money 
from research using your stored samples and information. 
 
Samples will be stored at National Jewish Health, University of Rochester Medical Center, University of California 
San Diego, University of Iowa, and University of Colorado. If you decide to allow storage, your samples and 
information may be stored for an unknown length of time. 
 
There may be a risk of loss of confidentiality associated with the storage and analysis of samples or the information 
resulting from the analysis of your samples.  
 
You can change your mind at any time and ask to have your samples destroyed. This request should be made in 
writing to the study doctor. If you make this request, all remaining stored samples will be destroyed. However, the 
results of any previous tests using your stored samples will be used. Your decision regarding the storage of samples 
or the information resulting from the analysis of your samples will not affect your ability to participate in this 
study.  
 


National Institute of Allergy and Infectious Diseases (NIAID)/Protocol ADRN-09 
  
 
IRB Approved Informed Consent Form 
 
  
 
 
 
  
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Please indicate your response below: 
 
I agree to the storage and sharing of my blood, skin swabs, skin tape strips, and skin biopsies for genetic tests 
not currently planned.  
 
 Yes 
 No 
 
 
 
 
Initials of Research Participant 
 
I agree to the storage and sharing of blood, skin swabs, skin tape strips, skin biopsies, and information resulting 
from the analysis of my samples for other tests not currently planned.  
 
 Yes 
 No 
 
 
 
 
 
Initials of Research Participant 
 
SIGNATURE PAGE 
 
Please sign below if you agree to take part in this study.  
 
• 
You have read the informed consent and had it explained to you 
• 
You were given the opportunity to ask questions about the information  
• 
You understand the risks and benefits of this study as explained in this consent form 
• 
You voluntarily agree to take part in the study 
 
 
 
 
 
 
 
 
Research Participant’s Name 
Research Participant’s Signature 
Date 
(Please print) 
 
Signature of person explaining and obtaining the consent: 
 
 
 
 
 
 
 
 
Name and Title 
Signature 
Date 
(Please Print) 
 
(NOTE: This consent form with the original signatures MUST be retained on file by the principal investigator. A 
signed copy must be given to the research participant. A signed copy should be placed in the research participant’s 
medical record, if applicable.)