Conditions: Dermatitis, Atopic
Keywords: Eczema
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 202
Healthy volunteers: no

Brief summary:
This study is a 2-part (parts A and B) phase 2/3 study to evaluate the safety, pharmacokinetics (PK) and efficacy of dupilumab in participants 6 months to less than 6 years of age with moderate-to-severe atopic dermatitis (AD).

Detailed description:
1. Part A (open-label, single-ascending-dose, sequential cohort phase 2 study):

   * Primary objective is to characterize the safety and PK of dupilumab administered as a single dose in pediatric participants, 6 months to less than 6 years of age, with severe AD.
   * Secondary objective is to evaluate the efficacy and immunogenicity of a single dose of dupilumab in participants 6 months to less than 6 years of age with severe AD.
2. Part B (randomized, double-blind, parallel-group, placebo-controlled phase 3 study):

   * Primary objective is to demonstrate the efficacy of multiple doses of dupilumab over 16 weeks of treatment when administered concomitantly with topical corticosteroids (TCS) in pediatric participants, 6 months to less than 6 years of age, with moderate-to-severe AD.
   * Secondary objective is to assess the safety and immunogenicity of multiple doses of dupilumab over 16 weeks of treatment when administered concomitantly with TCS in participants 6 months to less than 6 years of age with moderate-to-severe AD.

Arms:
arm 1: Age cohort 1: ≥2 years old to \<6 years old

Age cohort 2: ≥6 months to \<2 years old arm 2: The results of part A will be used to guide the selection of dose levels and dosing frequency for part B. arm 3: The results of part A will be used to guide the selection of dose levels and dosing frequency for part B. arm 4: None

Interventions: intervention 1: Dupilumab intervention 2: Matching placebo
Intervention descriptions: intervention 1: Solution for injection, subcutaneous (SC) intervention 2: Solution for injection, subcutaneous (SC)

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
R668-AD-1539 Amendment 4 
EudraCT Number: 2016-000955-28 
IND Number: 107969 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2/3 STUDY INVESTIGATING THE PHARMACOKINETICS, 
SAFETY, AND EFFICACY OF DUPILUMAB IN PATIENTS AGED 
≥6 MONTHS TO <6 YEARS WITH MODERATE-TO-SEVERE ATOPIC 
DERMATITIS 
Compound: 
Dupilumab 
Study Name: 
Liberty AD PRESCHOOL 
Clinical Phase: 
2/3 
Protocol Number: 
R668-AD-1539 
Protocol Version: 
R668-AD-1539 Amendment 4 
Amendment 4 Date of Issue: 
See appended electronic signature page for 
approval date 
Amendment 3 Date of Issue: 
Amendment 2 Date of Issue: 
22 Nov 2019 
05 Jul 2017 
Amendment 1 UK Date of Issue: 
31 March 2017 
Original Date of Issue: 
19 Dec 2016 
Scientific/Medical Monitor: 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
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NCT03346434


Clinical Study Protocol 
R668-AD-1539 Amendment 4 
 
Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 4 
Amendment 4 consists of a non-substantial change only.  Changes to protocol and affected 
sections are summarized below. 
Change 
Sections Changed 
The number of patients with moderate AD 
(IGA=3) will be capped at approximately 40 in 
order to meet the European Union (EU) regulatory 
requirement (as per commitment in the approved 
Pediatric 
Investigational 
Plan) 
to 
enroll 
approximately 120 patients with severe AD 
(IGA=4).   
Study Synopsis: Study Design 
Study Synopsis: Population 
Section 3 Study Design 
Section 4.1 Number of Patients Planned 
Section 5.5 Method of Treatment Assignment 
 
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Amendment 3 
Protocol amendment 3 is a substantial amendment seeking approval of the dose regimens for part B 
of the study.  This amendment will be submitted to the Regulatory Authorities prior to the start of 
dosing in part B.  Changes to protocol and affected sections are summarized below. 
Change 
Sections Changed 
Based on data from part A and PK simulations, as 
well as data from study R668-AD-1652, dose 
regimens were added to the protocol for part B of 
study.  In part B, patients (≥6 mos-<6 yrs) will be 
randomized to receive either placebo or dupilumab 
(200 mg for patients ≥5-<15 kg or 300 mg for 
patients ≥15-<30 kg) every 4 weeks (Q4W).   
Randomization stratification in part B was changed 
from by age group and region to by body weight, 
baseline disease severity, and region/country.  PK 
data from part A and from other completed 
dupilumab studies have shown that weight rather 
than age is the most important covariate that 
determines exposure.  Accordingly, a weight-tiered 
fixed-dose regimen was chosen for part B.  
Randomization stratified by weight will enable 
patients to receive correct dose for weight category 
and normalize exposure across weight ranges. 
Study drug treatment will be administered by study 
site personnel during part B. Added description of 
how blinding will be maintained during part B.   
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Population 
Clinical Study Protocol Synopsis: Treatments 
Clinical Study Protocol Synopsis: Statistical Plan 
Section 1.2.1 Rationale for Study Design 
Section 1.2.2 Rationale for Dose Selection 
Figure 1 Randomization Scheme (Part B) 
Section 3.1 Study Description and Duration 
Section 4.1 Number of Patients Planned 
Section 5 Study Treatments 
Section 5.1 Investigational and Reference 
Treatments 
Section 5.5 Method of Treatment Assignment 
Table 2 Schedule of Events for the Screening, 
Treatment, and Follow-Up Period (Part B), 
footnote 9. 
Section 9.1 Statistical Hypothesis 
Section 9.2 Justification of Sample Size 
Section 9.5.2.1 Primary Efficacy Analysis 
The target population with respect to disease 
severity was changed from severe AD to moderate-
to-severe AD for part B.  In initial interactions with 
a Competent Authority which were held at a time 
when there was no data on the use of dupilumab in 
the pediatric population, the sponsor was advised 
to limit the patient population to severe patients.  
Since then, dupilumab has been tested in multiple 
clinical studies in pediatric patients and shown to 
provide considerable clinical benefit to pediatric 
patients with an acceptable safety profile.  
Accordingly, the sponsor was recently advised to 
broaden the patient population to moderate-to-
severe disease by a Competent Authority.  This will 
maximize the number of patients that will benefit 
from this drug and facilitate enrollment in study. 
Title 
Clinical Study Protocol Synopsis: Objectives 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Population 
Section 1.2.1 Rationale for Study Design 
Section 2.1 Primary Objective 
Section 2.2 Secondary Objectives 
Section 3.1 Study Description and Duration 
Section 4.2 Study Population 
Section 4.2.1 Inclusion Criteria #4, 5, and 6 
Added 2-week TCS standardization period using 
low potency TCS to part B of this study.  The 
screening period must not exceed 56 days 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Treatments 
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Change 
Sections Changed 
(including 
TCS 
standardization). 
TCS 
standardization 
ensures 
only 
patients 
with 
inadequate response to TCS are enrolled as patients 
who respond will be considered screen failures at 
the baseline visit.  This will enable a more accurate 
estimate of the true treatment effect of dupilumab. 
Use of medium potency steroids was changed to 
low potency steroids as required during the study. 
This age group is particularly vulnerable to the 
systemic side effects of TCS such as hypothalamic 
pituitary axis suppression due to increased 
systemic absorption resulting from a higher surface 
area to body weight ratio as compared to older 
children and adults.  Use of low potency TCS is 
expected to mitigate this risk and maximize patient 
safety. 
Clarified use of background and rescue treatments 
during the study, including treatments permitted 
and prohibited. 
Specified rescue treatment only allowed after 
day 14 in part B.  This ensures investigators give 
study drug adequate time for onset of effect before 
resorting to other available medications of rescue. 
As patients who are rescued are considered 
non-responders, this will enable an accurate 
assessment of treatment effect of the study drug.  
Medium potency TCS has been added as rescue 
treatment.  
In previous versions of this protocol, patients were 
required to have moisturizers applied at least twice 
daily during the 7 consecutive days prior to 
randomization (14/14 total applications) and 
during study. This criterion was relaxed to require 
at least 11/14 total applications prior to 
randomization for patient to be eligible. This 
change was based on feedback from investigators 
that the previous criterion was felt to be overly 
stringent in a pediatric population.  
Corrected 
post-randomization 
duration 
of 
application of moisturizers for part B to 28 weeks. 
A pre-specified algorithm will be used to classify 
rescue treatment for responder analysis. A blinded 
review of post-baseline medications will be done to 
adjudicate rescue treatment.  
Section 1.2.1 Rationale for Study Design 
Section 3.1 Study Description and Duration 
Section 4.2.1 Inclusion Criteria #3 and #7 
Section 4.2.2 Exclusion Criteria #3 and #7 
(previously #4 and #8) 
Figure 3 Study Flow Diagram (Part B) 
Section 5 Study Treatments 
Section 5.2 Background Treatments 
Section 5.3 Rescue Treatments 
Section 5.4.2.1 Reasons for Permanent 
Discontinuation of Study Drug  
Table 2 Schedule of Events for the Screening, 
Treatment, and Follow-Up Period (Part B) 
Section 6.2.2.17 Topical Corticosteroids 
Accountability 
Appendix 2  Permitted and Prohibited Steroid 
Medication 
Increased the duration of screening period for 
part B from a maximum of 35 days to a maximum 
of 56 days. This change was implemented to 
Clinical Study Protocol Synopsis: Study Design 
Section 3.1 Study Description and Duration 
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Change 
Sections Changed 
allow patients/caregivers more flexibility to 
complete all screening procedures to be eligible 
for randomization. Specifically, given the age 
group being studied, it is expected that a 
substantial proportion of patients would need a 
course of treatment with medium potency TCS for 
4 weeks during screening period to demonstrate 
inadequate response, and hence meet inclusion 
criterion 3 (Patients with documented recent 
history of inadequate response to topical AD 
medication(s)) 
Section 4.2.1 Inclusion Criteria #3 and #10 
Figure 3 Study Flow Diagram (Part B) 
Section 5.7.1 Prohibited Medications and 
Procedures  
Table 2 Schedule of Events for the Screening, 
Treatment, and Follow-Up Period (Part B) 
 
Added other (exploratory) objectives to assess 
effects of dupilumab on blood and skin 
biomarkers and to study its mechanism of action 
(related to efficacy and/or safety), why some 
patients respond better (safety and/or efficacy), 
and interleukin (IL)-4 receptor pathway, and AD 
and related diseases. 
Clinical Study Protocol Synopsis: Objectives 
Section 2.3 Other Objectives 
Japan and China added as participating countries 
for part B.  To ensure adequate representation of 
patients from Japan and China, randomization 
slots will be reserved for patients from these 
countries in an interactive web response system. 
This study will provide data for regulatory 
approval and labeling in Japan and China.  
Clinical Study Protocol Synopsis: Site Locations 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Sample Size 
Section 3.1 Study Description and Duration 
Section 4.1 Number of Patients Planned 
Section 5.5 Method of Treatment Assignment 
Section 13.1 Good Clinical Practice Statement 
Added that patients may be rescreened twice in 
part B if they have transient intercurrent events 
such as an active acute infection or need for 
vaccination which disqualifies them from an initial 
successful screening visit.  Many pediatric patients 
have transient incidental conditions like systemic 
infections and recent vaccinations.  The option for 
rescreening twice will allow such patients to be 
enrolled once these transient conditions have 
resolved, thus maximizing clinical benefit. 
Section 3.1 Study Description and Duration 
Clarified patient eligibility for the open-label 
extension (OLE) study. Any patient screened for 
the OLE will not participate in the follow-up 
period of current study. 
Updated age range for OLE study, 
R668-AD-1434, based on a protocol amendment 
for that study. 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Study Duration 
Section 1.1 Introduction  
Section 1.2.1 Rationale for Study Design 
Section 3.1 Study Description and Duration 
Section 5.8 Continuation of Dupilumab Treatment 
in an Open-Label Extension Study 
Section 9.5.3.1 Adverse Events  
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Change 
Sections Changed 
Noted that dupilumab has been approved for 
marketing in the US, EU, and Japan for treatment 
of moderate-to-severe AD in adults and 
adolescents.  Updated background information 
based on results of previous studies.  New 
sections were added to discuss the risks/benefits 
from previous studies. 
Section 1.1 Introduction 
Section 1.2.1 Rationale for Study Design  
Section 1.2.3 Risks/Benefits of Participating in 
Study(new) 
Section 1.2.3.1 Benefits (new) 
Section 1.2.3.2 Risks (new) 
Section 1.2.3.3 Risk/Benefit Conclusion (new) 
Updated planned sample size to 160 patients 
(80 patients per group) from 240 (80 patients per 
group). The previous study design assumed 
3 treatment groups (2 dupilumab and 1 placebo) 
while the current design includes 2 treatment 
groups (1 dupilumab and 1 placebo). 
Revised power calculations based on new data 
from pediatric studies with dupilumab.  The 
revised power calculations were based on data 
from the phase 3 TCS combination study in 
children (≥6 to <12 years) with severe AD 
(R668-AD-1652) and additional justification from 
the phase 3 TCS combination study in adults with 
moderate-to-severe 
AD 
(R668-AD-1224). 
Additional support was also provided by the 
phase 3 monotherapy study in adolescents with 
moderate-to-severe AD (R668-AD-1526). 
Clinical Study Protocol Synopsis: Population 
Clinical Study Protocol Synopsis: Statistical Plan 
Section 3.1 Study Description and Duration 
Section 4.1 Number of Patients Planned 
Section 5.5 Method of Treatment Assignment 
Section 9.2 Justification of Sample Size 
Added assessment of neutralizing antibodies 
(NAbs). This will be done on samples collected for 
ADA assessment. 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Procedures and 
Assessments 
Clinical Study Protocol Synopsis: Statistical Plan 
Section 8.4 Immunogenicity Variables (previously 
Anti-drug Variables) 
Section 9.3.4 Immunogenicity Analysis Sets (new) 
Section 9.5.5  Analysis of Immunogenicity Data 
(previously Analysis of Anti-drug Antibody Data) 
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Change 
Sections Changed 
An optional tape stripping sub-study at selected 
study sites was added to the protocol. Samples 
collected may be used for exploratory biomarker 
analysis. 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Procedures and 
Assessments 
Section 3.1 Study Description and Duration 
Table 2 Schedule of Events for the Screening, 
Treatment, and Follow-Up Period (Part B) 
Section 6.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
Section 6.2.7.2 Tape Stripping Sub-study - Optional 
Section 9.5.6 Analysis of Biomarker Data 
Added collection of assent from patients, as 
applicable, per local regulatory guidelines 
Clinical Study Protocol Synopsis: Study Design 
Section 3.1 Study Description and Duration 
Section 4.2.1 Inclusion Criteria #8 
Table 2 Schedule of Events for the Screening, 
Treatment, and Follow-Up Period (Part B), 
footnotes 
Section 6.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
Added inclusion criterion #10 for a weekly average 
worst scratch/itch score ≥4 at baseline (part B) to 
ensure that patients have a certain minimum 
intensity of pruritus at baseline so that a treatment 
effect can be detected.  Added inclusion criterion 
#11 for application of low potency TCS for at least 
11 days during TCS standardization period (part 
B). This is to ensure only patients adequately 
compliant with TCS application are enrolled.  
Section 4.2.1 Inclusion Criteria #10 and #11 (new) 
Revised exclusion criterion #1 to exclude patients 
who received prior treatment with dupilumab to 
prevent any confounding of treatment effect 
resulting from past use. 
Section 4.2.2 Exclusion Criteria #1 
Revised exclusion criterion #2 to exclude patients 
with history of important side effects of low 
potency TCS. Deleted previous exclusion criterion 
#3 which excluded patients with ≥30% of the total 
lesional surface located on areas of thin skin that 
cannot be safely treated with medium potency 
TCS. These changes followed the change in 
background therapy from medium potency to low 
potency TCS. 
Section 4.2.2 Exclusion Criteria #2 and previous 
exclusion criterion #3 
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Sections Changed 
Clarified live (attenuated) vaccines are prohibited, 
but inactivated vaccines are permitted.  Clarified 
timing of sample collection for vaccine sub-study.  
Added provision patients may be offered 
re-vaccination during the OLE in case of 
inadequate response to vaccines administered 
during study. The Vaccination Record Form was 
removed from protocol appendices as form and 
process described was not consistent with actual 
process.  
Section 4.2.2 Exclusion Criteria #8 (previously #9) 
Section 5.7.1 Prohibited Medications and 
Procedures  
Section 6.2.6 Vaccine Response – Optional 
Appendix Vaccine Record Form (deleted) 
Specified that tuberculosis testing will be 
performed according to local guidelines. 
Section 4.2.2 Exclusion Criteria #17 
(previously #18) 
Added exclusion criterion #27 for patients with 
body weight <5 kg or ≥30 kg  at baseline (part B 
only). Patients <5 kg excluded to prevent risks to 
patient safety due to exposure to study drug at 
levels that are higher than what have been studied 
in previous dupilumab studies in adults and 
pediatric patients.  Patients ≥30 kg excluded due to 
potential reduced efficacy from under exposure to 
study drug. 
Section 4.2.2 Exclusion Criteria #27 (new) 
Moved text regarding replacement of patients from 
Section 5.4.2 to Section 4.4 for appropriate 
placement. Clarified study drug discontinuation 
criteria only applicable to part B. 
Section 4.4 Replacement of Patients 
Section 5.4.2 Study Drug Discontinuation 
Specified that study drug will be temporarily 
discontinued in the event of serum creatinine 
>1.5×ULN 
Section 5.4.2.2  Reasons for Temporary 
Discontinuation of Study Drug 
Removed tanning in a bed/booth from list of 
prohibited concomitant procedures 
Section 5.7.1 Prohibited Medications and 
Procedures  
Made adjustment to or clarified some existing 
assessments and added assessments based on 
feedback from investigators and experience gained 
from conduct of part A of this study.  Made 
corresponding changes to assessments/ footnotes 
in schedule of events for part B. 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Procedures and 
Assessments 
Section 3.1 Study Description and Duration 
Table 2 Schedule of Events (Part B) 
Section 6.1.2 Unscheduled Visits 
Section 6.2.1 Procedures Performed Only at the 
Screening/Baseline Visit  
Section 6.2.2 Efficacy Procedures 
Section 6.2.2.1 Assessment of Pruritus 
Section 6.2.2.2 Assessment of Skin Pain 
Section 6.2.2.3 Assessment of Sleep Quality and 
Other Sleep-Related Concepts Using Sleep Diary 
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Change 
Sections Changed 
Section 6.2.2.4 Caregiver Global Impression of 
Disease 
Section 6.2.2.5 Caregiver Global Impression of 
Change  
Section 6.2.2.8 Infants’ Dermatology Quality of 
Life Index 
Section 6.2.2.9 Dermatitis Family Index 
Section 6.2.2.11 Investigator Global Assessment 
Section 6.2.2.17 Topical Corticosteroids 
Accountability 
Section 6.2.2.18 Patient Asthma Control 
Questionnaire 
Section 6.2.2.19 Caregiver-Reported Nasal 
Symptom Questionnaire 
Section 6.2.3.6 Ophthalmological Examination (Part 
B Only) 
Section 6.2.3.1 Vital Signs 
Section 6.2.4.2 Immunogenicity Measurements and 
Samples 
Section 6.2.5 Biomarker Procedures 
Section 6.2.7.1 Research Samples 
For consistency with criterion for temporary 
discontinuation 
of 
study 
drug, 
creatine 
phosphokinase 
(CPK) 
isoenzymes 
will 
be 
measured when CPK >2.5× upper limit of normal 
(ULN) (previously >5× ULN) 
Section 6.2.3.5 Laboratory Testing 
To be consistent with current practice DNA 
samples will be single-coded in part B instead of 
double-coded as done in part A. 
Section 6.2.7.3 Genomics Sub-study - Optional 
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Change 
Sections Changed 
Described how major protocol violations will be 
determined. 
Renamed first-step (1-step) analysis as primary 
analysis.  If performed, it will be the final analysis 
for primary and secondary efficacy endpoints.  
Further described analyses that may be performed, 
including multiple imputation method.  Added 
hierarchical procedure to be used for part B to 
control overall Type-1 error rate.  Added details on 
Immunogenicity analysis.   
Clinical Study Protocol Synopsis: Statistical Plan  
Section 3.2 Planned Interim Analysis 
Section 9.3.1 Efficacy Analysis Sets 
Section 9.5.2.1 Primary Efficacy Analysis 
Section 9.5.2.2 Secondary Efficacy Analysis 
Section 9.5.2.3 Multiplicity Considerations 
Table 3 Preliminary Statistical Hierarchy for 
Multiplicity Control 
Section 9.5.2.4 Primary Analysis of the Study 
Section 9.5.3.1 Adverse Events  
Section 9.5.3.2 Other Safety 
Section 9.5.3.3 Treatment Exposure 
Section 9.5.5 Analysis of Immunogenicity Data 
Clarified/updated list of adverse events of special 
interest (AESIs) including addition of clinically 
symptomatic 
eosinophilia 
and 
removal 
of 
malignancy. Also, specified that any patient with 
an AESI related to an eye disorder will be referred 
to an ophthalmologist (per health authority 
request). 
Section 7.2.3 Other Events that Require Accelerated 
Reporting, Adverse Events of Interest 
Clarified definition of serious adverse event related 
to hospitalization. Revised definitions of adverse 
event severity (mild, moderate, and severe) for the 
younger pediatric population in this study. 
Section 7.1.2 Serious Adverse Event 
Section 7.3.1 Evaluation of Severity 
Specified a new key secondary endpoint for 
pruritus and added other secondary endpoints for 
worst scratch/itch NRS, skin pain NRS, and sleep 
quality NRS scores, and improvement in worst 
scratch/itch NRS score ≥4 and ≥3. 
Clinical Study Protocol Synopsis: Endpoints 
Section 8.2.2 Secondary Endpoints 
Modified descriptions of PK variables and 
definition of PK analysis set. 
Section 8.3 Pharmacokinetic Variables 
Section 9.3.3 Pharmacokinetic Analysis Set 
(previously Other Analysis Sets) 
Edits/Clarifications/Updates  
Editorial changes were made throughout protocol 
for 
further 
clarification, 
consistency, 
and 
completeness, and, if appropriate, correction. 
All references to the study reference manual or 
study manual have been replaced with investigator 
site binder. 
Various  
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Amendment 2 
The changes to the protocol and the affected sections are highlighted below. 
* Changes noted with an “*” were included in Protocol Amendment R668-AD-1539.01UK 
approved on 31 March 2017 and were reviewed and approved by the MRHA.  However, the 
sponsor is incorporating these changes globally into one amendment, titled “R668 AD 1539 
Amendment 2” to harmonize the protocol across regions and to simplify regulatory submissions. 
Change 
Sections Changed  
Increased the follow-up period for patients who 
decline or are not eligible for a subsequent OLE 
study, from 4 weeks to 8 weeks.  This change has 
been implemented to comply with a request from a 
competent authority.  This change will ensure a 
sufficient follow-up period for patients who decline 
or are ineligible for enrollment into OLE at week 4 
and hence maximize patient safety. 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Study Duration 
Section 3.1 Study Description and Duration 
Figure 2 Study Flow Diagram (Part A) 
Section 3.1.2 Dose Escalation and Study Stopping 
Rules (Figure 4) 
Section 5.8 Continuation of Dupilumab Treatment 
in an Open-Label Extension Study 
Table 1 Schedule of Events for Screening, Single-
Dose Treatment and PK Sampling Period (Part A) 
Added an ADA assessment at day 8 (part A) based 
upon request from health authority 
Table 1 Schedule of Events for Screening, Single-
Dose Treatment and PK Sampling Period (Part A) 
The study day at Week 24 was corrected to day 169 
(listed incorrectly previously as day 141). 
Table 2 Schedule of Events for the Screening, 
Treatment, and Follow-Up Period (Part B) 
*Per request from a competent authority, stated that 
a substantial amendment (with supporting 
pharmacokinetic data) seeking approval of the part 
B doses will be submitted to the Regulatory 
Authorities prior to dosing in part B. 
Clinical Study Protocol Synopsis: Study Design 
Section 1.2.2 Rationale for Dose Selection 
Section 3.1 Study Description and Duration 
*Per request from a competent authority, clarified 
that an amendment to the ongoing open-label 
extension (OLE) study (R668-AD-1434) will be 
submitted to the Regulatory Authorities for 
approval to allow patients aged 6 months to <6 
years who participate in this study (R668-AD-1539) 
to enroll into the OLE. 
Clinical Study Protocol Synopsis: Study Design 
Section 3.1 Study Description and Duration  
*Per request from a competent authority, changed 
wording of the criterion for when dose escalation to 
the next cohort will not immediately proceed 
(removed “similar” before “severe AE”). 
Section 3.1.2 Dose Escalation and Study Stopping 
Rules 
*Per request from a competent authority, added end 
of study section and definition. 
Section 3.1.3 End of Study Definition  
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Change 
Sections Changed  
Added the following exclusion criteria: “Treatment 
with crisaborole within 2 weeks prior to the 
baseline visit.”  
This exclusion criterion has been added to minimize 
any carry-over effects into the treatment period.  
This will minimize any confounding of efficacy 
assessments for the study drug. 
Section 4.2.2 Exclusion Criteria #8 
Clarified the text indicating where moisturizers 
should be applied by the deletion of the following 
text in the third sentence “on the are(s) of 
nonlesional skin designated for such assessments” 
Section 5.2 Background treatment(s) 
Added text that stated “Investigators may also 
consider rescue with crisaborole.  Rescue treatment 
for these topical therapies should be used as per 
prescribing information and local guidelines.”   
Section 5.3 Rescue Treatment (s) 
Updated the text regarding replacement of who 
prematurely withdrawal from part A of the study. 
Section 5.4.2 Study Drug Discontinuation 
Changed “dupilumab” to “study drug” in the 
sentence “Anaphylactic reaction or other severe 
systemic reaction to study medication” 
Section 5.4.2.1 Reasons for Permanent 
Discontinuation of Study Drug 
Removed reference to the interactive IVRS 
(interactive voice response system) since the IWRS 
(interactive web response system) system is the 
only one used.   
Section 5.5 Method of Treatment Assignment 
Section 10.2 Electronic Systems 
Added 1 medication to the list of prohibited agents 
Treatment with crisaborole (only for part B).  
Crisaborole has been added to the list of prohibited 
medications to prevent any confounding of efficacy 
assessments.  Permitting use of crisaborole would 
have allowed patients to substitute crisaborole for 
TCS, thus preventing an accurate assessment of 
steroid sparing effect of the study drug.  Moreover, 
crisaborole is only approved for patients with 
moderate to severe AD, and the target patient 
population will have severe disease at baseline. 
Section 5.7.1 Prohibited Medications 
*Changed conditions for potential entry into the 
OLE (R668-AD-1434) so that all patients in part B 
will be able to roll over into the OLE at the end of 
the treatment period. 
Section 5.8 Continuation of Dupilumab Treatment 
in an Open-Label Extension Study 
Clarified wording for research samples, because 
only serum is being collected 
Table 2 Schedule of Events for the Screening, 
Treatment, and Follow-Up Period (Part B) 
Section 6.2.7.1 Research Samples 
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Change 
Sections Changed  
Added a copy of the Investigator Global 
Assessment (IGA) scale to Appendix 4 and cross-
referenced the IGA in this section. 
Section 6.2.2.5 Investigator Global Assessment 
Added an Ophthalmological Examination section:   
Patients who have history of certain eye disorders 
(conjunctivitis, blepharitis or keratitis) will be 
referred to an ophthalmologist (preferably with 
expertise in treating pediatric patients or Cornea 
and External Eye Disease [‘front-of-the-eye’] 
subspecialty expert).  Any baseline findings will be 
documented as part of the patient’s medical history 
and/or physical exam, as appropriate. 
Patients who experience adverse events of special 
interest related to eye disorders (refer to Section 
7.2.3) will also be referred to an ophthalmologist 
(preferably with expertise in treating pediatric 
patients or Cornea and External Eye Disease 
[‘front-of-the-eye’] subspecialty expert).  Further 
evaluation of these AESIs will be performed 
including any additional tests, if applicable, as per 
the discretion of the ophthalmologist. 
Certain types of eye disorders (conjunctivitis, 
blepharitis, keratitis) are an adverse event of special 
interest for the study drug.  Including referral to a 
specialist will allow a more robust and 
comprehensive evaluation of baseline disease status 
of patients with history of these disorders, as well 
as of any treatment emergent adverse events falling 
under this category. 
Section 6.2.3.6 Ophthalmological Examination 
(Part B Only) 
Clarified wording for vaccine response assessment, 
to allow more flexibility in timing 
Patients who do not get an adequate response to 
vaccine administration during part B of the study 
may be offered re-vaccination.  The details about 
re-vaccination procedure will be provided in a 
protocol amendment prior to the start of part B.  
Section 6.2.6 Vaccine Response - Optional 
Revised storage duration for DNA samples, to be 
consistent with the current practice 
Section 6.2.7.3 Genomics Sub-study - Optional 
The list of AESIs has been revised across the 
dupilumab program in AD and incorporates the data 
gathered from adult phase 3 studies, the dupilumab 
risk profile, and regulatory feedback.  This will 
enable focus of pharmacovigilance activities on 
identified and potential risks with this drug. 
Section 7.2.3 Other Events that Require 
Accelerated Reporting 
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Change 
Sections Changed  
The investigator will also assess whether the AES 
are related to any study procedures (as listed in 
Tables 1 and 2).   
Section 7.3.2 Evaluation of Causality 
Removed identification of patients by their initials 
due to privacy laws in some countries 
Section 13.3 Patient Confidentiality and Data 
Protection 
Made editorial changes/corrections 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Endpoints, 
Primary 
Clinical Study Protocol Synopsis: Endpoints, 
Secondary 
Figure 3 Study Flow Diagram (Part B) 
Table 1 Schedule of Events for Screening, Single-
Dose Treatment and PK Sampling Period (Part A) 
Section 8.2.1 Primary Endpoints 
Section 8.2.2 Secondary Endpoints 
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Amendment 1 UK 
The purpose of this amendment is to address a number of requests for revision of the protocol from 
the Medicines and Healthcare Products Regulatory Agency in the United Kingdom. 
The changes to the protocol and the affected sections are highlighted below. 
Change 
Sections Changed  
Clarified that an amendment to the ongoing open-label 
extension (OLE) study (R668-AD-1434) will be 
submitted to the Regulatory Authorities for approval to 
allow patients aged 6 months to <6 years who 
participate in this study (R668-AD-1539) to enroll into 
the OLE. 
Clinical Study Protocol Synopsis: Study 
Design 
Section 3.1 Study Description and Duration  
Stated that a substantial amendment (with supporting 
pharmacokinetic data) seeking approval of the part B 
doses will be submitted to the Regulatory Authorities 
prior to dosing in part B. 
Clinical Study Protocol Synopsis: Study 
Design 
Section 1.2.2 Rationale for Dose Selection 
Section 3.1 Study Description and Duration 
Changed wording of the criterion for when dose 
escalation to the next cohort will not immediately 
proceed. 
Section 3.1.2 Dose Escalation and Study 
Stopping Rules 
Added end of study section and definition. 
Section 3.1.3 End of Study Definition 
Changed conditions for potential entry into the OLE 
(R668-AD-1434) so that all patients in Part B will be 
able to roll over into the OLE at the end of the treatment 
period. 
Section 5.8 Continuation of Dupilumab 
Treatment in an Open-Label Extension Study 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2/3 Study Investigating the Pharmacokinetics, Safety, and Efficacy 
of Dupilumab In Patients Aged ≥6 Months to <6 Years With 
Moderate-to-Severe Atopic Dermatitis 
Site Locations 
 
Principal Investigator 
Multiple sites in North America, Europe, Japan, and China. 
Objectives 
Primary Objectives 
The primary objective for part A of the study is to characterize the safety 
and pharmacokinetics (PK) of dupilumab administered as a single dose in 
pediatric patients, 6 months to less than 6 years of age with severe atopic 
dermatitis (AD). 
The primary objective for part B of the study is to demonstrate the efficacy 
of multiple doses of dupilumab over 16 weeks of treatment when 
administered concomitantly with topical corticosteroids (TCS) in pediatric 
patients, 6 months to less than 6 years of age, with moderate-to-severe AD. 
Secondary Objectives 
The secondary objective of part A of the study is to evaluate the efficacy 
and immunogenicity of a single dose of dupilumab in patients 6 months to 
less than 6 years of age with severe AD. 
The secondary objective of part B is to assess the safety and immunogenicity 
of multiple doses of dupilumab over 16 weeks of treatment when 
administered concomitantly with TCS in patients 6 months to less than 
6 years of age with moderate-to-severe AD. 
Other Objectives (Part B) 
To assess the concentrations of dupilumab in serum following repeated 
subcutaneous (SC) dosing. 
To assess the effects of dupilumab on blood and skin biomarkers of 
inflammation in comparison with placebo.  
To study dupilumab’s mechanism of action (related to efficacy and/or 
safety), why some patients respond better than others (safety and/or 
efficacy), type 2 inflammation, as well as AD and related diseases. 
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Study Design 
This study is a 2-part (parts A and B) phase 2/3 study to evaluate the safety, 
PK, and efficacy of dupilumab in patients 6 months to less than 6 years of 
age with severe AD (part A), or moderate to severe AD (part B). 
Part A 
Part A of the study will be an open-label, single-ascending dose, sequential 
cohort study investigating the PK, safety and efficacy of a single dose of SC 
dupilumab in pediatric patients with severe AD (children aged ≥6 months to 
<6 years of age). 
Two sequential age cohorts are planned in part A: age cohort 1 (≥2 to <6 yrs 
old) and age cohort 2 (≥6 months to <2 yrs old).  Within each age cohort, 
approximately 10 patients will be enrolled in each of the 2 dose sub-cohorts: 
sub-cohort A (3 mg/kg) and sub-cohort B (6 mg/kg).  Enrollment and study 
dosing will start with cohort 1A (≥2 to <6 yrs old, 3 mg/kg dose, n=10).  
Following safety review of data from cohort 1A, enrollment will start in both 
cohort 1B (≥2 to <6 yrs. old, 6 mg/kg dose, n=10) and cohort 2A (≥6 months 
to <2 yrs old, 3 mg/kg dose, n=10).  Following safety review of data from 
cohort 2A, enrollment will start in cohort 2B (≥6 months to <2 yrs old, 
6 mg/kg dose, n=10). 
Part A of the study will consist of a screening period (day -35 to day -1), a 
baseline visit (day 1), a single-dose treatment followed by a 4-week PK 
sampling period, and an additional 4-week follow-up period (only for 
patients who decline to participate in a subsequent open-label extension 
[OLE] study).  After informed consent is provided by patients’ parents or 
legal guardians, patients will be assessed for study eligibility at the screening 
visit.  Patients who meet eligibility criteria will undergo baseline 
assessments and then proceed to part A to receive their single dose of study 
treatment on day 1 and undergo functional dupilumab PK sample collection 
during the following 4 weeks for characterizing the single-dose PK profile.   
All patients will be offered an opportunity to participate in the OLE study at 
week 4.  Patients who decline will be followed up for an additional 4 weeks 
(total of 8 weeks).  This will ensure a sufficient follow-up period for these 
patients and will maximize patient safety. 
Concomitant use of TCS with or without topical calcineurin inhibitors 
(TCIs) will be permitted during part A of the study. 
Part B 
Part B of the study is a randomized, double-blind, parallel-group, 
placebo-controlled study in which dupilumab will be administered 
concomitantly with TCS to patients ≥6 months to <6 years of age with 
moderate-to-severe AD.  Part B will consist of a screening period of up to 
56 days (including 2 weeks of TCS standardization), a treatment period of 
16 weeks, and a follow-up period of up to 12 weeks.  Patients who enrolled 
in part A of the study are not eligible to participate in part B.  After informed 
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consent is provided by patients’ parents or legal guardians, patients will be 
assessed for study eligibility at the screening visit.  Assent will be collected 
from patient, if applicable, as per local regulatory (competent 
authority/ethics) guidelines, based upon the age and level of maturity of the 
patient.  During the screening period, systemic treatments for AD will be 
washed out, as applicable, according to the eligibility requirements.  The use 
of TCS will be permitted during the screening period.  Starting on day -14, 
all patients will be required to initiate treatment with a low potency TCS 
using a standardized regimen.  Based on investigator discretion, low potency 
TCS may also be used on areas of thin skin.  The use of TCIs will be 
permitted during the screening period except for the 2-week period leading 
up to the baseline visit.   
During part B, patients will be required to apply moisturizers twice daily for 
at least 7 days before randomization (not including the day of 
randomization) and continue throughout the study.  Patients who continue 
to meet eligibility criteria at baseline will undergo day 1/baseline 
assessments and will be randomized in a 1:1 ratio stratified by baseline body 
weight (≥5-<15 kg and ≥15-<30 kg), baseline disease severity (IGA=3, 4), 
and region/country (North America, Europe, Japan, and China) as follows: 
• 
dupilumab (fixed dosing tiered by body weight every 4 weeks 
(Q4W): 200 mg Q4W for patients ≥5 to <15 kg or 300 mg for 
patients ≥15 to <30 kg Q4W. 
• 
placebo Q4W. 
The number of patients with moderate AD (IGA=3) will be capped at 
approximately 40.  
During the treatment period, patients will have in-clinic visits at week 1, 
week 2, and week 4, then monthly in-clinic visits through week 16 with 
weekly telephone visits in between the in-clinic visits.  
After completion of the treatment period, patients will enter a follow-up 
period of 12 weeks (only for patients who do not participate in a subsequent 
OLE study).  Follow-up visits for these patients will occur every 4 weeks 
from week 20 through week 28.  During the follow-up period, patients will 
be monitored for safety and tolerability and have laboratory and clinical 
assessments.  
Parts A and B 
Safety and laboratory assessments, samples for dupilumab concentration 
and anti-drug antibody (ADA) response to dupilumab, neutralizing antibody 
(NAbs), and efficacy assessments will be performed or collected at specified 
time points throughout parts A and B of the study.  Patients will also undergo 
sparse blood sample collection for characterizing the repeat-dose trough 
concentrations of dupilumab in serum during part B. 
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Patient participation in the genomics sub-study in parts A and B is optional.  
Samples for DNA analysis will be collected from patients whose parents or 
legal guardians agree to enroll them in the optional sub-study and sign a 
separate genomics sub-study informed consent form (ICF). 
Patient participation in the vaccination sub-study in part B is optional.  
Patients’ parents or legal guardians who plan to have their children 
vaccinated during the study and agree to enroll them in the optional 
sub-study, will sign a separate vaccination sub-study ICF for the collection 
of 2 blood samples (one sample will be drawn before administration of the 
vaccine, and the second sample will be drawn 3 to 4 weeks [maximum 
6 weeks] after administration of the vaccine) for assay of vaccine 
immunoglobulin G (IgG) in serum for each vaccine administered. 
Patient participation in a tape-stripping sub-study at selected study sites in 
part B is optional.  Tape stripping samples may be taken for exploratory 
biomarker analysis from patients whose parent(s) or legal guardian(s) 
consent for the child to participate in this optional sub-study. 
An OLE study (R668-AD-1434) in patients aged 6 months to <18 years old 
is currently ongoing.  Patients who complete the treatment period in either 
part A or part B may be eligible to enroll in this OLE study in which they 
will receive treatment with dupilumab. 
Study Duration 
The duration of the study for a patient in part A is approximately 8 weeks, 
excluding the screening period (patients would have the option to enroll into 
an OLE study at week 4), and duration of the study for a patient in part B is 
approximately 28 weeks, excluding the screening period (patients would 
have the option to enroll into an OLE study at week 16).  A patient cannot 
participate in both parts A and B of the study. 
Population 
 
 
Sample Size: 
For part A, approximately 40 pediatric AD patients aged ≥6 months to 
<6 years are planned to be enrolled in 4 cohorts as follows:  
• Cohort 1A:  ≥2 to <6 years of age, 3 mg/kg dose, n = 10 
• Cohort 1B:  ≥2 to <6 years of age, 6 mg/kg dose, n = 10 
• Cohort 2A:  ≥6 months to <2 years of age, 3 mg/kg dose, n = 10 
• Cohort 2B:  ≥6 months to <2 years of age, 6 mg/kg dose, n = 10 
To ensure adequate representation of patients from all age-groups, a cap will 
be placed on the number of patients who will be enrolled in each of the dose 
sub-cohorts (3 mg/kg and 6 mg/kg) as follows: 
Cohorts 1A and 1B: 
• 2 years to <4 years of age: 7 patients 
• 4 years to <6 years of age: 7 patients 
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Cohorts 2A and 2B: 
• 6 months to < 1 year of age: 7 patients 
• 1 year to <2 years of age: 7 patients 
For part B, approximately 160 pediatric AD patients aged ≥6 months to 
<6 years are planned to be randomized.  Randomization will be stratified by 
baseline weight (≥5 to <15 kg or ≥15 to <30 kg), by baseline disease 
severity (IGA=3, 4), and by region/country (North America, Europe, Japan, 
and China) in a 1:1 ratio to dupilumab or placebo.  To ensure adequate 
representation of patients from Japan and China, randomization slots will be 
reserved for patients from these countries in an interactive web response 
system.   The number of patients with moderate AD (IGA=3) will be capped 
at approximately 40.  The dose regimens are dupilumab Q4W tiered fixed-
dose regimen (200 mg or 300 mg) or placebo Q4W. 
 
Target Population: 
The study population includes pediatric patients with severe AD (part A) or 
moderate-to-severe AD (part B) aged ≥6 months to <6 years that cannot be 
adequately controlled with topical AD medications. 
Treatments 
Study treatment is administered by study site personnel.  Background and 
rescue treatment are to be applied by the patient’s caregiver. 
 
Study Drug 
 
Dose/Route/Schedule: 
For part A, dupilumab SC, 3 mg/kg for dose cohorts 1A and 2A, and 
6 mg/kg for dose cohorts 1B and 2B, given as a single dose on day 1. 
For part B, dupilumab is supplied in prefilled syringes for SC 
administration.  
• 
Patients with a baseline weight of ≥5 kg to <15 kg will receive 
dupilumab 200 mg SC on day 1 followed by the same dose given SC 
Q4W through week 12.  
• 
Patients with a baseline weight of ≥15 kg to <30 kg will receive 
dupilumab 300 mg SC on day 1 followed by the same dose given SC 
Q4W through week 12. 
 
Placebo 
 
Route/Schedule: 
For part B, 2 matching placebo formulations (without addition of active 
substance) will be used during the study: 
• 
placebo matching 200 mg dupilumab formulation 
• 
placebo matching 300 mg dupilumab formulation 
Patients in the ≥5 to <15 kg weight stratum will receive placebo-matching 
dupilumab 200 mg SC on day 1 and then Q4W through week 12.  Patients 
in the ≥15 to <30 kg weight stratum will receive placebo-matching 300 mg 
Q4W through week 12. 
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Background Treatment 
 
Dose/Route/Schedule: 
Background treatment is applied by the patient’s caregiver.  For part B, 
patients are required to have moisturizers (emollients) applied at least twice 
daily for at least the 7 consecutive days immediately before randomization 
(not including the day of randomization).  At least 11 of the 14 total 
applications must be applied for the subject to remain eligible for the study.  
Patients are to continue to have moisturizers applied throughout the 
remainder of the study (all 28 weeks where applicable).  However, to allow 
adequate assessment of skin dryness, moisturizers should not be applied for 
at least 8 hours before each clinic visit.  All types of moisturizers are 
permitted, but patients may not initiate treatment with prescription 
moisturizers or moisturizers containing additives during the screening 
period or during the study.  Patients may continue using stable doses of such 
moisturizers if initiated before the screening visit. 
For part B, starting on day -14, all patients are required to initiate treatment 
with low potency TCS using a standardized regimen according to 
protocol-specified guidelines.  A list of steroids that can be used during the 
study will be provided to the investigators as part of the investigator site 
binder.  Based on investigator discretion, low/mild potency TCS may also 
be used on areas of thin skin (face, neck, intertriginous, and genital areas, 
areas of skin atrophy, etc). 
 
Rescue Treatment 
 
Dose/Route/Schedule: 
For parts A and B, medium or high potency TCS, systemic corticosteroids 
or nonsteroidal immunosuppressants, or TCI may be provided as rescue 
treatment to study patients at the discretion of the investigator.  The use of 
rescue treatment is only allowed after day 14 of the study in part B.  
Investigators will be required to perform an Investigator Global Assessment 
(IGA) prior to starting rescue treatment and will initiate rescue treatment 
only in patients who either have an IGA score = 4 or have intolerable 
symptoms.   
Endpoints 
 
 
Primary: 
The primary endpoints in part A are: 
• Concentration of total dupilumab in serum over time and PK 
parameters (summary statistics of drug concentration and PK 
parameters) 
• The incidence and severity of treatment-emergent adverse events 
(TEAEs) through the end of part A. 
The primary endpoint in part B is the proportion of patients with an IGA 
score of 0 to 1 (on a 5-point scale) at week 16. 
The co-primary endpoints in part B (only in European Union [EU] and 
EU Reference Market Countries): 
• Proportion of patients with Eczema Area and Severity Index (EASI)-
75 (≥75% improvement from baseline) at week 16 
• Proportion of patients with an IGA score of either 0 or 1 (on a 5-point 
scale) at week 16 
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Secondary: 
The secondary endpoints in part A are: 
• The incidence of serious adverse events (SAEs) and severe TEAEs to 
week 4 
• Percent change in EASI score from baseline to week 4 
• Percent change in SCORing Atopic Dermatitis (SCORAD) from 
baseline to week 4 
• Proportion of patients with an IGA score of either 0 or 1 (on a 5-point 
scale) at week 4 
Immunogenicity will be addressed by the ADA parameters described in the 
protocol. 
The key secondary endpoints in part B are: 
• Proportion of patients with EASI-75 (≥75% improvement from 
baseline) at week 16 (not applicable for EU or EU Reference 
Market Countries) 
• Percent change in EASI score from baseline to week 16 
• Percent change from baseline to week 16 in weekly average of daily 
worst scratch/itch numeric rating scale (NRS) score 
Procedures and Assessments 
Safety and tolerability will be assessed by vital signs, physical examinations, 
clinical laboratory tests, and clinical evaluations.  Parents/caregivers will be 
asked to monitor all adverse events (AEs) experienced from the time of 
informed consent until their last study visit. 
Serum samples will be collected for assay of dupilumab concentrations, and 
PK parameters will be calculated using the dupilumab concentration data.  
Serum samples will be collected for ADA and NAb assessments and 
biomarker analyses, and research testing.  Tape stripping samples (optional) 
may also be taken for exploratory biomarker analysis at a subset of study 
sites. 
Efficacy will be assessed during the study at specified clinic visits using the 
investigator-assessed IGA, EASI, SCORAD, and Body Surface Area (BSA) 
involvement, parent/caregiver-reported worst scratch/itch NRS, skin pain 
NRS, and parent/caregiver-reported measures of AD symptoms, sleep, and 
quality of life (QOL). 
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Statistical Plan 
In part A of the study, the sample size of 40 patients was empirically based 
on the number of patients required to adequately characterize the safety/PK 
profile in this population. 
For part B of the study, it is estimated that a sample size of 160 patients 
(80 patients per group), at the 2-sided 5% significance level, will provide: 
• 88% power to detect a difference of 21.4% between the dupilumab and 
placebo groups in the percentage of patients who achieve an IGA score 
of 0 to 1 at week 16, assuming that the percentages are 32.8% and 
11.4% for the dupilumab and placebo groups, respectively.  
• 99% power to detect a difference of 42.9% in the percentage of patients 
who achieve an EASI-75 response at week 16, assuming that the 
percentages are 69.7% and 26.8% for the dupilumab and placebo 
groups, respectively. 
The analyses for parts A and B will be performed separately.   
For parts A and B, demographic and baseline characteristics, safety, PK, 
ADA, and NAb data will be summarized descriptively by treatment group.  
For part A, the open-label portion of the study, descriptive statistics of the 
efficacy endpoints will be summarized.  No statistical hypothesis will be 
tested. 
For part B, the efficacy analysis will be performed for the comparisons 
between the dupilumab treatment groups and the placebo group.  Patients 
will be randomized in a 1:1 ratio, stratified by baseline weight, baseline 
disease severity, and region/country. 
No multiplicity adjustments will be made for part A.  For part B, a 
hierarchical procedure will be used to control the overall Type-1 error rate 
at 0.05 for the primary endpoint(s) and the secondary endpoints for the 
dupilumab dose regimen vs placebo.  The abbreviated, preliminary plan for 
hierarchical testing order for the primary endpoint and key secondary 
endpoints are provided in the protocol.  Details of the multiplicity 
adjustment will be provided in the statistical analysis plan (SAP). 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................16 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................31 
1. 
INTRODUCTION AND RATIONALE .....................................................................35 
1.1. 
Introduction .................................................................................................................35 
1.2. 
Rationale .....................................................................................................................38 
1.2.1. 
Rationale for Study Design .........................................................................................38 
1.2.2. 
Rationale for Dose Selection ......................................................................................40 
1.2.3. 
Risk/Benefits of Participating in the Study ................................................................43 
1.2.3.1. 
Benefits .......................................................................................................................43 
1.2.3.2. 
Risks ...........................................................................................................................43 
1.2.3.3. 
Risk/Benefit Conclusion .............................................................................................44 
2. 
STUDY OBJECTIVES ..............................................................................................45 
2.1. 
Primary Objectives .....................................................................................................45 
2.2. 
Secondary Objectives .................................................................................................45 
2.3. 
Other Objectives .........................................................................................................45 
3. 
STUDY DESIGN .......................................................................................................45 
3.1. 
Study Description and Duration .................................................................................45 
3.1.1. 
Study Cohorts .............................................................................................................50 
3.1.2. 
Dose Escalation and Study Stopping Rules ................................................................51 
3.1.3. 
End of Study Definition ..............................................................................................52 
3.2. 
Planned Interim Analysis ............................................................................................52 
3.3. 
Study Committees .......................................................................................................53 
3.3.1. 
Independent Data Monitoring Committee ..................................................................53 
3.3.2. 
Dose Escalation Review Committee ..........................................................................53 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............53 
4.1. 
Number of Patients Planned .......................................................................................53 
4.2. 
Study Population .........................................................................................................54 
4.2.1. 
Inclusion Criteria ........................................................................................................54 
4.2.2. 
Exclusion Criteria .......................................................................................................56 
4.3. 
Premature Withdrawal from the Study .......................................................................59 
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4.4. 
Replacement of Patients .............................................................................................59 
5. 
STUDY TREATMENTS............................................................................................60 
5.1. 
Investigational and Reference Treatments ..................................................................60 
5.2. 
Background Treatments ..............................................................................................61 
5.3. 
Rescue Treatments ......................................................................................................62 
5.4. 
Dose Modification and Study Drug Discontinuation Rules .......................................63 
5.4.1. 
Dose Modification ......................................................................................................63 
5.4.2. 
Study Drug Discontinuation .......................................................................................63 
5.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................63 
5.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................64 
5.5. 
Method of Treatment Assignment ..............................................................................65 
5.5.1. 
Blinding ......................................................................................................................65 
5.5.2. 
Emergency Unblinding ...............................................................................................65 
5.6. 
Treatment Logistics and Accountability .....................................................................66 
5.6.1. 
Packaging, Labeling, and Storage ..............................................................................66 
5.6.2. 
Supply and Disposition of Treatments .......................................................................66 
5.6.3. 
Treatment Accountability ...........................................................................................66 
5.6.4. 
Treatment Compliance ................................................................................................66 
5.7. 
Concomitant Medications and Procedures .................................................................66 
5.7.1. 
Prohibited Medications and Procedures .....................................................................67 
5.7.2. 
Permitted Medications and Procedures ......................................................................68 
5.8. 
Continuation of Dupilumab Treatment in an Open-Label Extension Study ..............69 
6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS.........................69 
6.1. 
Schedule of Events .....................................................................................................69 
6.1.1. 
Early Termination Visit ..............................................................................................80 
6.1.2. 
Unscheduled Visits .....................................................................................................80 
6.2. 
Study Procedures ........................................................................................................80 
6.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................80 
6.2.2. 
Efficacy Procedures ....................................................................................................81 
6.2.2.1. 
Assessment of Pruritus ...............................................................................................81 
6.2.2.2. 
Assessment of Skin Pain .............................................................................................82 
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6.2.2.3. 
Assessment of Sleep Quality and Other Sleep-Related Concepts Using Sleep 
Diary ...........................................................................................................................82 
6.2.2.4. 
Caregiver Global Impression of Disease ....................................................................83 
6.2.2.5. 
Caregiver Global Impression of Change ....................................................................83 
6.2.2.6. 
Caregiver Assessment of Missed Workdays ..............................................................83 
6.2.2.7. 
Childrens’ Dermatology Life Quality Index ...............................................................84 
6.2.2.8. 
Infants’ Dermatology Quality of Life Index ...............................................................84 
6.2.2.9. 
Dermatitis Family Index .............................................................................................85 
6.2.2.10. 
Patient-Oriented Eczema Measure .............................................................................85 
6.2.2.11. 
Investigator Global Assessment .................................................................................85 
6.2.2.12. 
Eczema Area and Severity Index ................................................................................86 
6.2.2.13. 
Body Surface Area Involvement of Atopic Dermatitis ..............................................86 
6.2.2.14. 
Global Individual Signs Score ....................................................................................86 
6.2.2.15. 
SCORing Atopic Dermatitis .......................................................................................86 
6.2.2.16. 
Atopic Dermatitis Area Photographs ..........................................................................87 
6.2.2.17. 
Topical Corticosteroids Accountability ......................................................................87 
6.2.2.18. 
Pediatric Asthma Symptom Questionnaire .................................................................87 
6.2.2.19. 
Caregiver-Reported Nasal Symptom Questionnaire ..................................................88 
6.2.3. 
Safety Procedures .......................................................................................................88 
6.2.3.1. 
Vital Signs ..................................................................................................................88 
6.2.3.2. 
Body Weight and Height ............................................................................................88 
6.2.3.3. 
Physical Examination .................................................................................................88 
6.2.3.4. 
Electrocardiogram .......................................................................................................88 
6.2.3.5. 
Laboratory Testing ......................................................................................................89 
6.2.3.6. 
Ophthalmological Examinations (Part B only) ...........................................................90 
6.2.4. 
Pharmacokinetic and Antibody Procedures ................................................................90 
6.2.4.1. 
Drug Concentration Measurements and Samples .......................................................90 
6.2.4.2. 
Immunogenicity Measurements and Samples ............................................................90 
6.2.5. 
Biomarker Procedures ................................................................................................90 
6.2.6. 
Vaccine Response - Optional ......................................................................................91 
6.2.7. 
Research Testing .........................................................................................................92 
6.2.7.1. 
Research Samples .......................................................................................................92 
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6.2.7.2. 
Tape Stripping Sub-study - Optional ..........................................................................92 
6.2.7.3. 
Genomics Sub-study - Optional..................................................................................92 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................93 
7.1. 
Definitions ..................................................................................................................93 
7.1.1. 
Adverse Event .............................................................................................................93 
7.1.2. 
Serious Adverse Event ................................................................................................93 
7.2. 
Recording and Reporting Adverse Events ..................................................................94 
7.2.1. 
Adverse Events ...........................................................................................................94 
7.2.2. 
Serious Adverse Events ..............................................................................................94 
7.2.3. 
Other Events that Require Accelerated Reporting ......................................................95 
7.2.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................95 
7.2.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................95 
7.2.6. 
Follow-up ....................................................................................................................96 
7.3. 
Evaluation of Severity and Causality .........................................................................96 
7.3.1. 
Evaluation of Severity ................................................................................................96 
7.3.2. 
Evaluation of Causality ...............................................................................................96 
7.4. 
Safety Monitoring .......................................................................................................97 
7.5. 
Investigator Alert Notification ....................................................................................97 
8. 
STUDY VARIABLES................................................................................................97 
8.1. 
Demographic and Baseline Characteristics ................................................................97 
8.2. 
Primary and Secondary Endpoints..............................................................................97 
8.2.1. 
Primary Endpoints ......................................................................................................97 
8.2.2. 
Secondary Endpoints ..................................................................................................98 
8.2.3. 
Other Endpoints and Assessments ..............................................................................99 
8.3. 
Pharmacokinetic Variables .........................................................................................99 
8.4. 
Immunogenicity Variables ..........................................................................................99 
8.5. 
Vaccine Response Variables .......................................................................................99 
9. 
STATISTICAL PLAN................................................................................................99 
9.1. 
Statistical Hypothesis ..................................................................................................99 
9.2. 
Justification of Sample Size......................................................................................100 
9.3. 
Analysis Sets .............................................................................................................100 
9.3.1. 
Efficacy Analysis Sets ..............................................................................................100 
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9.3.2. 
Safety Analysis Set ...................................................................................................101 
9.3.3. 
Pharmacokinetic Analysis Sets .................................................................................101 
9.3.4. 
Immunogenicity Analysis Sets .................................................................................101 
9.4. 
Patient Disposition ....................................................................................................101 
9.5. 
Statistical Methods ....................................................................................................102 
9.5.1. 
Demography and Baseline Characteristics ...............................................................102 
9.5.2. 
Efficacy Analyses .....................................................................................................102 
9.5.2.1. 
Primary Efficacy Analysis ........................................................................................102 
9.5.2.2. 
Secondary Efficacy Analysis ....................................................................................102 
9.5.2.3. 
Multiplicity Considerations ......................................................................................103 
9.5.2.4. 
Primary Analysis of the Study ..................................................................................104 
9.5.3. 
Safety Analysis .........................................................................................................104 
9.5.3.1. 
Adverse Events .........................................................................................................104 
9.5.3.2. 
Other Safety ..............................................................................................................105 
9.5.3.3. 
Treatment Exposure ..................................................................................................106 
9.5.3.4. 
Treatment Compliance ..............................................................................................106 
9.5.4. 
Analysis of Drug Concentration Data .......................................................................106 
9.5.5. 
Analysis of Immunogenicity Data ............................................................................106 
9.5.6. 
Analysis of Biomarker Data .....................................................................................107 
9.6. 
Additional Statistical Data Handling Conventions ...................................................107 
9.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .......108 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................108 
10.1. 
Data Management .....................................................................................................108 
10.2. 
Electronic Systems ....................................................................................................108 
11. 
STUDY MONITORING ..........................................................................................108 
11.1. 
Monitoring of Study Sites .........................................................................................108 
11.2. 
Source Document Requirements ..............................................................................109 
11.3. 
Case Report Form Requirements ..............................................................................109 
12. 
AUDITS AND INSPECTIONS ...............................................................................109 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................110 
13.1. 
Good Clinical Practice Statement .............................................................................110 
13.2. 
Informed Consent .....................................................................................................110 
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13.3. 
Patient Confidentiality and Data Protection .............................................................111 
13.4. 
Institutional Review Board/Ethics Committee .........................................................111 
14. 
PROTOCOL AMENDMENTS ................................................................................111 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................111 
15.1. 
Premature Termination of the Study .........................................................................111 
15.2. 
Close-out of a Site ....................................................................................................112 
16. 
STUDY DOCUMENTATION .................................................................................112 
16.1. 
Certification of Accuracy of Data .............................................................................112 
16.2. 
Retention of Records ................................................................................................112 
17. 
CONFIDENTIALITY ..............................................................................................113 
18. 
FINANCING AND INSURANCE ...........................................................................113 
19. 
PUBLICATION POLICY ........................................................................................113 
20. 
REFERENCES .........................................................................................................114 
21. 
INVESTIGATOR’S AGREEMENT ........................................................................117 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................118 
 
LIST OF TABLES 
Table 1: 
Schedule of Events for the Screening, Single-Dose Treatment and PK 
Sampling Period (Part A) ............................................................................................70 
Table 2: 
Schedule of Events for the Screening, Treatment, and Follow-Up Period 
(Part B) ........................................................................................................................72 
Table 3: 
Preliminary Statistical Hierarchy for Multiplicity Control .......................................103 
 
LIST OF FIGURES 
Figure 1: 
Randomization Scheme (Part B) ................................................................................48 
Figure 2: 
Study Flow Diagram (Part A) .....................................................................................50 
Figure 3: 
Study Flow Diagram (Part B) .....................................................................................50 
Figure 4: 
Study Design and Dose Escalation Scheme (Part A) .................................................52 
 
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LIST OF APPENDICES 
Appendix 1. Factors to Consider in Assessing the Relationship of AEs to Study Drug ...........119 
Appendix 2. Permitted and Prohibited Steroid Medication ......................................................120 
Appendix 3. IGA Scale .............................................................................................................121 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
Anti-IL-4Rα 
Anti-interleukin 4 receptor subunit alpha 
AST 
Aspartate aminotransferase 
BL 
Baseline 
BSA 
Body surface area  
BUN 
Blood urea nitrogen 
CDLQI 
Childrens’ Dermatology Life Quality Index 
CGIC 
Caregiver Global Impression of Change 
CGID 
Caregiver Global Impression of Disease 
CL 
Clearance 
CLA 
Cutaneous lymphocyte antigen 
Cmax,ss 
Maximum concentrations at steady-state 
CNSQ 
Caregiver-Reported Nasal Symptom Questionnaire 
Ctrough 
Lowest concentration in a dosing interval 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
DERC 
Dose-Escalation Review Committee 
DFI 
Dermatitis Family Index 
DPT 
Diphtheria, tetanus, pertussis 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI-50 
≥50% improvement from baseline in EASI score 
EASI-75 
≥75% improvement from baseline in EASI score 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
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EDC 
Electronic data capture 
e-diary 
Electronic diary 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
EU 
European Union 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GISS 
Global Individual Signs Score 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IDQOL 
Infants’ Dermatology Quality of Life Index 
IGA 
Investigator Global Assessment 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IL 
Interleukin 
IPV 
Inactivated polio vaccine 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
LOQ 
Limit of quantitation 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
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MI 
Multiple imputation 
NAb 
Neutralizing antibody 
NCA 
Non-compartmental analysis 
NRS 
Numeric rating scale 
ObsRO 
Observation reported outcome 
OLE 
Open-label extension 
PASQ 
Pediatric Asthma Symptom Questionnaire 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
POEM 
Patient Oriented Eczema Measure 
PRO 
Patient reported outcome 
PT 
Preferred term 
PV 
Phone visit 
Q1 
First quartile 
Q2W 
Every 2 weeks 
Q3 
Third quartile 
Q4W 
Every 4 weeks 
QOL 
Quality of Life 
QW 
Once weekly 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SCORAD 
SCORing Atopic Dermatitis 
SCN 
Screening 
SD 
Standard deviation 
SMT 
Safety monitoring team 
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SOC 
System organ class 
TARC 
Thymus and activation regulated chemokine 
TB 
Tuberculosis 
TCI 
Topical calcineurin inhibitor 
TCS 
Topical corticosteroids 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
ULN 
Upper limit of normal 
US 
United States 
V 
Volume of distribution 
WBC 
White blood cell 
WOCF 
Worst observation carried forward 
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1. 
INTRODUCTION AND RATIONALE 
1.1. 
Introduction 
Atopic dermatitis (AD), also known as atopic eczema, is a pruritic skin condition characterized by 
a chronic, relapsing form of skin inflammation, a disturbance of the epidermal-barrier function 
associated with immune changes in the skin, and a high prevalence of immunoglobulin E (IgE) 
mediated sensitization to food and environmental allergens (Bieber 2008). 
Atopic dermatitis is one of the most common skin disorders in infants and children (Mortz 2015).  
The prevalence of AD in the first 2 years of life has been reported to be 21.5% (Ileli 2004).  Phase 
3 of the International Study of Asthma and Allergies in Childhood showed a 1-year period 
prevalence rate higher than 15% in the 6 to 7-year-old age group in Australia, England, and 
Scandinavia (Asher 2006).  The clinical pattern of AD varies with age.  Infants typically present 
with erythematous papules and vesicles on the cheeks, forehead, or scalp, which are exudative and 
intensely pruritic.  The childhood phase typically occurs from 2 years of age to puberty.  Children 
present with lichenified papules and plaques representing the more chronic disease involving the 
hands, feet, wrists, ankles, and antecubital and popliteal regions.  In adults, predominant areas of 
involvement include the flexural folds, the face and neck, the upper arms and back, and the dorsa 
of the hands, feet, fingers, and toes.  The eruption is characterized by dry, scaling erythematous 
papules and plaques, and the formation of large lichenified plaques from lesional chronicity. 
The disease has been shown to have a marked impact on the quality of life (QOL) of pediatric 
patients, greater than that seen in other common skin disorders like psoriasis and urticaria 
(Beattie 2006).  A study comparing the impact on the QOL of family members of children 
suffering from eczema and type 1 diabetes found that all families of children with 
moderate-to-severe eczema had significantly higher impact scores than those of diabetic children 
(Su 1997).  Often, severe pruritus is a universal finding in AD and often results in sleep disruption, 
irritability, and generalized stress for both the affected patients as well as family members 
(Kim 2012). 
Of particular interest in younger children is the phenomenon of “Atopic March” which is 
characterized by a typical sequence of progression of clinical signs of atopic disease.  In general, 
the clinical signs of AD and of food allergies predate the development of asthma and allergic 
rhinitis, suggesting that AD is an “entry point” for subsequent allergic disease (Spergel 2003).  
Severity of AD is correlated with development of asthma and allergic rhinitis (Zheng 2011). 
Infants and young children with severe AD have a reported risk rate of around 60% for developing 
asthma later on in life compared to a risk of around 30% in patients with mild AD (Ricci 2006). 
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Atopic dermatitis is caused by a complex interaction of genetics, defects in skin barrier function, 
environmental exposure, and immunologic responses.  Type 2 helper T cell (Th2) mediated 
immune response is believed to play a central role in the pathogenesis of AD.  The skin lesions of 
AD are characterized by increased expression of proinflammatory Th2 cytokines, such as 
interleukin (IL)-4 and IL-13, and by skin infiltration of Th2 cells.  The elevated IgE responses and 
eosinophilia observed in the majority of patients with AD reflects an increased expression of the 
Th2 cytokines IL-4 and IL-13 (Leung 1999).  Type 2 helper T cell-associated cytokines regulate 
important barrier related functions, such as epidermal cornification and production of 
antimicrobial proteins.  These cytokines inhibit the production of major terminal differentiation 
proteins, such as loricrin, filaggrin, involucrin, and the antimicrobial proteins human beta defensin 
2 and 3, which in turn, is associated with development of AD (Howell 2007, 
Guttman Yassky 2011a, Guttman Yassky 2011b). 
The Th2 cytokines also act on keratinocytes and induce production of chemokines, including 
chemokine (C-C motif) ligand 17 (also known as thymus and activation regulated chemokine 
[TARC]), and chemokine (C-C motif) ligand 26 (also known as eotaxin-3), which are 
chemo-attractants for Th2 cells and eosinophils; thus, perpetuating the inflammatory response.  
Since activation of IL-4 and IL-13 signaling precedes the release of proinflammatory mediators, 
antagonism of these cytokines has the potential to reduce the Th2 response and provide therapeutic 
benefit. 
A study was recently conducted with the aim of identifying differences and similarities between 
cutaneous lymphocyte antigen (CLA) +ve, polarized T-cell subsets in children versus adults with 
AD.  In this study, peripheral blood from children less than 5 years old was compared with that of 
adults with well-characterized moderate-to-severe AD, using flow cytometry.  The study 
concluded that Th2 activation within skin-homing T cells might drive AD in children.  Moreover, 
the spreading to additional Th subsets, particularly Th22, is seen in adults but not in children 
(Czarnowicki 2015).  Based on the results of this study, it is speculated that therapeutics that target 
Th2 cytokines, such as dupilumab, might be particularly valuable in the pediatric population with 
AD. 
There is currently a high unmet medical need for an effective therapy for AD with an acceptable 
safety profile in infants and young children who suffer with moderate-to-severe AD.  
Nonpharmacological management of AD, which includes environmental control measures 
(eg, avoidance of antigen and skin irritants) and skin care measures (eg, maintaining the hydration 
of the skin through the use of emollients) play a supportive role, especially in children with 
moderate-to-severe disease.  Pharmacological management of AD in children is mainly limited to 
topical therapy with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs).  
However, long-term use of TCS in children is not recommended because of the risk of irreversible 
skin atrophy, dyspigmentation, acneiform eruptions, and risks associated with systemic absorption 
(eg, growth retardation, hypothalamic pituitary axis effects, etc).  Topical calcineurin inhibitors, 
such as tacrolimus and pimecrolimus, are also used in AD as an alternative to or in combination 
with TCS.  However, both tacrolimus and pimecrolimus are not indicated for use in children <2 
years of age.  Moreover, the use of TCI is frequently associated with skin irritation.  Furthermore, 
a possible increased risk of malignancy (lymphoma and skin cancers) has been noted for TCIs. 
Systemic agents are used off-label in children (cyclosporine, systemic steroids, methotrexate, 
azathioprine, and mycophenolate mofetil).  A recent survey conducted in Europe, “European 
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Treatment of Severe Atopic Eczema in Children Taskforce (TREAT)” found that approximately 
70% of respondents initiated systemic therapy for children with severe AD (Proudfoot 2013).  All 
of these systemic agents have significant side effects in children, including stunted growth, 
diabetes, hypertension, osteoporosis (corticosteroids), myelosuppression and hepatotoxicity 
(methotrexate), nephrotoxicity and hypertension (cyclosporine), and gastrointestinal disturbances 
and leucopenia (azathioprine).  Moreover, a high proportion of patients in which disease is initially 
controlled by systemic agents suffer from relapse soon after therapy is discontinued 
(Schmitt 2009). 
Type 2 inflammation (including Th2 responses) and the dysregulated activation of Th2 cells have 
been recognized as the key underlying disease drivers of AD and other associated atopic/allergic 
diseases.  Targeting the key upstream type 2 cytokines, IL-4 and IL-13, has the potential for 
treating the pathology of AD as well as other associated atopic/allergic diseases.  Since activation 
of IL-4 and IL-13 signaling precedes the release of proinflammatory mediators, antagonism of 
these cytokines has the potential to reduce the type 2 inflammatory responses seen in AD and other 
associated atopic/allergic diseases.  In addition, type 2/Th2 cytokines are believed to induce altered 
epidermal responses, inhibit terminal differentiation proteins, and produce and/or amplify the skin 
barrier defect in AD; therefore, antagonism of IL-4 and IL-13 signaling has the potential to restore 
barrier function. 
Dupilumab is a novel targeted immunoregulatory agent that selectively and simultaneously inhibits 
IL-4 and IL-13 signaling by blocking the obligate shared component of the IL-4/IL-13 receptor 
complex.  It is intended to inhibit key disease drivers to achieve clinical benefit without the side 
effects commonly observed with existing non-selective systemic immunosuppressants.  
Dupilumab has been approved for marketing in the US, EU, and Japan for treatment of moderate-
to-severe AD in adults and adolescents.   
Dupilumab, given subcutaneously (SC), is currently in clinical trials for multiple indications, 
including treatment of moderate-to-severe AD in patients intolerant of, or whose disease is not 
adequately controlled with, topical treatments.  As of 28 March 2019, dupilumab clinical data in 
AD are available from 22 completed and 6 ongoing (phase 1, 2, and 3) studies in adult healthy 
subjects and in patients with AD.  A total of 202 healthy subjects, and 3931 patients with AD have 
been exposed to dupilumab in phase 1, single-dose studies at doses up to 12 mg/kg intravenous 
(IV) and 600 mg SC, and phase 1 through 3 multiple-dose studies at doses up to 300 mg once a 
week (QW), preceded by a 600 mg loading dose.  Sixteen of the 22 completed studies were 
conducted in patients with AD.  Data from these studies showed rapid and dose-dependent 
improvement in pharmacodynamic (PD) and efficacy endpoints in dupilumab-treated patients.  
Dupilumab has also been consistently well-tolerated across these clinical studies.   
Dupilumab has been studied in 2 completed studies in pediatric patients with AD.  R668-AD-1412 
was a phase 2 study investigating the safety, pharmacokinetics (PK), immunogenicity, and 
exploratory efficacy of dupilumab in patients aged ≥6 to <12 years with severe AD and ≥12 to <18 
years with moderate-to-severe AD (77 patients were exposed to dupilumab).  R668-AD-1526 was 
a phase 3 study investigating the efficacy and safety of dupilumab in patients ≥12 to <18 years of 
age with moderate-to-severe AD (166 patients were exposed to dupilumab).  Data from these 
completed studies in pediatric patients with AD showed that dupilumab had an acceptable safety 
profile and was well tolerated in patients aged ≥6 to <18 years of age (see Section 1.2.3.2), and 
provided significant clinical benefit (Section 1.2.3.1). 
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In addition, dupilumab is currently being studied in 2 other ongoing pediatric studies: a phase 3 
study (R668-AD-1652) investigating the efficacy and safety of dupilumab administered 
concomitantly with TCS in patients 6 years to <12 years of age with AD, and an open-label 
extension (OLE) study (R668-AD-1434) to assess the long-term safety and efficacy of dupilumab 
in patients aged ≥6 months to <18 years with AD.  Study R668 AD 1652 has completed the primary 
analysis period and the OLE study R668-AD-1434 has completed the secondary analysis period. 
Dupilumab has also been studied in 2 completed (EFC13579 and EFC13691) and 1 ongoing 
(EFC14153) phase 3 double-blind, placebo-controlled studies evaluating the efficacy and safety 
of dupilumab in patients, including pediatric patients, with uncontrolled asthma (see 
Section 1.2.3.2). 
In addition, pediatric patients aged ≥12 to <18 years (n=50) were included in study R668-AD-1607 
(a phase 1b actual use study of dupilumab auto-injector device in patients with AD). 
Completed and ongoing clinical studies with dupilumab in AD are further described in 
Section 1.2.3.   
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
1.2. 
Rationale 
1.2.1. 
Rationale for Study Design 
This study is part of the pediatric clinical development plan for dupilumab in AD.  The primary 
purpose of the study is to provide data to support registration and labeling for the use of dupilumab 
in pediatric patients, 6 months to less than 6 years of age, suffering from moderate-to-severe AD, 
whose disease cannot be adequately controlled with topical medications, or for whom topical 
treatment is medically inadvisable (eg, intolerance, other important side effects, or safety risks). 
This study is a 2-part (parts A and B) phase 2/3 study to evaluate the safety, PK and efficacy of 
dupilumab in patients 6 months to less than 6 years of age with moderate-to-severe AD.  Part A is 
an open-label, single-ascending-dose, sequential cohort phase 2 study in patients ≥6 months to 
<6 years of age with severe AD.  The primary objective of part A is to obtain safety and PK data 
in this patient population, to guide dose selection for part B.  
In part A, all patients will receive treatment with dupilumab.  This approach will minimize the 
number of patients required in the study to obtain adequate dupilumab PK and safety data. 
The ascending dose cohort and descending age subset design in part A was chosen to allow the 
lower dose and older, less vulnerable age subset to be evaluated first.  Review, at internal safety 
review meetings, of safety data from cohorts who have already been dosed before opening up a 
new cohort, will further ensure patient safety. 
Part B is a randomized, double-blind, parallel-group, placebo-controlled study in which study 
treatments will be administered concomitantly with topical therapy to patients.  The primary 
objective of part B is to demonstrate efficacy of dupilumab in combination with prescription 
topical therapy in pediatric patients, 6 months to less than 6 years of age, suffering from 
moderate-to-severe AD.   
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In initial interactions with a Competent Authority which were held at a time when there was no 
data from clinical studies on the use of dupilumab in the pediatric population, the sponsor was 
advised to limit the patient population to severe patients in patients <12-years-old.  Since then, 
dupilumab has been tested in multiple clinical studies in pediatric patients and shown to provide 
considerable clinical benefit to pediatric patients with an acceptable safety profile.  Subgroup 
analysis from dupilumab phase 3 studies in both adult and adolescent patients showed comparable 
efficacy and safety profile patients with moderate and severe disease at baseline. Moreover, an 
analysis performed on patients ≥6 to <12 years of age in the open-label extension study with a 
baseline disease of moderate severity (IGA=3) showed that the drug was well tolerated in this 
subpopulation with a comparable safety profile to the overall study population.  The sponsor was 
recently advised to broaden the patient population to moderate-to-severe disease by the United 
States Food and Drug Administration.  This approach will maximize the number of patients that 
will benefit from this drug and also facilitate enrollment in this study. 
An add-on study design will ensure that patients who are randomized to the placebo group will 
continue to receive standard treatment for their disease; an important consideration given the target 
population consists of infants and young children with moderate-to-severe disease.  Moreover, this 
approach mirrors the therapeutic paradigm envisaged for dupilumab post approval in this age-
group.  Clinicians are expected to continue treatment with topical therapies upon initiation of 
dupilumab, and to taper use of topical treatment following onset of clinical effect of dupilumab.   
The 16-week treatment duration is similar to what was used in the adult pivotal trials 
(R668-AD-1416 and R668-AD-1334).  Patients were treated with dupilumab every 2 weeks 
[Q2W] dose regimen for 52 weeks in another adult phase 3 study (R668-AD-1224) and no 
incremental therapeutic benefit was noticed for the overall patient population between week 16 
and week 52.  Treatment duration of 16 weeks has been chosen because the maximum, or close to 
maximal, therapeutic effect for dupilumab in this patient population is expected to be achieved by 
this time based on data from these studies and also from R668-AD-1526 (phase 3 study of 
dupilumab in adolescent patients with AD.  Data gathered from the dose-range-finding study in 
adults (R668-AD-1021) showed that all dosing regimens (100 mg every 4 weeks [Q4W], 200 mg 
QW, 200 mg Q2W, 300 mg Q2W, 300 mg Q4W) achieved steady-state concentration on or before 
week 16.  These findings suggest that 16 weeks will be sufficient time for the selected doses for 
part B (fixed dosing tiered by body weight strata: 200 mg Q4W [≥5-<15 kg] and 300 mg Q4W 
[≥15-<30 kg]) to achieve steady-state concentration and saturation of the target-mediated pathway.  
The 12-week follow-up period is based on the expected PK of dupilumab after the last dose, ie, the 
time for systemic concentrations to decline to non-detectable levels (below the lower limit of 
quantification) in most patients.  
The co-primary endpoints (proportion of patients with Investigator Global Assessment (IGA) 0/1 
and ≥75% improvement from baseline in Eczema Area and Severity Index [EASI] score [EASI-75] 
at week 16) (proportion of patients with EASI-75 is a co-primary endpoint for EU and EU 
Reference Market Countries only, key secondary endpoint for US) were chosen because they are 
similar to those used in the adult pivotal studies (SOLO trials), and to address the varying primary 
endpoint requests by differing health authorities.  Eczema Area and Severity Index has been 
validated in the pediatric population in a prior study (Barbier 2004). 
The approach to combine parts A and B into a single study will ensure earlier availability of a 
potentially effective therapy in a target population with high unmet medical need.  
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As the efficacy and safety of dupilumab for the treatment of AD has not yet been established in 
patients ≥6 months to <6 years, a placebo control is a scientifically essential element of the study 
design to enable adequate assessment and interpretation of the treatment effect and safety profile.  
It is particularly relevant for pediatric patients, in whom spontaneous remission of AD over time 
has been described.  Several features of the protocol are intended to mitigate any potential concerns 
in patients randomized to the placebo group: 
• Mandatory requirement for use of concomitant TCS 
− Starting on day -14 (applicable to part B only), all patients will initiate a 
standardized TCS treatment regimen with a low-potency TCS that may be 
adjusted based on clinical response (see Section 5.2).  Topical corticosteroids 
represent the mainstay of pharmacologic treatment of AD and have been shown to 
have some benefit even in a patient population selected for their inadequate 
response to TCS. 
• Availability of rescue treatment 
− Patients who experience AD exacerbations or intolerable symptoms may receive 
rescue treatment with a range of treatments available to all patients with AD:  
medium or high-potency TCS, systemic corticosteroids, nonsteroidal 
immunosuppressive drugs, and TCI (see Section 5.3).  
• Open-Label Extension (OLE) Study 
− Patients who complete the treatment period of part B (week 16) will be offered an 
opportunity to screen for the OLE study at end-of-treatment (EOT) visit.  
Additional details concerning eligibility for the OLE can be found in Section 5.8. 
As described in Section 3.3.1, an Independent Data Monitoring Committee (IDMC), will monitor 
patient safety by conducting formal reviews of accumulated safety data on a program-wide level. 
1.2.2. 
Rationale for Dose Selection  
In the adult phase 3 studies (SOLO-1 and SOLO-2, both studies had identical study designs), 
patients were randomized into 1 of 3 treatment groups: dupilumab 300 mg SC QW, dupilumab 
300 mg SC Q2W, or placebo for 16 weeks following an initial dupilumab loading dose of 600 mg 
SC, or placebo.  Both dose regimens of 300 mg QW and 300 mg Q2W provided significant clinical 
benefit and had an acceptable safety profile.  For the 16-week treatment period, the overall rate of 
adverse events (AEs) (65% to 73% dupilumab and 65% to 72% placebo) was comparable between 
the dupilumab and the placebo groups.  The rate of serious adverse events (SAEs) was 1% to 3% 
for dupilumab and 5% to 6% for placebo.  Serious and severe infections were also numerically 
higher in the placebo groups in both studies (0.5% to 1% dupilumab and 2% to 3% placebo). 
Assuming an average adult body weight of 75 kg, a dose of 4 mg/kg would be equivalent to 300 mg 
and would seem to provide matching dose levels in children.  However, PK parameters, like 
clearance (CL) and volume of distribution (V), do not scale linearly with body weight for younger 
children (Zhang 2015).  Therefore, the reductions of CL and V in children are less than weight-
proportional.  A weight-normalized dose directly scaled down from an adult dose is likely to yield 
sub-optimal exposure in children. 
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Given this background, a dose of 6 mg/kg in pediatric patients is expected to provide an exposure 
similar to a single dose of 300 mg in adult patients.  This is supported by PK simulations using a 
PK model developed with data from adult AD patients and from pediatric AD patients in study 
R668-AD-1412 (A phase 2 study investigating the safety, PK, immunogenicity, and exploratory 
efficacy of dupilumab in patients aged ≥6 to <18 years with AD). 
As part of the ascending-dose sequential cohort design, the dose regimen of 3 mg/kg was chosen 
as the initial starting dose to first evaluate the safety of dupilumab at the lower dose before 
progressing to the higher, 6 mg/kg, dose cohort.  The first study with dupilumab in pediatric 
patients 6 to 17 years of age (R668-AD-1412) evaluated doses of 2 mg/kg and 4 mg/kg.  A review 
of the data from this study showed that these doses were well tolerated with an acceptable safety 
profile, in addition to showing some clinical benefit.  A dose of 3 mg/kg in patients 6 months to 
<6 years of age is expected to provide exposure lower than that seen with a dose of 4 mg/kg in 
patients 12 to 17 years of age in study R668-AD-1412. 
In study R668-AD-1412, a trend for a higher incidence of persistent anti-drug antibodies (ADAs) 
was seen in the lower dose cohorts (2 mg/kg) compared to the higher dose cohorts (4 mg/kg).  A 
lower dose is typically more immunogenic than a larger dose (European Medicines Agency 2007, 
Food and Drug Administration 2014) and the use of high-dose monoclonal antibodies (mAbs) has 
been shown to reduce immunogenicity and induce tolerance through exhaustion of the immune 
response (Maini 1998).  Given this background, a starting dose of 3 mg/kg is expected to lower 
the likelihood of an immune response compared to a 2 mg/kg dose. 
In part A of the current study (R668-AD-1539), 20 patients in the age group ≥2 to <6 years and 
20 patients in the age group ≥6 months to <2 years were enrolled.  Single-dose treatment with 
dupilumab 3 mg/kg or 6 mg/kg led to reduction in both signs (as measured by percent reduction in 
EASI score from baseline, proportion of patients achieving ≥50% improvement from baseline in 
EASI score [EASI-50]) and symptoms (as measured by percent reduction in pruritus numeric 
rating scale [NRS] from baseline) of AD.  Mean body weight was 17.1 kg in the ≥2 to <6 years of 
age and 9.8 kg in the ≥6 months-<2 years age group. 
• In the ≥2 to <6 years of age group, single doses of 3 mg/kg SC dupilumab provided a 
mean reduction from baseline in EASI score of 44.6% at week 3 and 26.6% at week 4 
and single doses of 6 mg/kg SC dupilumab provided a mean reduction of 49.7% at 
week 3 and 48.7% at week 4.  
• In the ≥6 months to <2 years of age group, single doses of 3 mg/kg SC dupilumab 
provided a mean reduction from baseline in EASI score of 42.7% at week 3 and 
22.4% at week 4 and single doses of 6 mg/kg SC dupilumab provided a mean 
reduction of 38.8% at week 3 and 43.2% at week 4. 
Single-dose treatment with dupilumab 3 mg/kg or 6 mg/kg had an acceptable safety profile and 
was well tolerated in both age groups. 
The dupilumab treatment group in part B of the current study is a weight-tiered fixed-dose regimen 
of 200 mg Q4W SC for children with a baseline body weight ≥5 to <15 kg and 300 mg Q4W SC 
for children with a baseline body weight ≥15 to <30 kg.   
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The dose regimen of 300 mg Q4W was evaluated in pediatric patients ≥6 to <12 years of age with 
severe AD in the ongoing phase 3 study, R668-AD-1652, which included 61 patients in the 
≥15 to <30 kg weight range.  In the primary analysis completed at the end of the treatment period, 
the 300 mg Q4W dose regimen led to clinically relevant and statistically significant reduction in 
both signs and symptoms of AD.  In the ≥15 kg to <30 kg weight range: 
• Approximately 30% of patients achieved an IGA score of 0/1 (total n=61) in the 
300 mg Q4W treatment group compared to 13% patients for the same weight 
category in the placebo group (total n=63).  Similarly, 75% of patients achieved an 
EASI-75 in the 300 mg Q4W treatment group compared to 28% patients in the 
placebo group. 
• Approximately 55% of patients achieved an NRS reduction ≥4 points in the 300 mg 
Q4W treatment group compared to 12% of patients in the placebo group. 
The 300 mg Q4W regimen was shown to have an acceptable safety profile and was well tolerated 
in these patients, supporting use of the same doses in younger AD patients with similar body 
weights.  
The doses selected for part B of the study were based on PK data gathered from part A (patients 
≥2 years to <6 years of age or ≥6 months to <2 years of age) and integrated in a population PK 
model for pediatric patients with observations in patients ≥6 to <12 years of age or ≥12 to <18 years 
of age. Supporting PK simulations using this pediatric population PK model are summarized 
below.  The goal of dose selection for part B was to achieve dupilumab exposure in pediatric 
patients at steady-state equivalent to exposure in adults where tolerability and efficacy have been 
demonstrated.   
In adults, dupilumab regimens of 300 mg Q2W and QW were both shown to be well tolerated and 
efficacious in Phase 3 studies.  Hence, various weight-tiered regimens were simulated using an 
established population PK model with the aim of selecting pediatric regimens that 1) achieved a 
distribution (5th, median, and 95th percentile) of Ctrough,ss (lowest concentration in a dosing interval 
at steady-state) that was similar to or greater than that of the standard 300 mg Q2W regimen in 
adults and 2) for which predicated maximum concentrations at steady-state (Cmax,ss) did not exceed 
the Cmax,ss obtained with the 300 mg QW regimens in adults. 
The predicted 5th percentile of Ctrough,ss for 200 mg Q4W SC in children ≥5 to <15 kg and 300 mg 
Q4W SC in children ≥15 to <30 kg were similar to the 5th percentile of Ctrough,ss for adult and 
adolescent Q2W concentrations.  The predicted 95th percentile of Cmax,ss of 200 mg Q4W SC in 
children ≥5 to <15 kg and 300 mg Q4W in children ≥15 to <30 kg did not exceed the adult 300 mg 
QW Cmax,ss. 
Safety considerations in this study will be informed with data obtained from the IDMC for the 
remaining subjects in part A.   
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1.2.3. 
Risk/Benefits of Participating in the Study 
1.2.3.1. 
Benefits 
The efficacy of dupilumab was evaluated in multiple randomized, double-blind, 
placebo-controlled studies in adults.  In addition, the efficacy of dupilumab was evaluated in 
separate randomized, double-blind, placebo-controlled studies carried out in adolescents and in 
pediatric patients ≥6 to <12 years old.  In each of these studies, dupilumab demonstrated clinically 
meaningful and statistically significant improvements compared to placebo in disease activity 
measures assessing objective AD signs (IGA, EASI, SCORing Atopic Dermatitis [SCORAD], 
body surface area [BSA] affected by AD), subjective symptoms (eg, Pruritus NRS, Patient 
Oriented Eczema Measure [POEM]), and quality of life (Dermatology Life Quality Index [DLQI] 
in adults, Childrens’ Dermatology Life Quality Index [CDLQI] in adolescents and patients 
≥6 to <12 years old).  These results formed the basis for approval of dupilumab for 
moderate-to-severe AD in adults worldwide, and in adolescents in US and EU.   
A first-step analysis was conducted on data (data cutoff of 21 Apr 2018) from adolescent patients 
(≥12 to <18 years old) enrolled in the OLE study, R668-AD-1434.  The results of this first-step 
analysis support the long-term efficacy of dupilumab in adolescent patients with 
moderate-to-severe AD.   
A second-step analysis was conducted on data (data cutoff of 22 Jul 2019) from pediatric patients 
≥6 to <12 years of age enrolled in the OLE study, R668-AD-1434.  The results of this second-step 
analysis support the long-term efficacy of dupilumab in patients ≥6 to <12 years of age with AD.  
Based on data available to date for part A of the current study, single-dose treatment with 
dupilumab 3 mg/kg or 6 mg/kg provided clinical benefit for both signs and symptoms in patients 
≥2 to <6 years, as well as patients ≥6 months to <2 years, of age with severe AD (see 
Section 1.2.2). 
1.2.3.2. 
Risks 
The most common adverse drug reactions identified in the dupilumab adult AD clinical program 
were injection site reactions common (≥10%).  Other common adverse reactions (≥1% and <10%) 
included conjunctivitis, allergic conjunctivitis, eye pruritus, blepharitis, oral herpes, and 
eosinophilia.  In the completed adolescent AD studies and in the ongoing study in patients 
≥6 to <12 years old, the safety profile was consistent with that reported in adults and there were 
no new safety signals detected with dupilumab in the adolescent population.  An acceptable safety 
profile has also been demonstrated in adolescent patients enrolled in the asthma study EFC13579 
(n=107). 
The results of the first-step analysis of adolescent OLE study R668-AD-1434 also showed that 
long-term treatment with dupilumab was well tolerated in adolescent patients, with a long-term 
safety profile similar to that of adolescent patients treated with dupilumab for shorter durations.    
The results of the second-step analysis of the OLE study R668-AD-1434 also showed that 
long-term treatment with dupilumab was well tolerated in pediatric patients ≥6 to <12 years old, 
with a long-term safety profile similar to that of adolescent patients treated with dupilumab for a 
similar duration. 
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In part A of the current study, single-dose treatment with dupilumab 3 mg/kg or 6 mg/kg appeared 
to be well tolerated in patients aged ≥2 to <6 years.  The incidence of TEAEs was comparable in 
patients in the 3 mg/kg and 6 mg/kg dose groups (3/10 [30%] and 2/10 [20%], respectively).  None 
of these events was severe.  One patient had a serious TEAE of anaphylactic reaction.  This event 
was assessed as not related to dupilumab, as an alternate cause for the event was present (history 
of allergy to nuts and patient had consumed nuts just prior to onset of event). 
Moreover, in part A of the current study, single-dose treatment with dupilumab 3 mg/kg or 
6 mg/kg also appeared to be well tolerated in patients aged ≥6 months to <2 years.  The incidence 
of TEAEs was comparable in patients in the 3 mg/kg and 6 mg/kg dose arms (7/10 [70%] for each 
treatment regimen).  The only TEAE that was reported in >2 patients was nasopharyngitis.  One 
patient had a serious TEAE of anaphylactic reaction, which was assessed as not related to 
dupilumab as an alternate cause for the event was present (had consumed shell fish [crab] just prior 
to onset of event). 
Overall, systemic hypersensitivity has been established as an important identified risk with 
dupilumab.  As protein therapeutics, all monoclonal antibodies (mAbs) are potentially 
immunogenic.  Rare serious and systemic hypersensitivity reactions have been observed in the 
dupilumab program including serum sickness/serum sickness-like reaction in the adult AD and 
anaphylaxis related to dupilumab in the adult asthma clinical studies.  No event of serum 
sickness/serum sickness-like reaction or anaphylaxis related to dupilumab has been reported in the 
adolescent AD program. 
In study R668-AD-1539, patients will be monitored at the study center for 2 hours post-dose for 
the first 3 visits at which study drug is administered to facilitate detection and treatment of any 
immediate hypersensitivity reactions to the study drug. 
An important potential risk “Eosinophilia associated with clinical symptoms” has been observed 
in the asthma clinical trials (few cases of eosinophilic granulomatosis with polyangiitis and 
eosinophilic pneumonia) but not in AD clinical studies. 
Nonclinical repeat-dose toxicity studies and reproductive and developmental toxicity studies have 
not identified any general or reproductive toxicology or postnatal effects of anti-IL-4 receptor 
subunit alpha (anti-IL-4Rα) surrogate antibodies in cynomolgus monkeys and mice.  These 
nonclinical data, together with the clinical safety profile of dupilumab to date, support the 
evaluation of dupilumab in pediatric patients. 
1.2.3.3. 
Risk/Benefit Conclusion 
The safety data and the clinical benefit of dupilumab demonstrated in part A of this study as well 
as in multiple AD studies in adult, adolescent, and pediatric (≥6 to <12 years of age) patients, 
support a favorable benefit-risk profile for dupilumab. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objective for part A of the study is to characterize the safety and PK of dupilumab 
administered as a single dose in pediatric patients, 6 months to less than 6 years of age, with severe 
AD. 
The primary objective for part B of the study is to demonstrate the efficacy of multiple doses of 
dupilumab over 16 weeks of treatment when administered concomitantly with TCS in pediatric 
patients, 6 months to less than 6 years of age, with moderate-to-severe AD. 
2.2. 
Secondary Objectives 
The secondary objective of part A of the study is: 
• To evaluate the efficacy and immunogenicity of a single dose of dupilumab in patients 
6 months to less than 6 years of age with severe AD 
The secondary objective of part B of the study is: 
• To assess the safety and immunogenicity of multiple doses of dupilumab over 16 weeks 
of treatment when administered concomitantly with TCS in patients 6 months to less 
than 6 years of age with moderate-to-severe AD 
2.3. 
Other Objectives 
The other objectives of part B of the study is: 
• To assess the concentrations of dupilumab in serum following repeated SC dosing. 
• To assess the effects of dupilumab on blood and skin biomarkers of inflammation in 
comparison with placebo.  
• To study dupilumab’s mechanism of action (related to efficacy and/or safety), why 
some patients respond better than others (safety and/or efficacy), type 2 
inflammation, as well as AD and related diseases. 
3. 
STUDY DESIGN 
3.1. 
Study Description and Duration 
This study will be conducted in 2 parts:  
 
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Part A 
Part A of the study will be an open-label, single ascending-dose, sequential cohort study 
investigating the PK, safety, and efficacy of a single dose of SC dupilumab in pediatric patients 
with severe AD (children aged ≥6 months to <6 years of age).   
Study cohorts will only be used in part A of the study.  Two sequential age cohorts are planned in 
part A: age cohort 1 (≥2 to <6 yrs. old) and age cohort 2 (≥6 months to <2 yrs. old).  Within each 
age cohort, approximately 10 patients will be enrolled in each of the 2 dose sub-cohorts: sub-cohort 
A (3 mg/kg) and sub-cohort B (6 mg/kg).  Enrollment and study dosing will start with cohort 1A 
(≥2 to <6 yrs. old, 3 mg/kg dose, n=10).  Following safety review of data from cohort 1A, 
enrollment will start in both cohort 1B (≥2 to <6 yrs. old, 6 mg/kg dose, n=10) and cohort 2A (≥6 
months to <2 yrs. old, 3 mg/kg dose, n=10) (see details in Section 3.1.2 and Figure 4).  Following 
safety review of data from cohort 2A, enrollment will start in cohort 2B (≥6 months to <2 yrs. old, 
6 mg/kg dose, n=10). 
To ensure adequate representation of patients from all age-groups, a cap will be placed on the 
number of patients that will be enrolled in each of the dose sub-cohorts (3 mg/kg and 6 mg/kg) as 
follows: 
Cohorts 1A and 1B: 
• 2 years to <4 years of age: 7 patients 
• 4 years to <6 years of age: 7 patients 
Cohorts 2A and 2B: 
• 6 months to <1 year of age: 7 patients 
• 1 year to <2 years of age: 7 patients 
Part A of the study will consist of a screening period (day -35 to day -1), a baseline visit (day 1), 
a single-dose treatment followed by a 4-week PK sampling period (Figure 2), and an additional 
4-week follow-up period (only for patients who decline to participate a subsequent OLE study).  
After informed consent is provided by patients’ parents or legal guardians, patients will be assessed 
for study eligibility at the screening visit.  Patients may be rescreened if they fail the screening 
evaluation for reasons related to incidental transitory conditions, unless the reason for the screen 
failure is related to failing the inclusion criteria for disease severity.  Patients who meet eligibility 
criteria will undergo baseline assessments and then proceed to part A to receive their single dose 
of study treatment on day 1 and undergo functional dupilumab PK sample collection during the 
following 4 weeks for characterizing the single-dose PK profile.  All patients will be offered an 
opportunity to participate in an OLE study at week 4.  Patients who decline will be followed up 
for an additional 4 weeks (total of 8 weeks).  This will ensure a sufficient follow-up period for 
these patients and will maximize patient safety. 
Concomitant use of TCS with or without TCIs will be permitted during part A of the study, 
including the screening period (Section 5.2).  Investigators will be instructed to standardize the use 
of topical steroids to medium, and/or low potency, and ensure that the use of TCS is consistent 
with product labels.  The use of high-potency TCS is not allowed (except for rescue).   
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The use of TCI will be reserved for problem areas (eg, face, intertriginous, and genital areas) and 
only in children ≥2 years of age. 
Safety and laboratory assessments, samples for dupilumab concentration, and efficacy assessments 
will be performed or collected at specified time points throughout part A of the study according to 
the schedule of events listed in Table 1.  Anti-drug antibody assessments will be conducted at time 
points analyzed as listed in Table 1.  Patient participation in the genomics sub-study in part A is 
optional.  Samples for DNA analysis will be collected from patients whose parents or legal 
guardians agree to enroll in the optional sub-study and sign a separate genomics sub-study 
informed consent form (ICF) (see Section 6.2.7.3). 
An OLE study (R668-AD-1434) in patients aged 6 months to <18 years old is currently ongoing.  
Patients who complete this study (ie, complete up to the end of study visit in part A [week 4]), 
may be eligible to enroll in this OLE study, in which they will receive treatment with dupilumab.  
Part B 
Part B of the study will be a randomized, double-blind, placebo-controlled, parallel-group study 
to investigate the efficacy and safety of SC dupilumab when administered concomitantly with TCS 
in pediatric patients, ≥6 months to <6 years of age, with moderate-to-severe AD.  The number of 
patients with moderate AD (IGA=3) will be capped at approximately 40. 
Part B of the study will consist of the following 3 periods: a screening period of up to 56 days 
(including 2 weeks of TCS standardization), a treatment period of 16 weeks, and a follow-up 
period of 12 weeks (Figure 3).  Patients who enrolled in part A of the study are not eligible to 
participate in part B.  After informed consent is provided by patients’ parents or legal guardians, 
patients will be assessed for study eligibility at the screening visit.  Assent will be collected from 
patients, if applicable, as per local regulatory (competent authority/ethics) guidelines, based upon 
the age and level of maturity of the patient.  During the screening period, systemic treatments for 
AD will be washed out, as applicable, according to the eligibility requirements.  The use of TCS 
will be permitted during the screening period.  Starting on day -14, all patients will initiate a 
standardized low potency TCS treatment regimen according to the guidelines in Section 5.2.  The 
use of TCIs will be permitted during the screening period, except for the 2-week period leading up 
to the baseline visit.  Patients may be rescreened twice if they fail the screening evaluation for 
reasons related to incidental transitory conditions, unless the reason for the screen failure is related 
to failing the disease severity inclusion criteria.   
Patients will be required to apply moisturizers twice daily for at least 7 days before randomization 
(not including the day of randomization) and continue throughout the study.  However, to allow 
adequate assessment of skin dryness, moisturizers should not be applied on the area(s) of 
non-lesional skin designated for such assessments for at least 8 hours before each clinic visit. 
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Patients who continue to meet eligibility criteria at baseline will undergo day 1/baseline 
assessments.  Patients will be randomized in a 1:1 ratio stratified by baseline body weight 
(≥5-<15 kg and ≥15-<30 kg), baseline disease severity (IGA=3 and 4), and region/country (North 
America, Europe, Japan, and China).  The number of patients with moderate AD (IGA=3) will be 
capped at approximately 40.  Approximately 160 patients will be randomized to 1 of the following 
2 treatment regimens: 
• dupilumab Q4W tiered fixed-dose (200 mg or 300 mg) treatment regimen:   
− Patients with baseline weight ≥5 to <15 kg will receive an SC injection of 200 mg 
dupilumab (1.14 mL of a 175 mg/mL solution) on day 1 and then 200 mg Q4W 
from week 4 to week 12.   
− Patients with baseline weight ≥15 to <30 kg will receive an SC injection of 
300 mg dupilumab (2 mL of a 150 mg/mL solution) on day 1 and then 300 mg 
Q4W from week 4 to week 12.  
• placebo Q4W treatment regimen:  patients will receive matching placebo on day 1 
and then Q4W from week 4 to week 12.   
− In the ≥5 to <15 kg weight stratum, patients randomized to placebo will receive 
Q4W injections of placebo (1.14 mL) matching 200 mg dupilumab.   
− In the ≥15 to <30 kg weight stratum, patients randomized to the placebo group 
will receive Q4W SC injections of placebo (2 mL) matching 300 mg dupilumab.  
Figure 1 shows the randomization scheme for part B of the study.  
Figure 1: 
Randomization Scheme (Part B) 
 
1 : 1 
1 : 1 
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Note: Randomization will be stratified by baseline weight (≥5-<15 kg and ≥15 to <30 kg), baseline disease severity 
(IGA=3, 4), and region/country (North America, Europe, Japan, and China). 
Starting on day -14, all patients will be required to initiate treatment with low potency TCS using 
a standardized regimen (see Section 5.2 for details). 
During the treatment period, patients will have in-clinic visits at baseline, week 1, week 2, and 
week 4, then monthly in-clinic visits through week 16 with weekly telephone visits in between the 
clinic visits. 
Safety and laboratory assessments, samples for dupilumab concentration and ADA response to 
dupilumab, and efficacy assessments will be performed or collected at specified time points 
throughout part B of the study according to the schedule described in Table 2.  The end of treatment 
period visit will occur at week 16, 4 weeks after the last dose of study drug.  The co-primary 
endpoints (proportion of patients with an EASI-75 is a co-primary endpoint for EU and EU 
Reference Market Countries only, key secondary endpoint for US) will be assessed at this visit.  
The study procedures and assessments for patients enrolled in Japan and China will be the same 
as for other patients enrolled outside of Japan and China. 
An OLE study (R668-AD-1434) in patients aged 6 months to <18 years old is currently ongoing.  
Patients who complete the treatment period in part B may subsequently be eligible to participate 
in the OLE study (see Section 5.8 for details).  
Patients who decline to participate in the OLE will enter a follow-up period of 12 weeks.  
Follow-up visits will occur every 4 weeks from week 20 through week 28.  During the follow-up 
period, patients will be monitored for safety and tolerability and have laboratory and clinical 
assessments as listed in the schedule of events, Table 2.  Patients who are ADA positive at their 
last study visit (early termination or end of study) and who do not participate in the OLE may be 
considered for follow-up based on the overall clinical presentation at that time.  Patients who are 
considered for follow-up may be asked to return to the clinic to have additional blood samples 
collected for ADA analysis. 
Patients will also undergo sparse blood sample collection for characterizing the repeat dose serum 
trough concentrations of dupilumab during part B.   
Tape stripping samples may be taken for exploratory biomarker analysis from patients whose 
parent(s) or legal guardian(s) consent for the child to participate in this optional sub-study at a 
subset of study sites (see Section 6.2.7.2). Patient participation in a tape stripping sub-study in part 
B is optional.   
Samples for DNA analysis will be collected from patients whose parents or legal guardians agree 
to enroll in the optional sub-study and sign a separate genomics sub-study ICF (see 
Section 6.2.7.3).  Patient participation in the genomics sub-study in part B is optional.   
Patient participation in the vaccination sub-study in part B is optional.  Patients’ parents or legal 
guardians who plan to have their children vaccinated during the study and agree to enroll them in 
the optional sub-study, will sign a separate vaccination sub-study ICF for the collection of 2 blood 
samples for assay of vaccine immunoglobulin G (IgG) in serum for each vaccine administered (see 
Section 6.2.1). 
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Figure 2: 
Study Flow Diagram (Part A) 
Screening 
Baseline 
Single-Dose Treatment and PK 
Sampling Period 
Follow-Up 
 
 
 
 
 
 
 
Single Dose Treatment 
PK Sampling 
End of Study  
(Day –35) 
(Day –1) 
(Day 1) 
(Days 1, 3, 8, 18, 29) 
(Day 57) 
Figure 3: 
Study Flow Diagram (Part B) 
 
Screening 
 
Treatment Period 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TCS Std 
Moisturizer 
Baseline 
Dosing 
End of Treatment 
Part B 
End of 
Study 
Part B 
(Day  
–56) 
(Day  
–14) 
(Day  
–7) 
(Day  
–1) 
(Day 1) 
 
(Days 1, 29, 57, 85) 
(Day 113) 
(Day 197) 
TCS Std: topical corticosteroid standardization 
Note:  The length of the screening period is not fixed but must not exceed 56 days (including TCS standardization).  
The length of the TCS standardization period is fixed at 14 days.  Moisturizers are to be applied at least twice daily 
during the 7 consecutive days prior to randomization (not including day of randomization) and are to be used 
throughout the study.  At least 11 of the 14 total applications of moisturizers prior to randomization must be applied 
for the patient to remain eligible for the study.   
3.1.1. 
Study Cohorts 
Study cohorts will only be used in part A of the study. 
In part A, 2 sequential ascending age cohorts are planned: age cohort 1 (≥6 months to <2 years) 
and age cohort 2 (≥2 to <6 years).  Each age cohort will consist of approximately 20 patients (an 
approximate total of 10 patients in 2 dose sub-cohorts):  sub-cohort A (dose of 3 mg/kg) and 
sub-cohort B (dose of 6 mg/kg): 
• Cohort 1A:  children age cohort (≥2 to <6 years), dose sub-cohort 3 mg/kg SC 
• Cohort 1B:  children age cohort (≥2 to <6 years), dose sub-cohort 6 mg/kg SC 
• Cohort 2A:  children age cohort (≥6 months to <2 years), dose-sub-cohort 3 mg/kg 
SC 
• Cohort 2B:  children age cohort (≥6 months to <2 years), dose sub-cohort 6 mg/kg SC 
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3.1.2. 
Dose Escalation and Study Stopping Rules 
Dose escalation and stopping rules are only applicable to part A of the study. 
A Dose-Escalation Review Committee (DERC) will be established for the purpose of dose 
escalation during part A of the study (see Section 3.3.2 for details on committee membership). 
The DERC will meet at the following pre-defined time points: 
1. When all of the patients enrolled in cohort 1A have completed the week 4 (day 29) safety 
assessments 
2. When all of the patients enrolled in cohort 2A have completed the week 4 (day 29) safety 
assessments 
During these meetings, the DERC will review all available safety data from completed cohorts.  
This will include data on AEs (including SAEs and adverse events of special interest [AESIs]), 
vital signs, and laboratory values.  The DERC will monitor AEs including, but not limited to, 
serious infections, severe injection site reactions, systemic immune reactions like hypersensitivity 
and severe conjunctivitis. 
Dose escalation to the next cohort will not immediately proceed if the following occurs: 
• If 2 or more patients in a cohort experience a severe AE that is deemed related to study 
drug by the investigator 
If this occurs, the DERC will evaluate all of the available safety information and inform senior 
scientific leadership at Regeneron who will make the final recommendation on dose escalation to 
the next cohort. 
For other unanticipated safety findings, the DERC, at their discretion, may defer to the senior 
scientific leadership at Regeneron for the decision on dose-escalation to the next cohort. 
In addition to the pre-defined time points mentioned above, DERC will also meet on an ad-hoc 
basis if the following occurs: 
• A treatment-emergent SAE occurs that is assessed by the investigator or the sponsor 
to be related to dupilumab treatment 
In this instance, a comprehensive review of the data gathered from the patient(s) in whom the 
SAE(s) occurred will be performed.  In addition, review of all safety data gathered from the study 
available at the time of the meeting will be performed.  Based on this review, DERC will inform 
senior scientific leadership at Regeneron who will make the final recommendation on whether to 
continue the study as planned, or to terminate the study. 
The dose escalation scheme in part A is presented in Figure 4. 
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Figure 4: 
Study Design and Dose Escalation Scheme (Part A) 
 
Note: cohort 1A:  ≥2 to <6 years of age, 3 mg/kg dose; cohort 1B:  ≥2 to <6 years of age, 6 mg/kg dose; cohort 2A:  
≥6 months to <2 years of age, 3 mg/kg dose, cohort 2B:  ≥6 months to <2 years of age, 6 mg/kg dose 
Patients will be offered an opportunity to participate in an OLE study at week 4.  Patients who 
decline the OLE study will be followed up for an additional 4 weeks. 
3.1.3. 
End of Study Definition 
The end of study is defined as the last visit for the last patient in part B. 
3.2. 
Planned Interim Analysis 
No interim analysis with alpha spending is planned. 
However, an unblinded primary analysis (see Section 9.5.2.4) may be performed once all patients 
in part B have completed the 16-week treatment period as specified in the protocol (week 16 visit 
or earlier for those patients who are withdrawn prematurely from the study).  If performed, this 
primary analysis will be considered the final analysis for the primary and secondary efficacy 
endpoints.  The submission of marketing applications to some regulatory authorities will be 
supported by these week 16 data. 
A description of the statistical methods to be employed and blinding implications are in 
Section 9.5.2.4. 
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3.3. 
Study Committees 
3.3.1. 
Independent Data Monitoring Committee 
An IDMC, composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety in parts A and B by conducting formal reviews of 
accumulated safety data.  If requested, the IDMC may have access to any other requested data for 
the purposes of a risk-benefit assessment. 
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study.  The IDMC 
will be informed about decisions made at the internal dose escalation review meetings and will be 
provided with a summary of the data analyzed during these meetings.  Advice of IDMC may be 
sought by the internal safety monitoring team (SMT) regarding decisions to suspend dosing (see 
Section 3.1.2 for details).  The IDMC will also institute any measures that may be required for 
ensuring the integrity of the study results during the study execution.  This committee will be in 
place for the duration of the study to monitor the safety of the patients and to provide the Sponsor 
with appropriate recommendations in due time to ensure patient safety. 
All activities and responsibilities of the IDMC are described in the IDMC charter. 
3.3.2. 
Dose Escalation Review Committee 
The DERC will review data from part A of the study and will make decisions on dose escalation 
(see Section 3.1.2 for details). 
The DERC will include the following core members: Regeneron Medical Monitor, Regeneron 
Risk Management Lead and designated Lead Principal Investigator.  Other members of this 
committee will include, but will not be limited to, representatives from Clinical Trial Management, 
Biostatistics and Data Management, and Pharmacovigilance.  Other individuals, including relevant 
site investigator(s), may be included as needed. 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS  
4.1. 
Number of Patients Planned 
Part A of the study was conducted at multiple sites in North America and Europe.  Part B of the 
study will be conducted at multiple sites in North America, Europe, Japan, and China. 
For part A of the study, approximately 40 pediatric AD patients are planned to be enrolled in 
4 cohorts.  To adequately characterize the safety/PK profile of this population, a total of 10 patients 
in each of the following cohorts will be enrolled: 
• Cohort 1A:  ≥2 to <6 years of age, 3 mg/kg dose, n = 10 
• Cohort 1B:  ≥2 to <6 years of age, 6 mg/kg dose, n = 10 
• Cohort 2A:  ≥6 months to <2 years of age, 3 mg/kg dose, n = 10 
• Cohort 2B:  ≥6 months to <2 years of age, 6 mg/kg dose, n = 10 
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For part B of the study, a sample size of approximately 160 patients is planned.  Randomization 
will be stratified by baseline weight (≥5-<15 kg and ≥15 to <30 kg), baseline disease severity 
(IGA=3, 4), and region/country (North America, Europe, Japan, and China). To ensure adequate 
representation of patients from Japan and China, randomization slots will be reserved for patients 
from these countries in an interactive web response system (IWRS).  The number of patients with 
moderate AD (IGA=3) will be capped at approximately 40. 
4.2. 
Study Population 
The study population includes pediatric patients (aged ≥6 months to <6 years at the time of 
screening visit) who have severe AD (part A) or moderate-to-severe AD (part B) that cannot be 
adequately controlled with topical AD medications. 
4.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female ≥6 months to <6 years of age at the screening visit 
2. Diagnosis of AD according to the American Academy of Dermatology consensus criteria 
at the screening visit 
3. Patients with documented recent history (within 6 months before the screening visit) of 
inadequate response to topical AD medication(s) 
NOTE: 
• Patients who are unable to achieve and/or maintain remission and low disease activity 
(comparable to IGA 0=clear to 2=mild) despite treatment with a daily regimen of 
medium to higher potency TCS (±TCI as appropriate), applied for at least 28 days of 
use, or for the maximum duration recommended by the product prescribing 
information, whichever is shorter, will meet the definition of inadequate response for 
the purpose of this study. 
• Patients with documented systemic treatment for AD in the past 6 months are also 
considered as inadequate responders to topical treatments and are potentially eligible 
for treatment with dupilumab after appropriate washout. 
• Acceptable documentation includes contemporaneous chart notes that record topical 
medication prescription and treatment outcome, or investigator documentation based 
on communication with the patient’s treating physician.  If documentation is 
inadequate, potential patients may be offered a course of treatment with a daily 
regimen of TCS of medium potency (±TCI as appropriate*), applied for at least 
28 days during the screening period or for the maximum duration recommended by 
the product prescribing information, whichever is shorter.  Patients who demonstrate 
inadequate response, as defined above, or develop important side effects (eg, 
significant skin atrophy, systemic effects) during this period will still be eligible for 
inclusion in the study. 
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* TCIs are not permitted during the 2-week TCS standardization period.  
Investigators may substitute TCIs with low potency steroids on areas of skin on 
which TCIs are typically applied (eg, face, neck, intertriginous, and genital areas). 
NOTE:  The target population with respect to disease severity differs for part A (severe AD) 
and part B (moderate-to-severe AD).  Therefore, disease severity criteria are specified 
separately for part A and part B in inclusion criterion 4 to 6 below: 
4. IGA score at screening and baseline visits: 
a. part A:  IGA = 4 
b. part B:  IGA ≥3 
5. EASI score at screening and baseline visits 
a. part A:  EASI ≥21 
b. part B:  EASI ≥16 
6. BSA involvement at screening and baseline visits: 
a. part A:  ≥15% 
b. part B:  ≥10% 
7. At least 11 (of a total of 14*) applications of a topical emollient (moisturizer) during the 
7 consecutive days immediately before the baseline visit (not including the day of 
randomization) (for part B of the study only) 
*  Based on application of moisturizer twice daily for 7 days leading up to randomization.  
Application of emollient more than twice in a day is permitted but the additional 
applications will not be counted in the 11 required applications to fulfil eligibility for the 
study. 
8. Parent(s) or legal guardian (s)-provided signed informed consent.  Assent collected from 
patient, if applicable, as per local regulatory (competent authority/ethics) guidelines, 
based upon the age and level of maturity of the patient. 
9. Parents/caregiver or legal guardians, as appropriate, are able to understand and complete 
the study requirements and study-related questionnaires 
10. Baseline worst scratch/itch score weekly average score for maximum scratch/itch 
intensity ≥4 (for part B of the study only) 
NOTE: Baseline worst scratch/itch average score for maximum itch intensity will be 
determined based on the average of daily worst scratch/itch NRS scores for maximum 
scratch/itch intensity (the daily score ranges from 0 to 10) during the 7 days immediately 
preceding randomization (does not include the day of randomization).  A minimum of 
4 daily scores out of the 7 days is required to calculate the baseline average score.  A 
daily score consists of answers to the following question. 
• “How would you rate your child’s scratching/itching at its worst in the past 
24 hours?” 
For patients who do not have at least 4 daily scores reported during the 7 days 
immediately preceding the planned randomization date, randomization should be 
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postponed until this requirement is met, but without exceeding the 56-day maximum 
duration for screening. 
11. At least 11 (of a total of 14) daily applications of low potency TCS during the 2-week 
TCS standardization period (beginning on day -14) leading up to the baseline visit (for 
part B of the study only). 
4.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Prior treatment with dupilumab. 
2. History of important side effects of low potency topical corticosteroids (eg, intolerance to 
treatment, hypersensitivity reactions to hydrocortisone 1%/hydrocortisone acetate 1% 
cream*, significant skin atrophy, systemic effects), as assessed by the investigator or 
patient’s treating physician (only applicable for part B of the study). 
*If a patient has a history of hypersensitivity reaction to hydrocortisone acetate 1% 
cream, and/or other ingredient in the particular TCS drug product, the patient can still be 
randomized if the investigator believes the patient can be safely treated during the study 
with a different low potency TCS drug product that does not have cross-reactivity to the 
drug product that caused the hypersensitivity (see Section 5.2 for further details). 
3. Treatment with a topical investigational drug within 2 weeks or within 5 half-lives (if 
known), whichever is longer, or treatment with a systemic investigational drug prior to the 
baseline visit. 
NOTE: Treatment with a systemic investigational drug refers to treatment received in a 
clinical study with a drug that is not yet available on the market. 
4. Treatment with a TCI within 2 weeks prior to the baseline visit (only applicable for part B 
of the study) 
5. Having used any of the following treatments within 4 weeks, or within a period equal to 
5 times the half-life of the drug, before the baseline visit, whichever is longer: 
a. Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, 
cyclosporine, mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, 
methotrexate, etc.) 
b. Phototherapy for AD 
6. Treatment with biologics, as follows: 
a. Any cell-depleting agents including but not limited to rituximab:  within 6 months 
before the baseline visit, or until lymphocyte and CD 19+ lymphocyte count returns 
to normal, whichever is longer 
b. Other biologics:  within 5 half-lives (if known) or 16 weeks, whichever is longer   
7. Treatment with crisaborole within 2 weeks prior to the baseline visit (only applicable for 
part B of the study)  
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8. Treatment with a live (attenuated) vaccine within 4 weeks before the baseline visit 
NOTE: For patients who have vaccination with live, attenuated vaccines planned during 
the course of the study (based on national vaccination schedule/local guidelines), it will 
be determined, after consultation with a pediatrician, whether the administration of a live 
(attenuated) vaccine can be postponed until after the end of study, or preponed to before 
the start of the study, without compromising the health of the patient: 
a. Patients for whom administration of live (attenuated) vaccine can be safely postponed 
would be eligible to enroll into the study. 
b. Patients who have their vaccination preponed can enroll in the study only after a gap 
of 4 weeks following administration of the vaccine. 
Note: This exclusion criterion is not applicable to inactivated vaccines (eg, diphtheria, 
tetanus, pertussis [DPT], hepatitis A, hepatitis B, inactivated polio vaccine [IPV], 
hemophilus influenza type b, meningococcal, pneumococcal, and flu shot) which are 
permitted during the study as well as during the screening period, without any requirement 
of washout prior to baseline visit. 
9. Planned or anticipated use of any prohibited medications and procedures during study 
treatment. 
10. Initiation of treatment of AD with prescription moisturizers or moisturizers containing 
additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products during 
the screening period (patients may continue using stable doses of such moisturizers if 
initiated before the screening visit) (for part B of the study only). 
11. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiprotozoals, or antifungals within 2 weeks before the baseline visit. 
NOTE: Patients may be rescreened after infection resolves.  A patient with mild, localized 
superficial infection can be included in the study based on investigator discretion. 
12. Established diagnosis of a primary immunodeficiency disorder (eg, Severe Combined 
Immunodeficiency, Wiskott Aldrich Syndrome, DiGeorge Syndrome, X-linked 
Agammaglobulinemia, 
Common 
Variable 
Immunodeficiency), 
or 
secondary 
immunodeficiency.  Patients suspected to have immunodeficiency based on their clinical 
presentation (history of invasive opportunistic infections eg, tuberculosis, histoplasmosis, 
listeriosis, coccidioidomycosis, pneumocystosis, chronic mucocutaneous candidiasis etc. 
or otherwise recurrent infections of abnormal frequency or prolonged duration suggesting 
an immune compromised status, as judged by the investigator) will also be excluded from 
the study. 
13. Eczema as part of a genodermatosis syndrome like Netherton's syndrome, Hyper IgE 
syndrome, Wiskott Alrdich syndrome etc. 
14. Known history of human immunodeficiency virus (HIV) infection or HIV seropositivity at 
the screening visit. 
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15. Established diagnosis of Hepatitis B viral infection at the time of screening or who are 
positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), at 
time of screening. 
NOTE: Patients who are HBsAg negative and hepatitis B surface antibody (HBsAb) 
positive are considered immune after a natural infection has cleared or they have been 
vaccinated against hepatitis B.  Therefore, they are acceptable for the study.  These patients 
will be allowed to enroll into the study but will be followed using routine clinical and liver 
function tests. 
16. Established diagnosis of hepatitis C viral infection at the time of screening or who are 
positive for hepatitis C antibody at the screening visit. 
17. History of past or current tuberculosis or other mycobacterial infection. 
Note: Irrespective of status of treatment or infection resolution.  Tuberculosis testing will 
be performed on a country-by-country basis according to local guidelines if required by 
regulatory authorities or ethic committees. 
18. Have known hepatic disease or are on current treatment for hepatic disease including but 
not limited to acute or chronic hepatitis, cirrhosis or hepatic failure, or has evidence of liver 
disease as indicated by persistent (confirmed by repeated tests ≥2 weeks apart), elevated 
transaminases (alanine aminotransferase [ALT], and/or aspartate aminotransferase [AST]) 
more than 3 times the upper limit of normal [ULN] during the screening period. 
19. Presence of any one or more of the following abnormalities in laboratory test results at 
screening: 
• Platelets ≤100×103/µL 
• Neutrophils ≤1.0×103/µL for patients <1 year of age; Neutrophils ≤1.5×103/µL for 
patients 1 year to <6 years of age 
• Eosinophils >5000/µL 
• Creatine phosphokinase (CPK) >2.5×ULN 
• Serum creatinine >1.5×ULN 
NOTE: If an abnormal value is detected at screening, a repeat test should be performed to 
confirm the abnormality.  If the repeat test confirms the abnormality, the patient will be 
categorized as a screen failure. 
20. Presence of skin comorbidities that may interfere with study assessments.  This includes, 
but is not limited to, conditions like scabies, seborrheic dermatitis, cutaneous T cell 
lymphoma, psoriasis, etc. 
21. History of malignancy at any time before the baseline visit. 
22. Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic 
infection, unless clinical and (if necessary) laboratory assessment have ruled out active 
infection before randomization. 
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23. Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect 
the patient's participation in the study.  Examples include, but are not limited to patients 
with short life expectancy, patients with major congenital malformations, patients with 
cardiovascular conditions (eg, major, clinically significant congenital cardiovascular 
abnormalities), severe renal conditions, hepato-biliary conditions (eg, Child-Pugh class B 
or C), active major autoimmune diseases (eg, lupus, inflammatory bowel disease etc.), 
other severe endocrinological, gastrointestinal, metabolic, pulmonary, neurological or 
lymphatic diseases.  The specific justification for patients excluded under this criterion will 
be noted in study documents (chart notes, case report forms [CRF], etc). 
24. Any other medical or psychological condition including relevant laboratory abnormalities 
at screening that, in the opinion of the investigator, suggest a new and/or insufficiently 
understood disease, may present an unreasonable risk to the study patient as a result of 
his/her participation in this clinical trial, may make patient's participation unreliable, or 
may interfere with study assessments.  The specific justification for patients excluded under 
this criterion will be noted in study documents (chart notes, CRF, etc). 
25. Planned major surgical procedure during the patient's participation in this study. 
26. Member of the investigational team or his/her immediate family. 
27. Body weight <5 kg or ≥30 kg at baseline (only applicable part B of the study). 
4.3. 
Premature Withdrawal from the Study 
A patient/parent or legal guardian has the right to withdraw the patient from the study at any time, 
for any reason, and without repercussion. 
The investigator and sponsor have the right to withdraw a patient from the study in the event of an 
intercurrent illness, AE, treatment failure, protocol violation, cure, and for administrative, or other 
reasons.  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who withdraw prematurely from the study will be asked to complete study assessments 
per Section 6.1.1. 
4.4. 
Replacement of Patients 
In part A, patients who are prematurely withdrawn from the study prior to completing the single 
dose PK sample collection (ie, prior to week 4, part A) may be replaced, if needed, to ensure an 
adequate number of evaluable patients.  The medical monitor, in cooperation with the study 
statistician and PK scientist, will decide if a patient who prematurely withdraws from the study 
should be replaced.  
Patients prematurely discontinued from the study in part B will not be replaced. 
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5. 
STUDY TREATMENTS 
Study drug treatment will be administered by study site personnel.  Background and rescue 
treatments will be applied by the patient’s caregiver. 
5.1. 
Investigational and Reference Treatments 
Part A 
Sterile dupilumab (REGN668) drug product 150 mg/mL will be provided in an aqueous buffered 
vehicle, pH 5.0.  It will be supplied in a 5-mL vial containing 2.5 mL (150 mg/mL) with a 
withdrawable volume of 2.0 mL or 300 mg of dupilumab.  Instructions on dose preparation are 
provided in the pharmacy manual. 
Study drug will be administered SC by the investigator or other qualified study personnel at the 
following dose and dosing schedules for part A: 
• For dose cohort 1A:  3 mg/kg at day 1 as a single dose  
• For dose cohort 1B:  6 mg/kg at day 1 as a single dose  
• For dose cohort 2A:  3 mg/kg at day 1 as a single dose  
• For dose cohort 2B:  6 mg/kg at day 1 as a single dose  
Part B 
Dupilumab 175 mg/mL:  Each 1.14 mL single-use, prefilled glass syringe with snap-off cap 
delivers 200 mg of study drug (1.14 mL of a 175 mg/mL solution). 
Dupilumab 150 mg/mL: Each 2.25 mL single-use, prefilled glass syringe with snap-off cap 
delivers 300 mg of study drug (2.0 mL of a 150 mg/mL solution). 
Placebo-matching dupilumab is prepared in the same formulation without the addition of protein 
(ie, active substance, anti-IL-4Rα mAb).  Two matching placebo formulations will be used:   
• 1.14 mL placebo matching 200 mg dupilumab formulation 
• 2 mL placebo matching 300 mg dupilumab formulation 
Patients will be randomized to receive either dupilumab (tiered fixed dose by body weight stratum: 
200 mg [patients ≥5 to <15 kg] or 300 mg [patients ≥15 to <30 kg]) Q4W or placebo Q4W.  Refer 
to Section 3.1 for further details. 
In part B, SC injection sites of the study drug should be alternated among the different quadrants 
of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms so that the same 
site is not injected for 2 consecutive injections.  To allow for adequate assessment of possible 
injection site reactions, study drug should be administered only into areas of normal looking skin 
(for patients with 100% BSA involvement, the injection should be administered into as near normal 
looking skin as possible).  Instructions for recording and reporting injection site reactions will be 
provided in the investigator site binder. 
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Patients will be monitored at the study site for a minimum of 2 hours after the first 3 doses of study 
drug (visits 3 [day 1/baseline], 7 [week 4]), and 11 [week 8]; vital signs (sitting systolic and 
diastolic blood pressures, heart rate, respiratory rate, and body temperature) and AE assessments 
will be done at 30 minutes (±10 minutes) post dose and then at 2 hours (±15 minutes).   
Instructions on dose preparation are provided in the pharmacy manual. 
5.2. 
Background Treatments 
Background treatment will only be required to be used by patients in part B of the study.   
In part B of the study, all patients are required to have moisturizers (emollients) applied at least 
twice daily for at least the 7 consecutive days immediately before randomization (does not include 
day of randomization).  At least 11 of the 14 total applications must be applied for the patient to 
remain eligible for the study.  Patients are to continue to have moisturizers applied throughout the 
remainder of the study (all 28 weeks where applicable).  However, to allow adequate assessment 
of skin dryness, moisturizers should not be applied for at least 8 hours before each clinic visit.  All 
types of moisturizers are permitted, but patients may not initiate treatment with prescription 
moisturizers or moisturizers containing additives during the screening period or during the study.  
Patients may continue using stable doses of such moisturizers if initiated before the screening visit.  
Starting on day -14, all patients in part B are required to initiate treatment with TCS using a 
standardized regimen according to the following guidelines: 
• Apply low potency TCS once daily to areas with active lesions.  Based on investigator 
discretion, low/mild potency TCS may also be used on areas of thin skin (face, neck, 
intertriginous, and genital areas, areas of skin atrophy, etc.).   
• Once the patient achieves an IGA score of 2 or less, lower frequency of use of low 
potency TCS to 3 times per week, and then stop once lesions are clear (IGA=0).  
Patients should be instructed to only use TCS on active lesions, and to stop use of TCS 
if lesions clear completely in between clinic visits. 
• If lesions return, reinstitute treatment with low potency TCS, with the same step-down 
approach described above upon lesion resolution. 
• For lesions persisting or worsening under daily treatment with low potency TCS, 
patients may be treated (rescued) with medium or high potency TCS (super potent 
TCS are not allowed to be used, even as rescue, see Section 5.3).  The use of medium 
or high potency TCS as rescue is only allowed after day 14.  A medium or high 
potency TCS should normally be restricted to use on non-delicate skin sites 
(excluding face, flexures, groin), and should not be used for a prolonged period in 
order to prevent the development of cutaneous atrophy and adrenal axis suppression.  
Low potency steroids should normally be used for delicate skin sites (face, flexures, 
groin) during these flares.  Topical calcineurin inhibitors may be used for rescue, 
alone or in combination with TCS, but the use of TCIs should be reserved for 
problem areas only (eg, face, neck, intertriginous, and genital areas, etc). 
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Steroids that can be used during the study are described below and in Appendix 2.  The use of TCS 
should be consistent with the product label.  The use of very high potency or super potent TCS is 
prohibited during the study, as their use is not recommended in patients under 12 years of age.  If 
patients have tolerance issues with any of these steroids, and/or to the excipients in a particular 
formulation (eg, hypersensitivity), or if they are not commercially available in some countries, 
they may substitute with products of the same potency from the list provided in the investigator 
site binder.  It is required that patients use hydrocortisone acetate 1% cream for low potency 
(hydrocortisone 1% cream can be used in case the acetate salt is not available).  Only in case of 
known side effects to hydrocortisone 1%/ hydrocortisone acetate 1% cream (eg, for 
hypersensitivity) or in case of non-availability due to any reason, other low potency TCS such as 
alclometasone dipropionate 0.05% cream or desonide 0.05% cream can be used. 
If rescue with TCS is needed, it is recommended that patients use triamcinolone acetonide 0.1% 
ointment for medium potency.  Other medium to high potency TCS can be used as per investigator 
discretion. (Please refer to Appendix 2 for a list of such agents). 
• It is required that moisturizers be applied twice daily during the 7 consecutive days 
immediately before randomization (does not include day of randomization) and 
patients are to continue to apply moisturizers throughout the study (once in the 
morning and once in the evening).  A 60-minute interval between the application of 
emollients and TCS is recommended wherever applicable. 
• Patients will return TCS tubes at each clinic visit through week 16, and these tubes 
will be weighed by the site staff to determine the actual amount of TCS used. 
5.3. 
Rescue Treatments 
Rescue treatment for worsening of AD may be provided to study patients at the discretion of the 
investigator in parts A and B of the study.  The use of rescue treatment is only allowed after day 14 
of the study in part B.  Investigators will be required to perform an IGA assessment prior to 
starting rescue treatment and initiate rescue treatment only in patients who either have an IGA 
score ≥3 or have intolerable symptoms.  If possible, investigators are encouraged to consider rescue 
initially with topical treatment (eg, medium or high potency TCS) and to escalate to systemic 
medications only for patients who do not respond adequately after at least 7 days of topical 
treatment.  Topical calcineurin inhibitors may be used for rescue, alone or in combination with 
TCS, but the use of TCIs should be reserved for problem areas only (eg, face, neck, intertriginous, 
and genital areas, etc).  Investigators may also consider rescue with crisaborole.  Rescue treatment 
for these topical therapies should be used as per prescribing information and local guidelines.  
Patients may continue study treatment if rescue consists of topical medications. 
Patients who receive systemic corticosteroids or systemic non-steroid immunosuppressive drugs 
(eg, cyclosporine, methotrexate, mycophenolate-mofetil, azathioprine, etc) as rescue medication 
during part B of the study, will be discontinued permanently from the study drug.  All patients will 
be asked to complete the scheduled study visits and assessments whether or not they complete 
study treatment and whether or not they receive rescue treatment for AD.  Investigators should 
make every attempt to conduct efficacy and safety assessments (eg, disease severity scores, safety 
laboratory tests) immediately before administering any rescue treatment.  An unscheduled visit 
may be used for this purpose, if necessary.  For the purpose of the efficacy responder analysis, a 
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pre-specified algorithm will be used to classify rescue (details in the Statistical Analysis Plan). In 
addition, a blinded review of all post-baseline medications to adjudicate rescue treatment, based 
on medical judgement, will be performed to adjudicate rescue.  Patients who receive rescue 
treatment as per this adjudication during the study will be considered treatment failures. 
5.4. 
Dose Modification and Study Drug Discontinuation Rules 
5.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
5.4.2. 
Study Drug Discontinuation 
The study drug discontinuation criteria are only applicable to part B of the study as patients receive 
a single dose of study drug in part A.  Patients who permanently discontinue from study drug and 
who do not withdraw from the study in part B, will be asked to return to the clinic for all remaining 
study visits per the visit schedule. 
Patients who opt to withdraw from the study (see Section 4.3) will be asked to complete study 
assessments, per Section 6.1.1. 
5.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently discontinued in the event of: 
• Anaphylactic reaction or other severe systemic reaction to the study drug 
• Diagnosis of a malignancy during study 
• Any infection that is opportunistic, such as active tuberculosis and other infections 
whose nature or course may suggest an immuno-compromised status 
• Severe laboratory abnormalities: 
− Neutrophil count ≤0.5×103 µL 
− Platelet count ≤50×103 µL 
− ALT and/or AST values greater than 3×ULN with total bilirubin >2×ULN (unless 
elevated bilirubin is related to confirmed Gilbert's Syndrome) 
− Confirmed AST and/or ALT >5×ULN (for more than 2 weeks) 
NOTE:  If the laboratory abnormality is considered causally related to study drug, 
study treatment will be permanently discontinued.  In cases in which a causal 
relationship to study drug can be reasonably excluded, (ie, an alternative cause is 
evident), study treatment will be discontinued but it may be resumed when the 
laboratory abnormality is sufficiently normalized.  A decision to resume study 
treatment will be made jointly by the investigator and medical monitor (medical 
monitor's written approval is required). 
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• Treatment with any prohibited concomitant medication or procedure (Section 5.7.1) 
NOTE: The use of TCI and crisaborole is prohibited during the 2 weeks of TCS 
standardization during part B (beginning on day -14 of the screening period) leading 
up the baseline visit, and during the treatment period.  The use of very high potency 
or super potent TCS is not allowed throughout the study (as their use is not 
recommended in patients under 12 years of age).  However, medium or high-potency 
TCS, TCIs, and crisaborole can be used as rescue treatment (see Section 5.3).  In this 
situation, the study drug may be continued.  Patients who receive systemic 
corticosteroids or systemic non-steroid immunosuppressive drugs (eg, cyclosporine, 
methotrexate, mycophenolate-mofetil, azathioprine, etc) as rescue medication during 
part B of the study, will be discontinued permanently from the study drug.   
5.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing will be temporarily discontinued in the event of: 
• Clinically important laboratory abnormalities, such as: 
− ALT or AST >3×ULN and ≤5xULN 
− Neutrophils ≤1.0×103/µL, but >0.5×103/µL for patients <1 year of age; Neutrophils 
≤1.5×103/µL, but >0.5×103/µL for patients 1 year to <6 years of age 
− Platelet count ≤100× 103/µL but >50×103/µL 
− Eosinophils >5000/µL  
− CPK >2.5×ULN 
− Serum creatinine >1.5× ULN 
• Other intercurrent illnesses or major surgery 
• An infection that requires parenteral treatment or oral treatment for longer than 2 weeks 
with antibiotic, antifungal, antiviral, antiparasitic, or antiprotozoal agents 
After the condition leading to suspension of dosing normalizes sufficiently, study treatment may 
resume at the discretion of the principal investigator in consultation with the medical monitor.  A 
decision to discontinue study drug and/or to reinstitute study treatment should be discussed with 
the medical monitor.  The investigator may suspend study treatment at any time, even without 
consultation with the medical monitor, if the urgency of the situation requires immediate action 
and if this is determined to be in the patient's best interest.  However, the medical monitor should 
be contacted as soon as possible in any case of study drug discontinuation.  Resumption of study 
treatment after temporary discontinuation should always be discussed with the medical monitor. 
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5.5. 
Method of Treatment Assignment 
Part A of the study is open-label; all patients will receive dupilumab.  To ensure adequate 
representation of patients from all age-groups, a cap will be placed on the number of patients that 
will be enrolled in each of the dose sub-cohorts (3 mg/kg and 6 mg/kg) as follows: cohorts 1A 
and 1B: 2 years to <4 years of age: 7 patients; 4 years to <6 years of age: 7 patients; cohorts 2A 
and 2B: 6 months to <1 year of age: 7 patients; 1 year to <2 years of age: 7 patients. 
Part B of the study is a randomized, double-blind, parallel group, placebo-controlled study in 
which approximately 160 patients will be randomized in a 1:1 ratio stratified by baseline weight 
(≥5-<15 kg and ≥15-<30 kg), baseline disease severity (IGA=3, 4), and region/country (North 
America, Europe, Japan, and China) to receive 1 of the following 2 treatment regimens.  
• dupilumab Q4W tiered fixed-dose (200 mg for patients ≥5-<15 kg or 300 mg for 
patients ≥15-<30 kg) regimen 
• placebo Q4W regimen 
Randomization will be performed according to a central randomization scheme provided by an 
IWRS to the designated study pharmacist (or qualified designee).  Randomization slots will be 
reserved for patients from Japan and China in the IWRS.  The number of patients with moderate 
AD (IGA=3) will be capped at approximately 40. 
5.5.1. 
Blinding 
Part A of the study is open-label, therefore blinding procedures will not be implemented. 
Part B of the study, except for IDMC members and the provisions specified in Section 5.5.2, will 
remain blinded to all individuals until the prespecified unmasking to conduct the primary analyses. 
Blinded study drug kits coded with a medication numbering system will be used in part B.  In order 
to maintain the blind, lists linking these codes with product lot numbers will not be accessible to 
individuals involved in study conduct. 
Anti-drug antibody and drug concentration results will not be communicated to the sites, and the 
sponsor’s operational team will not have access to results associated with patient identification 
until after the final database lock. 
5.5.2. 
Emergency Unblinding 
In part B of the study, unblinding of treatment assignment for a patient may be necessary due to a 
medical emergency, an SAE that is unexpected and for which a causal relationship to the study 
drug cannot be ruled out, or for any other significant medical event. 
• If unblinding is required in part B: 
− Only the investigator will make the decision to unmask the treatment assignment. 
− Only the affected patient will be unmasked. 
− The IWRS will provide the treatment assignment to the investigator. 
− The investigator will notify Regeneron and/or designee immediately that the patient 
has been unmasked.  
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5.6. 
Treatment Logistics and Accountability 
5.6.1. 
Packaging, Labeling, and Storage 
In part A of the study, open-label study drug will display the product lot number on the label. 
In part B of the study, a medication numbering system will be used in labeling blinded 
investigational study drug.  Lists linking medication numbers with product lot numbers will be 
maintained by the groups (or companies) responsible for study drug packaging.  In order to 
maintain the blind, these lists will not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2º to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
5.6.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2º to 8ºC to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be returned to the sponsor or designee. 
5.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
• dispensed to each patient, 
• returned from each patient (if applicable), and 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
5.6.4. 
Treatment Compliance 
In part B of the study, all drug compliance records, including information collected by 
parents/caregivers in the dosing electronic diary (e-diary), must be kept current and must be made 
available for inspection by the sponsor and regulatory agency inspectors. 
5.7. 
Concomitant Medications and Procedures 
Any treatment administered from the time of the first dose of study drug to the end of study visit 
will be considered concomitant medication.  This includes medications that were started before 
the study and are ongoing during the study. 
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5.7.1. 
Prohibited Medications and Procedures 
Treatment with the following concomitant medications is prohibited during the study.  Study drug 
will be immediately discontinued if any of the following are used during the study: 
• Treatment with a live (attenuated) vaccine; below is a list of examples of such 
vaccines; refer to investigator site binder for a current, comprehensive list of 
prohibited vaccines 
Chickenpox (Varicella) 
Oral typhoid 
FluMist-Influenza 
Rubella 
Measles (Rubeola) 
Smallpox (Vaccinia) 
Measles-mumps-rubella combination 
Yellow fever 
Measles-mumps-rubella-varicella combination 
Bacillus Calmette-Guerin 
Mumps 
Rotavirus 
Oral polio (Sabin) 
 
NOTE:  Treatment with an inactivated vaccine (eg, DPT, hepatitis A, hepatitis B, IPV, 
hemophilus influenza type b, meningococcal, pneumococcal, and flu shot) is permitted 
during the study as well as during the screening period, without any requirement of 
washout prior to baseline visit. 
• Treatment with an investigational drug (other than dupilumab) 
• Treatment with immunomodulating biologics 
• Treatment with systemic nonsteroidal immunosuppressant (may be used as rescue, 
see Section 5.3 for details)  
• For part A: 
− Treatment with high potency or very high potency topical corticosteroids (high 
potency steroids may be used as rescue, see Section 5.3 for details).  The 
investigator site binder will provide a list of steroids that fall under these classes. 
• For part B: 
− Treatment with medium potency, high potency, or very high potency topical 
corticosteroids (medium or high potency steroids may be used as rescue, see 
Section 5.3 for details.  A course of treatment with medium potency TCS may 
also be given during the screening period to demonstrate inadequate response to 
TCS and confirm eligibility for the study as per Section 4.2.1).  The investigator 
site binder will provide a list of steroids that fall under these classes. 
− Treatment with TCI* (may be used as rescue, see Section 5.3 for details) 
*Use is not permitted during the 2-week screening period leading up to the 
baseline visit, the treatment, and follow-up periods 
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− Treatment with crisaborole** (may be used as rescue, see Section 5.3 for details) 
**Use is not permitted during the 2-week screening period leading up to the 
baseline visit, the treatment, and follow-up periods 
• Initiation of treatment of AD with prescription moisturizers 
The following concomitant procedures are prohibited during study participation: 
• Major elective surgical procedures 
• Phototherapy (ultraviolet A and/or ultraviolet B) 
5.7.2. 
Permitted Medications and Procedures 
Other than the prohibited medications listed in Section 5.7.1, treatment with concomitant 
medications are permitted during parts A and B of the study.  This includes basic skin care 
(cleansing and bathing, including bleach baths), emollients (required as background treatment in 
part B), topical anesthetics, antihistamines, and topical and systemic anti-infective medications for 
any duration. 
The use of TCS will be permitted as a standardized regimen for part B (see Section 5.2 for details).  
The use of TCS is also permitted during part A.  It is recommended that patients use TCS of 
medium potency during part A (see investigator site binder for listing of TCS by class).  The use 
of TCS should be consistent with local country guidelines and product prescribing information. 
The use of TCIs is also permitted during part A, and during the screening period of part B, with 
the exception of the 2-week period leading up to the baseline visit.  However, TCI should be 
reserved for problem areas (eg, face, intertriginous, and genital areas).  The use of TCIs should be 
consistent with local country guidelines and product prescribing information.  Topical 
corticosteroids and TCI should not be used concomitantly to treat the same affected areas. 
The use of crisaborole is also permitted during part A, and during the screening period of part B, 
with the exception of the 2-week period leading up to the baseline visit.  The use of crisaborole 
should be consistent with local country guidelines and product prescribing information.   
Use of prescription moisturizers and moisturizers containing additives such as ceramide, 
hyaluronic acid, urea, or filaggrin degradation products, is allowed as long as the use of such 
moisturizers has already been initiated before the screening visit.  Initiation of treatment of AD 
with such moisturizers during the study is not allowed. 
Medications used to treat chronic disease such as diabetes, hypertension, and asthma are also 
permitted; if there is any question regarding whether a concomitant medication may be used during 
the study, the study site should contact the medical monitor. 
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5.8. 
Continuation of Dupilumab Treatment in an Open-Label Extension 
Study 
For Patients Enrolled in Part A 
Patients who complete the PK sampling period of part A (ie, through week 4), may be eligible to 
enroll in a subsequent extension study in which they will receive open-label treatment with 
dupilumab.   
In order to remain eligible for the OLE study, patients are required to adequately complete the 
assessments scheduled for the single-dose treatment and PK sampling period (through week 4) in 
part A, per the schedule of events described in Table 1. 
For Patients Enrolled in Part B 
Patients who complete the treatment period (week 16) will be offered an opportunity to screen for 
the OLE study at EOT visit.  These patients should complete the EOT visit (as per Table 2) before 
screening for the OLE.  Patients who discontinued prematurely (ie, patients who did not complete 
the protocol-defined EOT visit) cannot be screened for the OLE study before the date when the 
EOT visit (week 16) would have normally occurred.  In order to remain eligible for the OLE study, 
patients are required to adequately complete the assessments scheduled in the treatment period in 
part B, per the schedule of events described in Table 2.   
Patients who decline to participate in the OLE study will have a 12-week follow-up period. 
6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
6.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1 (Part A), and 
Table 2 (Part B). 
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Table 1: 
Schedule of Events for the Screening, Single-Dose Treatment and PK Sampling Period (Part A) 
Study Procedure 
Screening 
Period 
Single-dose Treatment and PK Sampling Period 
Additional Follow-Up 
Period8 
 
 
 
Screening 
Visit 1 
Baseline 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Unscheduled 
Visit7 
Early 
Termination Visit 
Week 
 
 
 
1 
3 
4 
6 
8 
 
 
Study Day(s) 
-35 to D-1 
1 
3 
8 
18 
29 
43 
57 
 
 
Visit window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
 
 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
Parental Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Parental Informed 
Consent for Optional 
Genomic Study1 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Treatment3: 
 
 
 
 
 
 
 
 
 
 
 
Administer Study 
Drug 
 
X2 
 
 
 
 
 
 
 
 
Concomitant Meds and 
Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy3 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
Pruritus, IGA, EASI, 
SCORAD, BSA 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Safety3: 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
 
X 
 
 
X 
X 
Adverse Events 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Procedure 
Screening 
Period 
Single-dose Treatment and PK Sampling Period 
Additional Follow-Up 
Period8 
 
 
 
Screening 
Visit 1 
Baseline 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Unscheduled 
Visit7 
Early 
Termination Visit 
Week 
 
 
 
1 
3 
4 
6 
8 
 
 
Study Day(s) 
-35 to D-1 
1 
3 
8 
18 
29 
43 
57 
 
 
Visit window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
 
 
LaboratoryTesting3,4,: 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
X 
 
X 
X 
X 
Blood Chemistry 
X 
 
 
 
 
X 
 
X 
X 
X 
HIV, HBsAg, HBsAb, 
HBcAb, Hepatitis C 
Ab, TB5 
X 
 
 
 
 
 
 
 
 
 
Biomarker6: 
 
 
 
 
 
 
 
 
 
 
TARC 
 
X 
 
 
 
X 
 
 
 
X 
Total serum IgE 
 
X 
 
 
 
X 
 
 
 
 
Research Testing: 
 
 
 
 
 
 
 
 
 
 
Optional DNA sample1 
 
X 
 
 
 
 
 
 
 
 
PK/Drug Concentration and ADA Samples: 
 
 
 
 
 
 
 
 
PK/Drug concentration 
sample6 
 
X 
X 
X 
X 
X 
 
 
X 
X 
ADA sample6 
 
X 
 
X 
 
X 
 
 
X 
X 
Note: AE = adverse event; BSA = body surface area; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; HBcAb = hepatitis B core antibody; 
HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IGA = Investigator Global Assessment; 
IgE = immunoglobulin E; PK = pharmacokinetic; SCORAD = SCORing Atopic Dermatitis; TARC = thymus and activation regulated chemokine; 
TB = tuberculosis. 
1 For patients who parents or legal guardians agree to their participation and provide a specific written informed consent for the optional genomics sub-study (DNA sample 
collection).  DNA sample should be collected at the day 1 visit, but can be collected at any visit during the study.   
2 Patients will be monitored at the study site at visit 2 for a minimum of 2 hours after study drug administration.  Vital signs and AE assessments will be done at 30 minutes 
(±10 minutes) post-injection, and then at 2 hours (±15 minutes) post-injection. 
3 Assessment/procedures should be conducted in the following order: patient-reported outcomes, investigator assessments, safety and laboratory assessments, administration of 
study drug. 
4 Samples to be collected prior to injection of study drug. 
5 TB testing will be performed on a country-by-country basis, according to local guidelines, if required by regulatory authorities or ethics boards. 
6 Samples to measure functional dupilumab concentration, ADA, and biomarkers will be collected prior to injection of study drug.  Patients who are ADA positive at their last 
study visit (early termination or end of study) and who do not participate in the OLE may be considered for follow-up based on the overall clinical presentation at that time.  
Patients who are considered for follow-up will be asked to return to the clinic to have additional samples collected for analysis. 
7 The specific assessments that will be performed at the unscheduled visit will depend upon the reason for the unscheduled visit. 
8 For patients who decline the subsequent open-label extension study.  
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Table 2: 
Schedule of Events for the Screening, Treatment, and Follow-Up Period (Part B) 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
scheduled 
Visit21 
ET 
Visit 
 
SCN 
TCS 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EOT 
 
 
EOS 
 
 
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-56 
to 
-15 
-14 
to 
-1 
1 
8 
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71 
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±4 
±4 
 
 
Screening/Baseline: 
 
Inclusion/ 
Exclusion22 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parental 
Informed 
Consent23 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parental 
Informed 
Consent for 
Optional 
Genomic 
Sub-study2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parental 
Informed 
Consent for 
Optional 
Vaccine 
Sub-study3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parental 
Informed 
Consent for 
Optional Tape 
Stripping 
Sub-study 
(selected study 
sites only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
scheduled 
Visit21 
ET 
Visit 
 
SCN 
TCS 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
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V1 
EOT 
 
 
EOS 
 
 
Visit 
1 
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81 
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101 
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141 
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- 
 
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-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
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64 
71 
78 
85 
92 
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113 
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±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Parental 
Informed 
Consent for 
Optional Use 
of Photographs 
(selected study 
sites only)30 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
vaccination 
plan4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology 
Exam (patients 
with history of 
certain eye 
disorders)32 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent/ 
Caregiver 
e-diary 
training5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
scheduled 
Visit21 
ET 
Visit 
 
SCN 
TCS 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EOT 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
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131 
141 
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-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
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64 
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85 
92 
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197 
 
 
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±3 
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±3 
±3 
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±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Treatment: 
TCS 
application6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TCS 
dispensation 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
X 
 
TCS 
accountability7 
 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Administer 
Study Drug8 
 
 
X
9 
 
 
 
X 
9 
 
 
 
X 
9 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Parent/ 
Caregiver 
Counseling for 
e-diary 
Completion 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
X 
 
Parent / 
Caregiver 
Recording of 
TCS Use via 
e-diary (daily) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Parent / 
Caregiver 
Recording of 
Emollient Use 
via e-diary 
(daily) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Meds and 
Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
scheduled 
Visit21 
ET 
Visit 
 
SCN 
TCS 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EOT 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit window 
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±3 
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±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Efficacy10: 
Assessment of 
Pruritus (worst 
scratch/itch) 
NRS11,12  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of 
Skin Pain NRS 
and Sleep 
Diary12,26  
 
 
X 
X  
X  
 
X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
IGA, EASI, 
SCORAD, 
BSA, GISS 
X 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
CDLQI12, 13 
IDQOL12, 13, 14, 
DFI12, 13 
POEM12, 14 
Caregiver 
Missed 
Workdays 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
CGID 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
CGIC 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
PASQ12,14,28 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
CNSQ12,14,29 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Photograph 
AD Areas 
(Selected 
Study Sites 
only) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
                                        VV-RIM-00131070-1.0 Approved - 28 Oct 2020 GMT-5:00


Clinical Study Protocol 
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 76 
CONFIDENTIAL 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
scheduled 
Visit21 
ET 
Visit 
 
SCN 
TCS 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EOT 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit window 
(days) 
- 
- 
 
±3 
±3 
±3 
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±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Safety: 
Weight 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Vital Signs 
X 
 
X
15 
X 
X 
 
X 
15 
 
 
 
X 
15 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
ECG27 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Adverse 
Events33 
X 
X 
X
15 
X 
X 
X 
X 
15 
X 
X 
X 
X 
15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing16: 
Hematology 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Blood 
Chemistry 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
HIV, HBsAg, 
HBsAb, 
HBcAb, 
Hepatitis C Ab, 
TB17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sample 
for vaccination 
response18 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Biomarkers19: 
TARC 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Serum 
Immunoglobuli
n profiling, 
antigen-
specific IgE 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
                                        VV-RIM-00131070-1.0 Approved - 28 Oct 2020 GMT-5:00


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Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
scheduled 
Visit21 
ET 
Visit 
 
SCN 
TCS 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EOT 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
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- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit window 
(days) 
- 
- 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Research 
Testing25: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional DNA 
buccal sample2 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional tape 
stripping 
sample31 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
PK/Drug Concentration and ADA Samples25: 
PK/Drug 
concentration 
sample19 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X  
ADA sample20 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Note: AD = atopic dermatitis; ADA = anti0drug antibody; AESI=adverse event of special interest; BL = Baseline; BSA = body surface area; CDLQI = 
Childrens’ Dermatology Life Quality Index; CGIC = Caregiver Global Impression of Change; CGID = Caregiver Global Impression of Disease; CNSQ = 
Caregiver-Reported Nasal Symptom Questionnaire; DFI = Dermatitis Family Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; e-
diary = electronic diary; EOT = End of treatment; EOS = End of Study; ET = Early Termination; GISS = Global Individual Signs Score; HBcAb = hepatitis B 
core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; ICF = informed consent 
form; IDQOL = Infants’ Dermatology Quality of Life Index; IGA = Investigator Global Assessment; IgE = immunoglobulin E; NRS = numeric rating scale;  
PASQ  = Pediatric Asthma Symptom Questionnaire; PK = pharmacokinetic; POEM = Patient Oriented Eczema Measure; PV = phone visit; Q4W = every 
4 weeks; SCN = screening; SCORAD = SCORing Atopic Dermatitis; TARC = thymus and activation regulated chemokine; TB = tuberculosis; TCS = topical 
corticosteroid; Std = standardization. 
1 
The site will contact the parent/caregiver by telephone to conduct these visits. 
2 
For patients whose parents or legal guardians agree to their participation and provide a specific written informed consent for the optional genomics sub-study (DNA sample 
collection), DNA sample should be collected at the day 1 visit but can be collected at any visit during the study.   
3 
Parents/caregivers of patients will be encouraged to provide vaccination plans for any vaccines which are in line with the patient’s age, and local medical practice (live 
attenuated vaccines are excluded) during the study.  Parents or legal guardians of patients planning to receive any vaccines during the study may optionally sign a separate 
informed consent for collection of 2 blood samples (a pre-vaccine and post-vaccine sample) for assay of vaccine IgG in serum for each vaccination. 
4 
The study team on site will collect information from the parents/caregivers regarding the vaccinations planned during the next 6 months from screening.  The study team 
should refer to the patient’s medical records and national vaccination schedule to gather this information.  The study team can also contact the patient’s primary physician 
and/or pediatrician to gather this information. 
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5 
Training of parents/caregivers regarding completion of e-diary at visit 1 to record a) completion of assessment of pruritus NRS (worst scratch/itch scale), skin pain NRS, sleep 
diary, and CNSQ and b) TCS and emollient usage.  Provide additional training as necessary based on review of e-diary use.  
6 
As per the standardized regimen outlined in Section 5.2 of the study protocol. 
7 
The type, amount, and potency of topical products used during the study will be recorded.  The amount of TCS used will be determined by weighing the tube at each visit 
through the end of the study. 
8 
The dose regimens, including frequency of administration in part B are placebo Q4W or dupilumab Q4W tiered fixed-dose (200 mg for patients ≥5-<15kg or 300 mg for 
patients ≥15-<30 kg). 
9 
Patients will be monitored at the study site at visits 3, 7 and 11 for a minimum of 2 hours after study drug administration. 
10 Assessments/procedures should be conducted in the following order: patient reported outcomes, investigator assessments, safety and laboratory assessments, administration of 
study drug. 
11 The assessment will be recorded daily.  Parents/caregivers will complete an e-diary daily to record pruritus (worst scratch/itch) NRS in patients. 
12 The questionnaires will be administered only to those patients and/or parents/caregivers who speak fluently the language in which the questionnaire is presented (based on 
availability of validated translations in participating countries).  It is recommended that the same person complete the questionnaire on behalf of the patient throughout the 
study. 
13 Childrens’ Dermatology Life Quality Index (CDLQI) for patients ≥4 years of age, Infants’ Dermatitis Quality of Life Index (IDQOL) for patients <4 years of age, Dermatology 
Family Index (DFI) to be completed by an adult family member of a child affected by dermatitis. 
14 Questionnaire will be completed by the parent/caregiver on behalf of the patient.  It is recommended that the same person complete the questionnaire on behalf of the patient 
throughout the study. 
15 Patients will be monitored at the study site at visits 3, 7, and 11 for a minimum of 2 hours after study drug administration.  Vital signs (sitting systolic and diastolic blood 
pressures, heart rate, respiratory rate, and body temperature) and AE assessments will be done at 30 minutes (±10 minutes) post-injection, and then at 2 hours (±15 minutes) 
post-injection. 
16 Samples will be collected before the injection of study drug.   
17 TB testing will be performed on a country-by-country basis, according to local guidelines, if required by regulatory authorities or ethics boards. 
18 Optional collection of blood for assay of vaccine IgG in serum for each vaccine administered.  The first sample should be drawn within 6 weeks prior to vaccination, and the 
second sample should be drawn 3 to 4 weeks (maximum 6 weeks) after vaccination.  Vaccinations should be performed in compliance with the patient’s recommended 
immunization schedule.  Blood collections should be conducted at regularly scheduled study visits but, if this is not feasible, samples can also be drawn at unscheduled visits.   
19 Samples to measure functional dupilumab concentration and biomarkers will be collected prior to injection of study drug.   
20 Samples to be collected prior to injection of study drug.  Patients who are ADA positive at their last study visit (early termination, or end of study) and who 
do not participate in the OLE may be considered for follow-up based on the overall clinical presentation at that time.  Patients who are considered for follow-
up may be asked to return to the clinic to have additional samples collected for analysis.  
21  The specific assessments that will be performed at the unscheduled visit will depend upon the reason for the unscheduled visit.  In the event of suspected 
SAEs, such as anaphylaxis or hypersensitivity, additional PK and ADA samples may be collected at or near to the event as practically possible. 
22  Eligibility based on age at time of screening visit. 
23  Assent collected from patient, if applicable, as per local regulatory (competent authority/ethics) guidelines, based upon the age and level of maturity of the 
patient. 
24  The length of the screening period is not fixed but must not exceed 56 days (including TCS standardization).  The length of the TCS standardization period is 
fixed at 14 days. 
25 Any unused serum samples collected for dupilumab concentrations or ADA measurements may be used for exploratory biomarker research related to AD, 
inhibition of the IL-4Rα pathway with an antibody, treatment response (PD and or predictive), or vaccine response, as well as to investigate unexpected AEs 
or to identify markers associated with adverse reactions. 
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26 Pain and sleep will be assessed daily for the 14 days leading up to the baseline visit, the 7 days leading up to the week 1 visit, the 7 days leading up to the 
week 2 visit, the 7 days leading up to the week 4 visit, the 7 days leading up to the week 16 visit, and 7 days leading up to the week 28 visit.  
Parents/caregivers will complete a daily e-diary on these days to record skin pain and sleep in patients. 
27 ECGs should be conducted prior to collection of blood samples at visits requiring blood draws. 
28 Completed only for the subset of patients with ongoing asthma. 
29 Completed only for the subset of patients with a medical history of allergic rhinitis.  Caregivers will be instructed on using the e-diary to record the CNSQ for 
14 days before baseline/day 1 and for the 7 days preceding visits 7, 19, and 22 (weeks 4, 16, and 28). 
30 Optional parental informed consent for use of photographs for educational/marketing purposes (selected study sites only). 
31 An optional tape stripping sub-study may be performed at a subset of study sites.  Parents or legal guardians who agree for their child to participate in the tape 
stripping sub-study will be required to sign a separate sub-study ICF before collection of the samples.  Baseline samples should be collected on day 1/baseline 
(pre-dose).  A second sample will be collected at week 16. 
32 Patients who have history of certain eye disorders (conjunctivitis, blepharitis or keratitis) within 12 months prior to the screening visit will be referred to an 
ophthalmologist (see Section 6.2.3.6).  Any baseline findings will be documented as part of the patient’s medical history and/or physical exam, as appropriate. 
33 Any patient who experiences an AESI related to an eye disorder will be referred to an ophthalmologist (see Section 7.2.3). 
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6.1.1. 
Early Termination Visit 
Patients who are withdrawn from the study will be asked to return to the clinic to complete early 
termination assessments, as described in Table 1 (Part A) and Table 2 (Part B). 
6.1.2. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
The specific assessments that will be performed at the unscheduled visit will depend upon the 
reason for the unscheduled visit.  In the event of suspected SAEs, such as anaphylaxis or 
hypersensitivity, additional PK and ADA samples may be collected at or near the event as 
practically possible. 
6.2. 
Study Procedures 
6.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed in parts A and B of the study for the sole purpose of 
determining study eligibility or characterizing the baseline population:  parental or legal guardian 
informed consent for the study and for the optional genomic sub-study, medical history, 
demographics, and HIV, HBsAg, HBsAb, HBcAb, and hepatitis C antibody testing.  Additionally, 
tuberculosis testing (will be performed on a country-by-country basis according to local guidelines 
if required by regulatory authorities or ethics boards).  Assent will be collected from patient, if 
applicable, as per local regulatory (competent authority/ethics) guidelines, based upon the age and 
level of maturity of the patient. 
In part B of the study, parental or legal guardian consent for the optional vaccine sub-study, 
parental/legal 
guardian 
informed 
consent 
for 
optional 
use 
of 
photographs 
for 
educational/marketing purposes (selected study sites only), parental/legal guardian informed 
consent for an optional tape-stripping sub-study (selected study sites only), and parent/caregiver 
e-diary training will also be performed at the screening/baseline visit.   
For the optional vaccine sub-study in part B, patients’ parents or legal guardians will be encouraged 
to provide vaccination plans for any vaccines which are in line with the patient’s age and local 
medical practice (live attenuated vaccines are excluded).  For patients’ parents or legal guardians 
who agree to participate in the vaccine sub-study, 2 blood samples will be collected from each 
patient for assay of vaccine IgG in serum for each vaccine administered.  The first sample should 
be drawn within 6 weeks prior to vaccination, and the second should be drawn 3 to 4 weeks 
(±6 weeks) after vaccination (see Table 2). 
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6.2.2. 
Efficacy Procedures 
A variety of parameters will be collected during parts A and B of the study to assess 
efficacy/effectiveness of dupilumab, including measures of AD severity, use of concomitant 
treatment for AD, and parent/caregiver-reported measures of AD symptoms and QOL. 
Questionnaires and patient-reported assessments should be administered prior to obtaining 
investigator assessments, safety and laboratory assessments, and study drug administration.  Please 
see investigator site binder for instructions on the administration and use of all patient-reported 
instruments (including Assessments of Pruritus [worst scratch/itch], Skin Pain, and Sleep Diary, 
CDLQI, Infants’ Dermatology Quality of Life Index [IDQOL], Dermatitis Family Index [DFI], 
Caregiver Missed Workdays, and POEM, Caregiver Global Impression of Disease [CGID], 
Caregiver Global Impression of Change [CGIC], Pediatric Asthma Symptom Questionnaire 
[PASQ], and Caregiver-Reported Nasal Symptom Questionnaire [CNSQ]).  
Instructions for taking photographs (in part B only) are provided in the photography reference 
manual. 
6.2.2.1. 
Assessment of Pruritus  
For part A, pruritus (scratch/itch) will be assessed by the parent/caregiver using a NRS at time 
points listed in Section 6.1, Table 1.  The parents/caregivers will be asked “On a scale of 0 to 10, 
with 0 being ‘no itch/scratching’ and 10 being the ‘worst itch/scratching imaginable’, how would 
you rate your child’s itch during the past 24 hours?” 
Itch will be measured during part B using a worst scratch/itch NRS that was developed and tested 
for the study-relevant age group.  This is an 11-point scale (0 to 10) in which 0 indicates no 
scratching/itching while 10 indicates worst scratching/itching possible.  The parents/caregivers 
will be asked to:  
“Answer the question below based on what you observe and what your child tells you (if 
applicable):” 
“How would you rate your child’s scratching/itching at its worst in the past 24 hours?” 
For part B, pruritus will be assessed by the parent/caregiver on a daily basis using an e-diary 
throughout the entire study (ie, screening, treatment, and follow-up periods; see Table 2). 
Parents/caregivers will be instructed on using the scale to record their child’s pruritus score at the 
screening visit.  Using the e-diary, parents/caregivers will complete the rating scale DAILY 
through the entire study (screening, treatment, and follow-up periods).  Clinical sites will check 
parent/caregiver data, collected using the e-diary, for protocol compliance and remind 
parents/caregivers to complete the e-diary throughout the study. 
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6.2.2.2. 
Assessment of Skin Pain 
Skin pain will be assessed by the parent/caregiver at time points during part B according to 
Section 6.1, Table 2.  Skin pain will be measured during part B using a skin pain NRS that was 
developed and tested for the study-relevant age group.  This is an 11-point scale (0 to 10) in which 
0 indicates no pain while 10 indicates worst pain possible.  The parents/caregivers will be asked 
to: 
“Think about all the areas of your child's skin with eczema.  Answer the question below based on 
what you observe and what your child tells you (if applicable).” 
“How would you rate your child's skin pain at its worst in the past 24 hours?” 
Clinical sites will check and remind the parent/caregiver to complete the scale according to the 
time points in Table 2 (Part B).  Parents/caregivers will be instructed on using the scale to record 
their child’s skin pain score at the screening visit.  Parents/caregivers will complete the rating scale 
DAILY for the 14 days prior to the baseline visit, for the 7 days prior to the week 2 visit, for the 7 
days prior to the week 4 visit, for the 7 days prior to the week 16 visit, and for the 7 days prior to 
the week 28 visit.  Clinical sites will check parent/caregiver data collected using an e-diary for 
protocol compliance and remind parents/caregivers to complete their e-diary throughout the study. 
6.2.2.3. 
Assessment of Sleep Quality and Other Sleep-Related Concepts Using Sleep 
Diary 
A sleep diary will be completed by the parent/caregiver at time points during part B according to 
Section 6.1, Table 2 (Part B).  The sleep diary includes 2 questions assessing the caregiver’s sleep, 
and 6 questions assessing the child’s sleep based on caregiver observation.  Sleep diary items, 
either alone or in combination will serve as subjective measures of sleep quality, difficulty falling 
asleep, nighttime awakenings, and sleep duration. Sleep quality will be measured using an 11-
point NRS (0 to 10) in which 0 indicates worst possible sleep while 10 indicates best possible 
sleep.  The parents/caregivers will be instructed to complete the questions about the child’s sleep 
upon awakening for the day.  
Clinical sites will check and remind the parent/caregiver to complete the diary according to the 
time points in Table 2 (Part B).  Parents/caregivers will be instructed on using the diary to record 
their child’s sleep quality score at the screening visit.  Parents/caregivers will complete the diary 
DAILY for the 14 days prior to the baseline visit, for the 7 days prior to the week 1 visit, for the 7 
days prior to the week 2 visit, for the 7 days prior to the week 4 visit, for the 7 days prior to the 
week 16 visit, and for the 7 days prior to the week 28 visit.  Clinical sites will check 
parent/caregiver data collected using an e-diary for protocol compliance and remind 
parents/caregivers to complete their e-diary throughout the study. 
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6.2.2.4. 
Caregiver Global Impression of Disease 
The CGID is an assessment instrument used by the parent/caregiver in clinical studies to rate their 
child’s eczema symptoms during the past 7 days.  An appropriate version of the CGID was being 
developed and tested for the study-relevant age group.   
Parents/caregivers will rate their child’s disease based on the 5-level scale as follows: 
“Overall, how would you rate your child’s eczema symptoms during the past 7 days?” 
• No symptoms 
• Mild 
• Moderate 
• Severe 
• Very severe 
The CGID score will be assessed at time points according to Section 6.1, Table 2 (Part B).  
6.2.2.5. 
Caregiver Global Impression of Change 
Caregiver global impression of change will be measured using a caregiver administered tool that 
is currently being developed and tested for the study-relevant age group. 
Parents/caregivers will respond to the following question based on the 7-level scale as follows:  
“Compared to before your child started the study, how would you rate his or her eczema 
now?” 
• Much better 
• Moderately better 
• A little better 
• No change 
• A little worse 
• Moderately worse 
• Much worse  
The CGIC is an instrument used by the parent/caregiver in clinical studies to compare their child’s 
eczema symptoms from the beginning of the study to when they completed the assessment.   
The CGIC score will be assessed at time points according to Section 6.1, Table 2 (Part B).  
6.2.2.6. 
Caregiver Assessment of Missed Workdays 
Caregivers who are employed will be asked to report the number of sick-leave days since the last 
study assessment.  Caregivers will undergo this assessment at time points according to Section 6.1, 
Table 2 (Part B). 
The assessment tool is provided in the investigator site binder. 
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6.2.2.7. 
Childrens’ Dermatology Life Quality Index 
The CDLQI is a validated questionnaire designed to measure the impact of skin disease on the 
QOL in children ≥4 years of age (Lewis-Jones 1995).  The aim of the questionnaire is to measure 
how much a patient’s skin problem has affected the patient over a recall period of the past week. 
A cartoon version of the CDLQI will be administered to patients 4 to 5 years of age, with the 
assistance of a parent or adult “as necessary”.  If assistance of parent or adult caregiver is required, 
it is recommended that the same person assist the patient throughout the study.  The cartoon version 
of the CDLQI uses the same text and scoring system as the original CDLQI but includes 10 color 
drawings of a dog illustrating the theme of each question. 
To complete the questionnaire, patients need to provide responses to 10 questions (the questions 
focus on domains such as symptoms feelings associated with disease, the impact of the disease on 
leisure, school or holidays, personal relationships, sleep, and side effects of treatment for the skin 
disease.  The instrument has a recall period of 7 days.  Nine of the 10 questions are scored as 
follows: 
• Very much = 3  
• Quite a lot = 2  
• Only a little = 1  
• Not at all = 0  
• Question unanswered = 0  
Question 7 has an additional possible response (prevented school), which is assigned a score of 3. 
The CDLQI for a patient is the sum of the score of each question with a maximum of 30 and a 
minimum of 0.  The higher the score, the greater the impact is on the QOL.  The CDLQI can also 
be expressed as a percentage of the maximum possible score of 30.  This assessment will only be 
performed in part B at time points according to Section 6.1, Table 2 (Part B). 
The CDLQI is provided in the investigator site binder. 
6.2.2.8. 
Infants’ Dermatology Quality of Life Index 
The IDQOL is a validated questionnaire developed to measure the impact of skin disease on the 
QOL of infants and preschool children <4 years of age (Lewis-Jones 2001).  The IDQOL is to be 
completed by the child’s parent or caregiver.  It is recommended that the same person complete 
the questionnaire on behalf of the patient throughout the study.  The questionnaire consists of 
10 questions related to itching and scratching; mood of the child; how long it takes for the child to 
get to sleep; whether the eczema has interfered with the child’s playing, swimming or participation 
in other family activities; problems during mealtimes; problems caused by treatment; level of 
comfort while dressing or undressing the child; and problems during bathing.  Each question asks 
about the impact over the previous week and is scored on a scale of 0 (minimum impact) to 3 
(maximum impact). 
The IDQOL for a patient is the sum of the score of each question with a maximum of 30 and a 
minimum of 0.  The higher the score, the greater the impact is on the QOL.  The IDQOL can also 
be expressed as a percentage of the maximum possible score of 30. 
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This assessment will only be performed in part B at time points according to Section 6.1, Table 2 
(Part B). 
The IDQOL questionnaire is provided in the investigator site binder. 
6.2.2.9. 
Dermatitis Family Index 
The impact on family life has been documented in families of children with very severe AD.  The 
DFI was the first instrument assessing the impact of having a child with AD on family QOL 
(Lawson 1998).  The 10-item disease specific questionnaire was formed after ethnographical 
interviews and focus groups revealed the areas of family QOL affected by AD.  The self-
administered instrument is completed by an adult family member of a child affected by dermatitis.  
It is recommended that the same person complete the questionnaire on behalf of the patient 
throughout the study.  The items inquire about housework, food preparation, sleep, family leisure 
activity, shopping, expenditure, tiredness, emotional distress, relationships and the impact of 
helping with treatment on the primary caregiver’s life.  The DFI questions are scored on a four-
point Likert scale ranging from 0 to 3, so that the total DFI score ranges from 0 to 30.  The time 
frame of reference is the past week.  A higher DFI score indicates greater impairment in family 
QOL as affected by AD.  This assessment will only be performed in part B at time points 
according to Section 6.1, Table 2 (Part B).  
The DFI questionnaire is provided in the investigator site binder. 
6.2.2.10. Patient-Oriented Eczema Measure 
An observation reported outcome (ObsRO) version of the POEM was developed simultaneously 
with the patient reported outcome (PRO) version and will be used here.  The ObsRO version is 
identical to the PRO version except that it asks about “your child’s skin” rather than “your skin”. 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults (Charman 2004).  The format is a response to 7 items 
(dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency of these 
disease symptoms during the past week (ie, 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 
6 days, and 4 = all days) with a scoring system of 0 to 28; the total score reflects disease-related 
morbidity.  The questionnaire will only be administered in part B to parents/caregivers at time 
points according to Section 6.1, Table 2 (Part B).  It is recommended that the same person complete 
the questionnaire on behalf of the patient throughout the study. 
The POEM is provided in the investigator site binder. 
6.2.2.11. Investigator Global Assessment 
The IGA is an assessment instrument used in clinical studies to rate the severity of AD globally, 
based on a 5-point scale ranging from 0 (clear) to 4 (severe).  The IGA score will be assessed at 
time points according to Section 6.1, Table 1 (Part A), and Table 2 (Part B). 
The IGA is provided in the investigator site binder and in Appendix 3.   
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6.2.2.12. Eczema Area and Severity Index 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin 2001).  The EASI is a composite index with scores ranging from 0 to 72.  
Four AD disease characteristics (erythema, thickness [induration, papulation, edema], scratching 
[excoriation], and lichenification) will each be assessed for severity by the investigator or designee 
on a scale of “0” (absent) through “3” (severe).  In young children, the head and neck (H), upper 
extremities (U), trunk (T), and lower extremities (L) are assigned proportionate body surface areas 
of 20% (H), 20% (U), 30% (T), and 30% (L), roughly consistent with the ‘rule of nines”.  In 
addition, the area of AD involvement will be assessed as a percentage by body area of head, trunk, 
upper limbs, and lower limbs, and converted to a score of 0 to 6.  In each body region, the area is 
expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), 
or 6 (90% to 100%).  The EASI will be collected at time points according to Section 6.1, Table 1 
(Part A), and Table 2 (Part B). 
The EASI assessment tool is provided in the investigator site binder. 
6.2.2.13. Body Surface Area Involvement of Atopic Dermatitis 
Body surface area affected by AD will be assessed for each section of the body using the rule of 
nines in children.  Patients will undergo this assessment at time points according to Section 6.1, 
Table 1 (Part A), and Table 2 (Part B). 
The BSA assessment tool is provided in the investigator site binder. 
Note:  The proportion assigned to different body regions varies by age in young children. 
6.2.2.14. Global Individual Signs Score 
Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and 
lichenification) will be rated globally (ie, each assessed for the whole body, not by anatomical 
region) on a 4-point scale (from 0=none to 3=severe) with the Global Individual Signs Score 
(GISS) using the EASI severity grading criteria.  The GISS will only be assessed during part B 
at time points listed in Table 2 (Part B). 
The GISS assessment tool is provided in the investigator site binder. 
6.2.2.15. SCORing Atopic Dermatitis 
The SCORAD is a validated tool used in clinical research and clinical practice that was developed 
to standardize the evaluation of the extent and severity of AD (European Task Force on Atopic 
Dermatitis 1993).  There are 3 components to the assessment: A = extent or affected BSA, B = 
severity, and C = subjective symptoms.  The extent of AD is assessed as a percentage of each 
defined body area (see Section 6.2.2.13) and reported as the sum of all areas, with a maximum 
score of 100% (assigned as “A” in the overall SCORAD calculation).  The severity of 6 specific 
symptoms of AD (redness, swelling, oozing/crusting, excoriation, skin thickening/lichenification, 
and dryness) is assessed using the following scale: none (0), mild (1), moderate (2), or severe (3) 
(for a maximum of 18 total points, assigned as “B” in the overall SCORAD calculation).  
Subjective assessment of itch and sleeplessness is recorded for each symptom by the 
parent/caregiver or relative on a Visual Analogue Scale, where 0 is no itch (or sleeplessness) and 
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10 is the worst imaginable itch (or sleeplessness), with a maximum possible score of 20.  This 
parameter is assigned as “C” in the overall SCORAD calculation.  The SCORAD is calculated as: 
A/5 + 7B/2 + C where the maximum is 103.  Patients will undergo this assessment at time points 
according to Section 6.1, Table 1 (Part A), and Table 2 (Part B). 
The SCORAD assessment tool is provided in the investigator site binder. 
NOTE: For the purpose of assessing the extent of disease (A), the proportion assigned to different 
body regions is different in children <2 years of age, as compared to older children.  Refer to the 
SCORAD assessment tool in the investigator site binder for details. 
6.2.2.16. Atopic Dermatitis Area Photographs 
At select study sites in part B, photographs will be taken of a representative area(s) of AD 
involvement (eg, the lesional area(s) used for SCORAD assessments on day 1/baseline [predose]).  
Subsequent photographs of the same area(s) will be taken at time points according to Section 6.1, 
Table 2 (Part B). 
Instructions for taking the photographs are provided in the photography reference manual. 
6.2.2.17. Topical Corticosteroids Accountability 
In part B, at every in-clinic visit following the baseline visit, the type, amount, and potency of TCS 
used will be recorded by site personnel.  The amount of TCS used will be determined by weighing 
the tube at each visit through the end of the study. 
In addition, caregivers will be asked to record TCS use daily, from start of 2-week TCS 
standardization period on day -14 through the end of the study, on an e-diary: 
• Use of TCS (yes/no) 
• Why did you not apply the topical corticosteroid to your child today? 
6.2.2.18. Pediatric Asthma Symptom Questionnaire 
The PASQ is a questionnaire developed by the sponsor to monitor asthma control in preschool 
children in clinical trial settings.  The advantage of the PASQ is the much shorter recall period for 
various items to fit the schedule of clinical trials and improvement in ability to recall as compared 
to existing instruments.  The questionnaire consists of 6 questions related to asthma control,  
The questionnaire will be completed only for the subset of patients with ongoing asthma.  It is to 
be completed by the child’s parent or caregiver who fluently speak a language in which the 
questionnaire is presented, at time points according to Section 6.1, Table 2 (Part B).  It is 
recommended that the same person complete the questionnaire on behalf of the patient throughout 
the study.   
The PASQ is provided in the investigator site binder. 
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6.2.2.19. Caregiver-Reported Nasal Symptom Questionnaire 
The CNSQ will be used to assess the effect of study drug on symptoms of allergic rhinitis.  The 
summed score will include the following 4 symptoms: runny nose, nasal congestion, nasal itching, 
and sneezing, each rated on a 0 to 3 scale of severity.  The questionnaire will be completed only 
for the subset of patients with a medical history of allergic rhinitis.  It is to be completed by the 
child’s parent or caregiver who fluently speak a language in which the questionnaire is presented 
(based on availability of translations in participating countries).   
Caregivers will be instructed on using the e-diary to record the CNSQ during the screening period 
(for the 14 days before baseline/day 1) and for the 7 days preceding visits 7, 19, and 22 (weeks 4, 
16, and 28) (see Table 2 [Part B]).  
6.2.3. 
Safety Procedures 
6.2.3.1. 
Vital Signs 
Vital signs (including sitting systolic and diastolic blood pressure, heart rate, respiration, and 
temperature) will be collected pre-dose at every in-clinic visit. 
During part A, at the baseline visit, patients will be monitored at the study site for a minimum of 
2 hours after study drug administration.  Vital signs (systolic and diastolic blood pressure, heart 
rate, respiration, and temperature) and AE assessments will be performed at 30 minutes 
(±10 minutes) post-injection and then at 2 hours (±15 minutes) post-injection.  See Section 6.1, 
Table 1 (Part A), for assessment time points.  
During part B, patients will be monitored at the study site at certain dosing visits for a minimum 
of 2 hours after study drug administration.  Vital signs (systolic and diastolic blood pressure, heart 
rate, respiration, and temperature) and AE assessments will be performed at 30 minutes (±10 
minutes) post-injection, and at 2 hours (±15 minutes) post-injection.  See Section 6.1, Table 2 (Part 
B), for assessment time points. 
6.2.3.2. 
Body Weight and Height 
Body weight and height will be measured at time points according to Section 6.1, Table 1 (Part A), 
and Table 2 (Part B). 
6.2.3.3. 
Physical Examination 
A thorough and complete physical examination will be performed at visits according to 
Section 6.1, Table 1 (Part A) and Table 2 (Part B).  Care should be taken to examine and assess 
any abnormalities that may be present, as indicated by the patient’s medical history. 
6.2.3.4. 
Electrocardiogram 
Electrocardiograms (ECGs) should be performed before blood is drawn during visits requiring 
blood draws.  A standard 12-lead ECG will be performed at time points according to Section 6.1, 
Table 1 (Part A), and Table 2 (Part B).  Heart rate will be recorded from the ventricular rate, and 
the PR, QRS, RR and QT intervals will be recorded.  The ECG strips or reports will be retained 
with the source. 
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6.2.3.5. 
Laboratory Testing 
Hematology and serum chemistry testing samples will be analyzed by a central laboratory.  
Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites. 
Samples for laboratory testing will be collected at time points according to Section 6.1, Table 1 
(Part A), and Table 2 (Part B).   
Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin1 
Potassium 
Creatinine 
Total cholesterol2 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK)3 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
1 
Direct and indirect bilirubin will be measured when the total bilirubin is above the ULN 
2 
Low-density lipoprotein [LDL] and high-density lipoprotein [HDL]) 
3 
CPK isoenzymes will be measured when CPK >2.5× the ULN 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Other Laboratory Tests 
The following tests will be performed at screening according to Section 6.1, Table 1 (Part A), and 
Table 2 (Part B):  HIV, HBsAg, HBsAb, HBcAb, hepatitis C antibody, and tuberculosis (will be 
performed on a country-by-country basis according to local guidelines if required by regulatory 
authorities or ethics boards). 
Abnormal Laboratory Values and Laboratory Adverse Events 
• All laboratory values must be reviewed by the investigator or authorized designee. 
• Significantly abnormal tests must be repeated to confirm the nature and degree of the 
abnormality.  When necessary, appropriate ancillary investigations should be initiated.  
If the abnormality fails to resolve or cannot be explained by events or conditions 
unrelated to the study medication or its administration, the medical monitor must be 
consulted. 
• The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 7.2.5. 
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6.2.3.6. 
Ophthalmological Examinations (Part B only) 
Patients who have history of certain eye disorders (conjunctivitis, blepharitis or keratitis) within 
12 months prior to the screening visit will be referred to an ophthalmologist (preferably with 
expertise in treating pediatric patients or Cornea and External Eye Disease [‘front-of-the-eye’] 
subspecialty expert).  Any baseline findings will be documented as part of the patient’s medical 
history and/or physical exam, as appropriate. 
Patients who experience AESIs related to eye disorders (refer to Section 7.2.3) will also be referred 
to an ophthalmologist (preferably with expertise in treating pediatric patients or Cornea and 
External Eye Disease [‘front-of-the-eye’] subspecialty expert).  Further evaluation of these AESIs 
will be performed including any additional tests, if applicable, as per the discretion of the 
ophthalmologist.  An ophthalmology examination form will be provided to patients by the site, 
which they will carry to the ophthalmologist on the day of examination.  This form will be 
completed by the ophthalmologist and this information will be transcribed into the study CRFs.  
Appropriate treatment for these AEs will be prescribed by the ophthalmologist.  The investigator 
may also have a conversation with the ophthalmologist to discuss the further course of action for 
these patients. 
6.2.4. 
Pharmacokinetic and Antibody Procedures 
6.2.4.1. 
Drug Concentration Measurements and Samples 
Serum samples for measuring functional dupilumab concentrations will be collected at time points 
listed in Section 6.1, Table 1 (Part A), and Table 2 (Part B).   
6.2.4.2. 
Immunogenicity Measurements and Samples 
Serum samples for ADA assessment will be collected at time points listed in Section 6.1, Table 1 
(Part A) and Table 2 (Part B).  Samples positive in the ADA assay will be analyzed for the presence 
of neutralizing antibody in the NAb assay. 
Long term follow-up of patients who are ADA positive at their last study visit (early termination 
or end of study) and who do not participate in the OLE study may be considered based on the 
overall clinical presentation at that time.  Patients who are considered for follow-up may be asked 
to return to the clinic to have additional samples collected for analysis. 
6.2.5. 
Biomarker Procedures 
Thymus and activation-regulated chemokine and total serum IgE are markers of Th2 activity as 
downstream mediators in the IL-4/IL-13 signaling pathway (Wirnsberger 2006, Takeda 1997).  
These analytes will be assessed as measures of Th2 activity and PD effect of dupilumab.  The 
results may be used for modeling dupilumab activity with drug levels in the comparison of dosing 
regimens.  Thymus and activation-regulated chemokine levels have also been closely associated 
with AD disease activity and severity (Beck 2014) and will be evaluated as an exploratory marker 
of efficacy.  These markers may also be assessed for their potential value in predicting treatment 
response. 
Lactate dehydrogenase (LDH) levels have also been shown to correlate with disease severity and 
activity in patients with AD (Mukai 1990). 
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Serum samples for measurements of biomarkers (including TARC, total IgE, immunoglobin 
profiling, antigen-specific IgE, and LDH [which will be measured as part of the blood chemistry]) 
to study the PD activity of dupilumab in pediatric AD patients will be collected at time points 
according to Section 6.1, Table 1 (Part A), and Table 2 (Part B).   
6.2.6. 
Vaccine Response - Optional 
Humoral immune responses to standard vaccines administered as part of the routine immunization 
schedule occurring during treatment with dupilumab, will be evaluated for those patients eligible 
for these vaccinations in part B of the study. 
Parents/caregivers will be encouraged to provide vaccination plans at screening for any vaccines 
that are planned to be administered to the patient, in accordance with the patient’s age, local 
medical practice and immunization schedule, during the study.  Inactivated vaccines are permitted 
during the study.  Live attenuated vaccines are excluded during the study.  Parents or legal 
guardians who agree for their child to participate in the optional vaccine response sub-study will 
be required to sign a separate vaccine-response sub-study ICF for the collection of 2 blood samples 
for assay of vaccine IgG in serum for each vaccine administered; one sample will be drawn before 
administration of the vaccine and the second sample after administration of the vaccine. 
The first sample (pre-vaccination) may be drawn at any time up to 6 weeks prior to the scheduled 
vaccination.  The second sample should preferably be drawn 3 to 4 weeks (maximum up to 
6 weeks) after vaccination.  Blood collections should be conducted at regularly scheduled study 
visits but if this is not feasible, the samples may also be collected at unscheduled visits.  Details 
on the date(s) of vaccination and the specific vaccines administered (ie, brand and antigenic 
strains) should be collected on the Vaccination Record Form. 
The humoral response endpoints will be described in the statistical analysis plan (SAP). 
Patients who do not get an adequate response to vaccine administration during part B of the study 
may be offered re-vaccination during the OLE.  The clinical study sites will be provided with 
post-vaccination titers only at the completion of the study due to risk of unblinding of this study.  
The determination of whether re-vaccination is needed will be made on a case-by case basis based 
on the titer results and the clinical relevance of these results.  The investigator may consult with 
the primary physician/ pediatrician of the patient to determine the further course of action on these 
patients.  The investigator may also report the cases of inadequate response as AEs, based on 
criteria in Section 7.1 of the protocol. 
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6.2.7. 
Research Testing 
6.2.7.1. 
Research Samples 
Use and Storage of Research Samples (Serum) 
Any unused serum samples collected for dupilumab concentrations or ADA measurements, may 
be used for exploratory biomarker research related to AD, inhibition of the IL-4Rα pathway with 
an antibody, treatment response (PD and or predictive), vaccine response, to investigate 
unexpected AEs, or to identify markers associated with adverse reactions. 
6.2.7.2. 
Tape Stripping Sub-study - Optional 
An optional tape stripping sub-study may be performed at a subset of study sites.  The purpose of 
the tape stripping sub-study is to identify molecular changes associated with clinical or biomarker 
response to IL-4/13 pathway inhibition (via IL-4Rα blockade); to study AD and related diseases, 
prognosis and progression, predicators of treatment response, or other clinical outcome measures, 
as well as why some patients may respond better than others.  Gene expression (by RNA 
sequencing and/or other methods) analyses will be performed on tape stripping samples.  Results 
from these exploratory analyses will not be included in the clinical study report. 
Parents or legal guardians who agree for their child to participate in the optional tape stripping 
sub-study will be required to sign a separate sub-study ICF before collection of the samples.  
Baseline samples should be collected on day 1/baseline (pre-dose).  A second sample will be 
collected at week 16 to assess treatment effects.  Patients are not required to participate in the tape 
stripping sub-study to enroll in the primary study.  
6.2.7.3. 
Genomics Sub-study - Optional 
The purpose of the genomic analyses is to identify genomic associations with clinical or biomarker 
response to IL-4/13 pathway inhibition (via IL-4Rα blockade), atopic disease risk, prognosis and 
progression, or other clinical outcome measures.  These data may be used or combined with data 
collected from other studies to identify genomic markers that may predict response and elucidate 
mechanisms of disease.  
Parents or legal guardians who agree for their child to participate in the genomics sub-study will 
be required to sign a separate genomics sub-study ICF before collection of the samples.  DNA 
cheek swab samples should be collected on day 1/baseline (pre-dose) but may be collected at any 
study visit.  Patients are not required to participate in the genomics sub-study in order to enroll in 
the primary study. 
DNA samples for the genomics sub-study were double-coded during part A and will be 
single-coded during part B as defined by the ICH guideline E15.  Sub-study samples may be stored 
for up to 15 years after the final date of the clinical study report and may be used for research 
purposes.  Analyses may include sequence determination or single nucleotide polymorphism 
studies of candidate genes and surrounding genomic regions.  Genome-wide studies, including 
(but not limited to) single nucleotide polymorphism analyses, genomic sequencing, and 
transcriptome sequencing may also be performed.  If indicated, genomic analyses may also be 
performed to identify markers associated with toxicity. 
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7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
7.1. 
Definitions 
7.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
7.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours.  Prolongation of existing hospitalization 
is defined as a hospital stay that is longer than was originally anticipated for the event 
or is prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent 1 of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  See Section 7.2 for more 
information on recording and reporting SAEs. 
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7.2. 
Recording and Reporting Adverse Events 
7.2.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study.  Refer to the investigator site binder for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 7.2.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 7.2.5. 
7.2.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug must be reported to the 
sponsor (or designee) within 24 hours.  Refer to the investigator site binder for the procedure to be 
followed. 
Information not available at the time of the initial report must be documented in a follow-up report.  
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
The investigator must promptly report to the Institutional Review Board/Ethics Committee 
(IRB/EC) all unanticipated problems involving risks to patients.  This includes death from any 
cause and all SAEs related to the use of the study drug.  It is recommended that all SAEs be 
reported to the IRB/EC, regardless of assessed causality. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
• SAE with an onset within 30 days of the end of study/early termination visit - the SAE 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome until the event is considered chronic and/or 
stable. 
• SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
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7.2.3. 
Other Events that Require Accelerated Reporting 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Adverse Events of Special Interest: 
AESI must be reported within 24 hours of identification.  
AESIs for this study include: 
• Anaphylactic reactions 
• Systemic hypersensitivity reactions 
• Helminthic infections  
• Any severe type of conjunctivitis or blepharitis 
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms) 
Any patient who experiences an AESI related to an eye disorder will be referred to an 
ophthalmologist.  Further evaluation of these AESIs will be performed including any additional 
tests, as per the discretion of the ophthalmologist. 
Refer to the investigator site binder for the procedures to be followed. 
7.2.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
Refer to the investigator site binder for the procedures to be followed. 
7.2.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
• the test result is associated with accompanying symptoms, and/or 
• the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the medical monitor in the event the investigator feels that an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
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Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 7.3.1. 
7.2.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious AE information will be collected until the event is considered chronic and/or stable. 
7.3. 
Evaluation of Severity and Causality 
7.3.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
• Mild:  Causes no or minimal interference with age appropriate daily activities.  No 
intervention needed.  
• Moderate:  Causes more than minimal interference with age appropriate daily 
activities.  Local or non-invasive intervention indicated.  
• Severe:  Causes inability to perform age appropriate daily activities.  Hospitalization 
or invasive intervention indicated. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
7.3.2. 
Evaluation of Causality 
The relationship of AEs to study drug will be assessed by the investigator and will be a clinical 
decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the adverse event may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the study 
drug 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug 
For a list of factors to consider in assessing the relationship of AEs to study drug, see Appendix 1. 
The investigator will also assess whether the AEs are related to any study procedures (as listed in 
Table 1 and Table 2). 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
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7.4. 
Safety Monitoring 
The investigator will monitor the safety of study patients at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The medical monitor will have primary responsibility for 
the emerging safety profile of the compound.  The medical monitor will be supported by other 
departments (eg, Pharmacovigilance and Risk Management; Biostatistics and Data Management).  
Safety monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on 
a periodic cumulative aggregate basis. 
7.5. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the Investigator’s 
Brochure, and has a reasonable suspected causal relationship to the medicinal/study drug). 
8. 
STUDY VARIABLES 
8.1. 
Demographic and Baseline Characteristics 
Demographic characteristics will include variables such as age, race, weight, height, etc.  Baseline 
characteristics will include variables such as disease severity, medical history, medication history, 
etc for each patient. 
8.2. 
Primary and Secondary Endpoints 
8.2.1. 
Primary Endpoints 
The primary endpoints in part A of the study are: 
• Concentration of total dupilumab in serum over time and PK parameters (summary 
statistics of drug concentration and PK parameters) 
• The incidence and severity of treatment-emergent adverse events (TEAEs) through 
the end of part A. 
The primary endpoint in part B of the study is: 
• Proportion of patients with an IGA score of 0 to 1 (on a 5-point scale) at week 16 
The co-primary endpoints in part B of the study are (only in the EU and EU Reference Market 
Countries): 
• Proportion of patients with EASI-75 (≥75% improvement from baseline) at week 16 
• Proportion of patients with an IGA score of either 0 or 1 (on a 5-point scale) at 
week 16 
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8.2.2. 
Secondary Endpoints 
The secondary endpoints in part A are: 
• The incidence of SAEs and severe TEAEs to week 4 
• Percent change in EASI score from baseline to week 4 
• Percent change in SCORAD score from baseline to week 4 
• Proportion of patients with an IGA score of either 0 or 1 (on a 5-point scale) at 
week 4  
Immunogenicity will be addressed by the ADA parameters described in Section 8.4. 
The key secondary endpoints in part B are: 
• Proportion of patients with EASI-75 (≥75% improvement from baseline) at week 16 
(not applicable for EU or EU Reference Market Countries) 
• Percent change in EASI score from baseline to week 16 
• Percent change from baseline to week 16 in weekly average of daily worst 
scratch/itch NRS score  
Other secondary efficacy endpoints in part B are: 
• Proportion of patients with EASI-50 at week 16 
• Proportion of patients with EASI-90 at week 16 
• Change from baseline to week 16 in percent BSA affected by AD 
• Percent change from baseline to week 16 in SCORAD 
• Change from baseline to week 16 in weekly average of daily worst scratch/itch NRS 
score 
• Proportion of patients with improvement (reduction) of weekly average of daily worst 
scratch/itch NRS score ≥4 from baseline at week 16 
• Proportion of patients with improvement (reduction) of weekly average of daily worst 
scratch/itch NRS score ≥3 from baseline at week 16 
• Change from baseline to week 16 in skin pain NRS 
• Change from baseline to week 16 in sleep quality NRS 
• Change from baseline to week 16 in health-related quality of life, as measured by 
CDLQI (patients ≥4 years of age) and IDQOL (patients <4 years of age) 
• Change from baseline to week 16 in DFI 
• Change from baseline to week 16 in POEM 
• Topical treatment for AD – proportion of TCS medication-free days from baseline to 
week 16 
• Mean weekly dose of low potency TCS through week 16 
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• Mean of caregiver missed workdays from baseline to week 16 
• Incidence of skin infection TEAEs (excluding herpetic infections) through week 16 
• Incidence of SAEs through week 16 
8.2.3. 
Other Endpoints and Assessments 
Other endpoints and assessments, as applicable, will be specified in the SAP. 
8.3. 
Pharmacokinetic Variables 
The PK variable is the concentration of functional/total dupilumab at each time point.  Samples in 
this study will be collected using a sparse sampling schedule, eg, only 1 blood sample for drug 
concentration measurement is collected at any single clinic visit.  These sampling timepoints are 
specified in Table 1 (part A) and Table 2 (part B). 
8.4. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, NAb status, and time-point/visit.  Samples in 
this study will be collected at the clinic visits specified in Table 1 (part A) and Table 2 (part B). 
8.5. 
Vaccine Response Variables 
For patients who receive vaccinations, vaccine response parameters will be summarized by 
treatment groups using descriptive statistics. 
9. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study.  The SAP may be revised during the 
study to accommodate amendments to the clinical study protocol and to make changes to adapt to 
unexpected issues in study execution and data that may affect the planned analyses.  The final SAP 
will be issued before the database is locked. 
Analysis variables are listed in Section 8. 
9.1. 
Statistical Hypothesis 
Part A of the study is open-label; therefore, no statistical hypotheses will be tested in this portion 
of the study. 
For part B of the study, the following null hypothesis and alternative will be tested for the 
dupilumab treatment group: 
H0: There is no treatment difference between dupilumab and placebo 
H1: There is a treatment difference between dupilumab and placebo 
Baseline weight group, baseline disease severity (IGA=3, 4), and region/country will be the 
3 stratification factors for patient randomization that will be accounted for in the statistical 
modeling for efficacy. 
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9.2. 
Justification of Sample Size 
In part A of the study, the sample size of 40 patients was empirically based on the number of 
patients required to adequately characterize the safety/PK profile in this population. 
For part B of the study, it is estimated that a sample size of 160 patients (80 patients per treatment 
group), at the 2-sided 5% significance level, will provide the following: 
• 88% power to detect a difference of 21.4% between the dupilumab and placebo groups 
in the percentage of patients who achieve an IGA score of 0 to 1 at week 16, assuming 
that the percentages are 32.8% and 11.4% for the dupilumab and placebo groups, 
respectively. 
• 99% power to detect a difference of 42.9% in the percentage of patients who achieve 
an EASI-75 response at week 16, assuming the percentages are 69.7% and 26.8% for 
the dupilumab and placebo groups, respectively. 
The assumptions used for the above power calculations were based on results from patients in the 
R668-AD-1652 study (phase 3 combination study for patients ≥6 to <12 years of age with severe 
AD).  As outline in Section 1.2.2, the tiered fixed-dose regimen (200 mg Q4W in patients ≥5-
<15 kg, 300 mg Q4W in patients ≥15-<30 kg) is expected to provided exposure comparable to that 
seen with 300 mg Q4W in patients ≥6 to <12 years of age or 300 mg Q2W in adult patients. 
Further justification for the sample size comes from the results from the R668-AD-1224 study (a 
phase 3 combination study for adult patients with moderate-to-severe AD).  In this study, the 
proportions of patients who achieved an IGA score of 0 to 1 at week 16 were 38.7% and 12.4% 
for dupilumab and placebo, respectively.  The proportions of patients who achieved an EASI-75 
response at week 16 were 23.3% and 68.9% for dupilumab and placebo, respectively.  The study 
will have a power of 96% on both the co-primary endpoints based on the results from the 
R668-AD-1224 study.  Additional support for the sample size comes from the R668-AD-1526 
study (a phase 3 study for adolescent patients with moderate-to-severe AD).   
The sample size calculations were done using nQuery (7.0). 
9.3. 
Analysis Sets 
9.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients in part B; it is based on the treatment 
allocated (as randomized).   
The per protocol set (PPS) includes all patients in the FAS, except for those who are excluded 
because of major protocol violations.  A major protocol violation is one that may affect the 
interpretation of study results and will be reviewed and adjudicated by study team.  A final list of 
major protocol violations will be generated prior to the primary database lock. 
All efficacy variables for part B will be evaluated using the FAS.  The primary efficacy endpoint 
will also be evaluated using the PPS.  The analysis using the FAS will be considered primary. 
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9.3.2. 
Safety Analysis Set 
For part A, the safety analysis set (SAF) includes all patients who received any study drug in 
part A; it is based on the treatment received (as treated).  Both safety and efficacy variables for 
part A will be analyzed using the SAF. 
For part B, the SAF includes all randomized patients who received any study drug in part B. 
Treatment compliance/administration and all clinical safety variables in parts A and B will be 
analyzed using the SAF, as treated. 
9.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result following the first dose of study drug. 
The PK analysis set will be defined in parts A and B separately. 
9.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received study drug and had at least 1 non-missing 
ADA result following the first study dose. 
The neutralizing antibody (NAb) analysis set includes all patients who received any study drug 
and had at least 1 non-missing result in the NAb assay (patients who are ADA negative will be set 
to negative in the NAb analysis set). 
The ADA and NAb analysis sets will be defined in parts A and B separately. 
9.4. 
Patient Disposition 
The following will be provided for parts A and B separately: 
• The total number of screened patients 
• The total number of enrolled patients in part A 
• The total number of randomized patients in part B 
• The total number of patients in each analysis set (eg, FAS, provided in Section 9.3) 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
• The total number of patients who completed the study treatment and discontinued the 
study treatment with reasons for discontinuation 
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9.5. 
Statistical Methods 
The analyses for parts A and B will be performed separately.   
For continuous variables, descriptive statistics will include the following:  the number of patients 
reflected in the calculation (n), mean, standard deviation, median, first quartile (Q1), third quartile 
(Q3), minimum, and maximum.   
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
9.5.1. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group for 
parts A and B, respectively. 
9.5.2. 
Efficacy Analyses 
For part A, the open-label portion of the study, descriptive statistics of the efficacy endpoints 
will be summarized. 
For part B, the efficacy analysis will be performed for the comparisons between the dupilumab 
treatment group and the placebo group. 
9.5.2.1. 
Primary Efficacy Analysis 
The Cochran-Mantel-Haenszel test adjusted by randomization strata (region/country, baseline 
disease severity, and baseline weight group) will be used for the percentage of patients with IGA 
0 or 1 at week 16, or percentage of patients with EASI-75 at week 16. 
To account for the impact of rescue treatment on the efficacy effect: For the primary efficacy 
endpoints (which are binary efficacy endpoints), if rescue treatment is used (see Section 5.3), the 
patient will be specified as a non-responder from the time the rescue is used. 
If a patient withdraws from study, this patient will be counted as a non-responder for endpoints 
after withdrawal. 
Sensitivity analysis will be conducted to assess the robustness of the primary efficacy analysis 
with regards to the handling of missing data, such as using the last observation carried forward 
(LOCF) approach or worst observation carried forward (WOCF) approach to determine patient’s 
status at week 16.  Details will be specified in the SAP. 
In addition, the Cochran-Mantel-Haenszel method adjusted by randomization strata will also be 
performed on all observed data regardless if rescue treatment is used.  Patients with missing data 
will be counted as non-responders. 
9.5.2.2. 
Secondary Efficacy Analysis 
For binary endpoints, the secondary efficacy analysis will use the same approach as that used for 
the primary efficacy analysis. 
For continuous endpoints, an analysis of covariance (ANCOVA) model will be used for the FAS 
with treatment group, randomization stratification factors (region/country, baseline disease 
severity, and baseline weight group) and relevant baseline measurement included in the model.  
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Similarly, to account for the impact of rescue treatment on the efficacy effect, patients' efficacy 
data through week 16 after the rescue treatment use will be set to missing.  The missing data for 
continuous endpoints will be imputed by the pattern-mixture approach where the WOCF approach 
will be used for the missing due to rescue treatment, AE, and lack of efficacy and the multiple 
imputation (MI) approach will be used for the missing due to other reasons.  The MI Statistical 
Analysis Software (SAS) procedure with Markov Monte Carlo algorithm will be applied for 
multiple times.  The complete datasets created based on the pattern-mixture approach will be 
analyzed using the ANCOVA model defined previously, and the SAS MIANALYZE procedure 
will be used to generate valid statistical inferences by combining results from these multiple 
analyses using Rubin’s formula (Rubin, 1987). 
All efficacy data will be used for analysis regardless of whether the patient is on study treatment 
or discontinues the study treatment but remains in the study.  In addition, the MI with the 
ANCOVA model and the ANCOVA model based on LOCF or WOCF imputation method will be 
performed as the sensitivity analyses.  Additional details on sensitivity analyses will be provided 
in the SAP. 
9.5.2.3. 
Multiplicity Considerations 
No multiplicity adjustments will be made for part A. 
For part B, a hierarchical procedure will be used to control the overall Type-1 error rate at 0.05 for 
the primary endpoint(s) and the secondary endpoints for the dupilumab dose regimen versus 
placebo.  The abbreviated, preliminary plan for hierarchical testing order for the primary endpoint 
and key secondary endpoints is shown in Table 3.  The complete hierarchy including all the 
secondary endpoints will be provided in the SAP.  
Table 3: 
Preliminary Statistical Hierarchy for Multiplicity Control 
 
Endpoints 
Dupilumab 
 
Q4W tiered fixed-dose treatment 
groupa 
Primary endpoint  Proportion of patients with IGA 0 to 1 (on a 5-point 
scale) at week 16 
1 
Co-primary 
endpoint for EU 
and EU Reference 
Market Countries 
only, key secondary 
for US 
Proportion of patients with EASI-75 (≥75% 
improvement from baseline) at week 16 
 
 
2 
Key Secondary 
Endpoints 
Percent change in EASI score from baseline to 
week 16 
3 
Percent change from baseline to week 16 in weekly 
average of daily worst scratch/itch score 
4 
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9.5.2.4. 
Primary Analysis of the Study 
In order to expedite the submission to regulatory agencies, a primary analysis may be performed 
when the last patient completes 16 weeks of treatment in part B.  No changes in the conduct of the 
study will be made based on this primary analysis.  The assessment of primary and secondary 
endpoints specified in Section 8.2.1 and Section 8.2.2 performed during the analysis will be the 
final analysis of the primary and secondary endpoints.  Hence, there will be no need for alpha 
adjustment due to the primary analysis.   
If a decision is made to perform the primary analysis, in order to maintain study integrity with 
respect to the post-treatment follow-up visits, safety visits and analyses, a dissemination plan will 
be written.  This plan will clearly identify the unblinded team (including the statistician) that will 
perform the primary analysis and all related activities, restrict other clinical team members and 
other sponsor personnel from access to individual patient treatment allocation and site level 
analysis results (ie, remain blinded), and ensure that the dedicated unblinded team will not 
participate in the data review or data decisions for the subsequent post-treatment analyses.  
However, the dedicated unblinded team can participate in the analysis following the final database 
lock.   
9.5.3. 
Safety Analysis 
The safety analysis will be based on the SAF.  This includes reported TEAEs, AESIs, and other 
safety information (eg, clinical laboratory evaluations, vital signs, and 12-lead ECG results).  A 
summary of safety results for each treatment group will be presented. 
9.5.3.1. 
Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined separately for parts A and B: 
• The pre-treatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The treatment-emergent period is defined as the day from the first dose of study drug 
to the end of the study.  In Part B, the treatment-emergent period includes the 
16-week treatment period and follow-up period. 
− Treatment period:  date of the first dose of study drug to week 16 visit date (study 
day 113 starting from the first dose of study drug if week 16 visit date is 
unavailable) or early termination date, whichever comes first. 
− Follow-up period:  date after week 16 visit date (study day 113 starting from first 
dose of study drug if week 16 visit date is unavailable) or early termination date, 
to end of study.  Patients who continue into the OLE after the treatment period 
will not have a follow-up period. 
Treatment-emergent AEs are defined as those that are not present at baseline or represent the 
exacerbation of a pre-existing condition during the overall study period. 
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Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group will be provided separately for parts A and B.  The 
summary will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 7.3.1), presented 
by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
In addition, to account for potential differential exposure time, the exposure-adjusted analyses for 
part B may be provided.  The details will be specified in the SAP. 
9.5.3.2. 
Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
The number and percentage of patients with a treatment-emergent potentially clinically significant 
value (PCSV) will be summarized for each vital sign variable.  The criteria for treatment-emergent 
PCSV will be defined in the SAP. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for vital signs. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a treatment-emergent PCSV will be summarized for each 
clinical laboratory test.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
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9.5.3.3. 
Treatment Exposure 
The duration of exposure in part A is 7 days. 
The duration of exposure in part B will be presented by treatment group and calculated as: 
(Date of last study drug injection – date of first study drug injection) + 28 days 
The number and percentage of patients exposed to study drug will be presented by specific time 
periods for each dose group.  The time periods of interest will be specified in the SAP. 
In addition, duration of exposure during the study will be summarized for each dose group using 
number of patients, means, standard deviation (SD), minimums, medians, and maximums. 
A summary of the number of doses by treatment group will be provided. 
9.5.3.4. 
Treatment Compliance 
Compliance with study treatment will be calculated separately for parts A and B as follows: 
Treatment Compliance = (Number of study drug injections during exposure period)/(Number 
of planned study drug injections during exposure period) × 100% 
Treatment compliance will be presented by specific ranges for each treatment group.  The ranges 
of interest will be specified in the SAP. 
9.5.4. 
Analysis of Drug Concentration Data 
No formal statistical analysis will be performed in parts A and B.  Functional dupilumab 
concentration in serum will be summarized at each time point using descriptive statistics.  In 
part A, PK parameters will be derived using non-compartmental analysis (NCA) and summarized 
by treatment and age group.  The data may be combined with data from other pediatric studies for 
analysis using population methods.  Any population PK analysis will be reported separately. 
9.5.5. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA and NAb responses observed:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 4-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative or missing 
• Treatment boosted ADA response, defined as any post-dose positive ADA assay 
response that is 4-fold over baseline titer levels when baseline is positive in the ADA 
assay 
• Maximum ADA Titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000) 
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• NAb status for samples that are positive in the ADA assay 
Analyses described below will be performed separately for parts A and B unless otherwise 
specified. Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, 
ADA titers, and NAb positivity presented by patient, time point, and dose group will be provided. 
Incidence of treatment-emergent ADA and NAb will be assessed as absolute occurrence (N) and 
percent of patients (%), grouped by study cohorts and ADA titer level.   
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles may be evaluated. Assessment of impact of ADA and NAbs on safety and efficacy 
may be provided. 
9.5.6. 
Analysis of Biomarker Data 
In parts A and B, all exploratory biomarker data analyses will be performed on the SAF and no 
multiplicity adjustment is planned.  Analyses of blood biomarker endpoints (TARC and IgE) will 
be provided in the SAP and results will be presented in the final clinical study report.  Analyses 
from tape stripping and genomics sub-studies will not be reported in the clinical study report. 
9.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
• The baseline assessment in part A will be the latest valid, pre-first-dose assessment 
available in part A 
• The baseline assessment in part B will be the latest valid, pre-first-dose assessment 
available in part B 
General rules for handling missing data: 
• Rules for handling missing data for efficacy assessments are provided in 
Section 9.5.2. 
• If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed, 
otherwise, the missing day or month by the first day or the first month will be imputed.  
• No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
Visit windows: 
• Assessments taken outside of protocol allowable windows will be displayed according 
to the CRF assessment recorded by the investigator. 
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Unscheduled assessments: 
• Extra assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries.  If more than 1 laboratory value is available for a given 
visit, the first observation will be used in summaries and all observations will be 
presented in listings. 
9.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
10.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an Electronic Data Capture (EDC) tool. 
10.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IWRS system – randomization, study drug supply 
• EDC system – data capture 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Argus – a pharmacovigilance and clinical safety software system (Regeneron)  
• AWARE, Business Objects XI – pharmacovigilance activities (Sanofi)  
11. 
STUDY MONITORING 
11.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study.  In accordance 
with International Council for Harmonisation (ICH) guidelines, the monitor will compare the CRF 
entries with the appropriate source documents.  Additional review may include, but is not limited 
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to, patient ICFs, documentation of patient recruitment and follow-up, AEs, SAEs, and concomitant 
therapy; as well as records of study drug dispensing, compliance, and accountability.  A copy of 
the drug dispensing log must be provided to the sponsor upon request. 
11.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
11.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs by 
trained site personnel.  A CRF must be completed for each and every patient enrolled in the study.  
After review of the clinical data for each patient, the investigator must provide an electronic 
signature.  A copy of each CRF page is to be retained by the investigator as part of the study record 
and must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the system.  For corrections made via data queries, a reason for any alteration must 
be provided. 
12. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
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addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP, the Japanese GCP, the China 
National Medical Product Administration’s GCP, and applicable regulatory requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH Guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient’s parent(s) or legal guardian(s) prior to the patient’s 
participation in the study and after the aims, methods, objectives, and potential hazards of the study 
have been explained to the patient in language that the parent(s) or legal guardian(s) can 
understand.  The ICF should be signed and dated by the patient’s parent(s) or legal guardian(s) and 
by the investigator or authorized designee who reviewed the ICF with the patient’s parent(s) or 
legal guardian(s). 
Local law must be observed in deciding whether 1 or both parents/guardians consent is required.  
If only 1 parent or guardian signs the consent form, the investigator must document the reason the 
other parent or guardian did not sign.   
• Parent(s) or legal guardian(s) who can write but cannot read will have the ICF read to 
them before writing their name on the form. 
• Parent(s) or legal guardian(s) who can understand but who can neither write nor read 
will have the ICF read to them in presence of an impartial witness, who will sign and 
date the ICF to confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient's study record, and a 
copy of the signed ICF must be given to the parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately.  All study patients and their parent(s) or legal guardian(s) 
s must be informed of the new information and provide their written consent if they wish to 
continue in the study.  The original signed revised ICF must be maintained in the patient’s study 
record and a copy must be given to the patient’s parent(s) or legal guardian(s). 
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13.3. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by their patient identification number 
only, on CRFs or other documents submitted to the sponsor.  Documents that will not be submitted 
to the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient's and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH Guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patient’s parent(s) or 
their legal guardian(s) (eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB/ EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk 
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design or operation of the protocol or ICF without 
an IRB/EC-approved amendment. 
15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
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15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others: 
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable 
ICH guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
STUDY DOCUMENTATION 
16.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRFs must be signed 
by the investigator.  This certification form accompanies each set of CRFs.  The signed form will 
be provided to the sponsor with the final set of CRFs for each patient. 
16.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer if a longer period is required by relevant 
regulatory authorities.  The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  Records 
must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
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17. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
18. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
19. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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21. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A PHASE 2/3 STUDY INVESTIGATING THE 
PHARMACOKINETICS, SAFETY, AND EFFICACY OF DUPILUMAB IN PATIENTS AGED 
≥6 MONTHS TO <6 YEARS WITH MODERATE-TO-SEVERE ATOPIC DERMATITIS, and 
agree to abide by all provisions set forth therein. 
I agree to comply with the current International Conference on Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
 
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Clinical Study Protocol 
R668-AD-1539 Amendment 4 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 118 
CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
A Phase 2/3 Study Investigating the Pharmacokinetics, Safety, and Efficacy of 
Dupilumab In Patients Aged ≥6 Months to <6 Years with Moderate-to-Severe Atopic Dermatitis 
Protocol Number: R668-AD-1539 
Protocol Version:  R668-AD-1539 Amendment 4 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
 
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Clinical Study Protocol 
R668-AD-1539 Amendment 4 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 119 
CONFIDENTIAL 
APPENDIX 1. FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF AES TO STUDY DRUG  
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
• due to external causes such as environmental factors or other treatment/s being 
administered 
• due to the patient’s disease state or clinical condition 
• do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug  
• do not reappear or worsen when dosing with study drug is resumed 
• are not a known response to the study drug based upon pre-clinical data or prior clinical 
data 
Yes: 
• could not be explained by environmental factors or other treatment/s being 
administered 
• could not be explained by the patient’s/subject’s disease state or clinical condition 
• follow a reasonable temporal sequence following the time of administration of the dose 
of study drug  
• resolve or improve after discontinuation of study drug  
• reappear or worsen when dosing with study drug is resumed 
• are known to be a response to the study drug based upon pre-clinical data or prior 
clinical data 
NOTE: This list is not exhaustive. 
 
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Clinical Study Protocol 
R668-AD-1539 Amendment 4 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 120 
CONFIDENTIAL 
APPENDIX 2. PERMITTED AND PROHIBITED STEROID 
MEDICATION 
Low potency steroids (permitted) 
Medium potency steroids (permitted as rescue, 
prohibited otherwise) 
Hydrocortisone acetate 1% cream / Hydrocortisone 1% 
cream (provided to sites by sponsor) 
Desonide 0.05% cream 
Alclometasone dipropionate 0.05% cream 
Triamcinolone acetonide 0.1% ointment (provided to 
sites by sponsor)  
Triamcinolone acetonide 0.1% cream 
Fluticasone propionate 0.05% cream  
Fluocinolone acetonide 0.025% ointment 
High Potency steroids (permitted as rescue, 
prohibited otherwise) 
Very high potency steroids (prohibited) 
Mometasone furoate 0.1% ointment  
Triamcinolone acetonide 0.5% ointment 
Clobetasol propionate 0.05% ointment 
Betamethasone dipropionate 0.05% ointment 
This is a representative list of TCS to be used in the study based on the American Academy of 
Dermatology classification (Eichenfield 2014).  Starting on day -14, all patients will be required 
to initiate treatment with a low potency TCS using a standardized regimen.  Based on investigator 
discretion, low/mild potency TCS may also be used on areas of thin skin (face, neck, intertriginous, 
and genital areas, areas of skin atrophy, etc.).  Hydrocortisone acetate 1% cream / 
hydrocortisone 1% cream should be used unless there are known side effects to these agents or 
due to non-availability due to any reason.  In those cases, other low potency TCS such as desonide 
0.05% cream or alclometasone dipropionate 0.05% cream can be used.  The use of medium/high 
potency steroids should be reserved for rescue.  It is recommended that triamcinolone acetonide 
0.1% ointment be used for rescue.  However, other medium or high potency TCS may be used as 
per investigator discretion. The use of very high potency steroids is not allowed during the study. 
 
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Clinical Study Protocol 
R668-AD-1539 Amendment 4 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 121 
CONFIDENTIAL 
APPENDIX 3. IGA SCALE 
Please refer to the instructions below and place a checkmark next to the appropriate score below: 
 
_____    0   Clear 
_____    1   Almost Clear 
_____    2   Mild Disease 
_____    3   Moderate Disease 
_____    4   Severe Disease 
 
 
_____________________________________________ _________ ______________________________ 
______________________ 
Print Name (First/Last) of Investigator Completing Assessment Signature  
 
 
Date 
 
Instructions: 
The Investigator’s Global Assessment is a static 5-point measure of disease severity based on an overall assessment of the skin lesions. 
IGA: Disease Severity Scale and Definitions of the scoring:  
Score 
Investigator’s Global Assessment (IGA)  
Standard Definitions 
Investigator’s Global Assessment (IGA):  
Proposed Morphological Descriptors 
0 = Clear 
No inflammatory signs of atopic dermatitis 
No inflammatory signs of atopic dermatitis 
1 = Almost clear 
Just perceptible erythema, and just perceptible 
papulation/infiltration  
Barely perceptible erythema and/or minimal lesion elevation 
(papulation/infiltration) 
2 = Mild disease 
Mild erythema and mild papulation/infiltration  
Visibly detectable, light pink erythema and very slight 
elevation (papulation/infiltration) 
3 = Moderate disease 
Moderate erythema and moderate 
papulation/infiltration   
Dull red, clearly distinguishable erythema; clearly perceptible 
elevation (papulation/infiltration), but not extensive 
4 = Severe disease 
Severe erythema and severe 
papulation/infiltration  
Deep/dark red erythema; marked and extensive elevation 
(papulation/infiltration) 
 
                                        VV-RIM-00131070-1.0 Approved - 28 Oct 2020 GMT-5:00


Signature Page for VV-RIM-00131070 v1.0
Signature Page for VV-RIM-00131070 v1.0 Approved
ESig Approval
2020 19:07:54 GMT+0000
ESig Approval
20 19:16:11 GMT+0000
ESig Approval
00
ESig Approval
2020 20:08:07 GMT+0000
                                        VV-RIM-00131070-1.0 Approved - 28 Oct 2020 GMT-5:00

SAP_001.pdf: 
Clinical and Regulatory Development 
Biostatistics and Data Management 
STATISTICAL ANALYSIS PLAN 
R668-AD-1539 PART B 
Title: A PHASE 2/3 STUDY INVESTIGATING THE PHARMACOKINETICS, SAFETY, AND 
EFFICACY OF DUPILUMAB IN PATIENTS AGED ≥6 MONTHS TO <6 YEARS 
WITH MODERATE-TO-SEVERE ATOPIC DERMATITIS 
Protocol: R668-AD-1539B.04 
Investigational product: Dupilumab (REGN668) 
Sponsor: Regeneron Pharmaceuticals, Inc. 
Version/Date: Version 1.0 / 28Apr2021 
VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00
NCT03346434


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 2 of 104 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
  
 
(Author) 
 
Print Name  
Signature 
Date (DDMMMYYYY) 
 
 
(Approver) 
 
Print Name  
Signature 
Date (DDMMMYYYY) 
 
 
(Approver) 
 
Print Name  
Signature 
Date (DDMMMYYYY) 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 3 of 104 
TABLE OF CONTENTS 
1. 
OVERVIEW ....................................................................................................................8 
1.1. Background and Rationale ...............................................................................................8 
1.2. Study Objectives ............................................................................................................10 
1.2.1. 
Primary Objective ...............................................................................................10 
1.2.2. 
Secondary Objectives ..........................................................................................10 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ........................10 
1.2.4. 
Revision History for SAP Amendments .............................................................11 
2. 
INVESTIGATIONAL PLAN ........................................................................................12 
2.1. Study Design and Randomization ..................................................................................12 
2.2. Statistical Hypothesis .....................................................................................................13 
2.3. Sample Size and Power Considerations (Part B) ...........................................................14 
2.4. Study Plan (Part B) ........................................................................................................14 
3. 
ANALYSIS POPULATIONS .......................................................................................16 
3.1. The Full Analysis Set (FAS) ..........................................................................................16 
3.2. The Safety Analysis Set (SAF) ......................................................................................16 
3.3. The Pharmacokinetic Analysis Set (PKAS) ..................................................................17 
3.4. The Immunogenicity Analysis Set .................................................................................17 
3.5. Subgroups ......................................................................................................................17 
4. 
ANALYSIS VARIABLES ............................................................................................19 
4.1. Demographic and Baseline Characteristics ...................................................................19 
4.2. Medical History and Atopic Disease Medical History ..................................................19 
4.3. Prior / Concomitant Medications and Procedures .........................................................19 
4.4. Efficacy Variables ..........................................................................................................21 
4.4.1. 
Primary Efficacy Variable ...................................................................................21 
4.4.2. 
Secondary Efficacy Variables .............................................................................22 
4.4.3. 
Exploratory Efficacy Variable(s) ........................................................................29 
4.5. Safety Variables .............................................................................................................32 
4.5.1. 
Adverse Events and Serious Adverse Events Variables .....................................32 
4.5.2. 
Laboratory Safety Variables................................................................................34 
4.5.3. 
Vital Sign Variables ............................................................................................35 
4.5.4. 
Body Weight and Height .....................................................................................35 
4.5.5. 
Physical Examination Variables .........................................................................35 
4.5.6. 
12-Lead Electrocardiography (ECG) Variables ..................................................35 
4.6. Pharmacokinetic (PK) Variables....................................................................................36 
4.7. Immunogenicity Variables .............................................................................................36 
4.8. Biomarkers Variables.....................................................................................................37 
5. 
STATISTICAL METHODS ..........................................................................................37 
5.1. Demographics and Baseline Characteristics ..................................................................37 
5.2. Medical and AD History ................................................................................................37 
5.3. Prior/Concomitant Medications/Procedures ..................................................................37 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 4 of 104 
5.4. Subject Disposition ........................................................................................................38 
5.5. Extent of Study Treatment Exposure and Compliance ..................................................39 
5.5.1. 
Measurement of Compliance ..............................................................................39 
5.5.2. 
Exposure to Study Drug and Observation Period ...............................................39 
5.6. Analyses of Efficacy Variables ......................................................................................39 
5.6.1. 
Analysis of Primary/Co-Primary Efficacy Variable ...........................................42 
5.6.2. 
Analyses of Secondary Efficacy Variables .........................................................43 
5.6.3. 
Adjustment for Multiple Comparison .................................................................45 
5.6.4. 
Subgroup Analysis ..............................................................................................46 
5.6.5. 
Analyses of Other Efficacy Variables .................................................................47 
5.7. Analysis of Safety Data .................................................................................................47 
5.7.1. 
Adverse Events ....................................................................................................47 
5.7.2. 
Analysis of Clinical Laboratory Measurements ..................................................48 
5.7.3. 
Analysis of Vital Signs ........................................................................................49 
5.7.4. 
Analysis of 12-Lead ECG ...................................................................................49 
5.7.5. 
Analysis of Physical Exams ................................................................................49 
5.8. Analysis of Pharmacokinetic Data .................................................................................49 
5.9. Analysis of Immunogenicity Data .................................................................................50 
5.9.1. 
Analysis of ADA Data ........................................................................................50 
5.9.2. 
Analysis of Neutralizing Antibodies (NAb)........................................................50 
5.10. Association of Immunogenicity with Exposure, Safety and Efficacy ...........................50 
5.10.1. Association of immunogenicity with exposure ...................................................50 
5.10.2. Immunogenicity and Safety/ Efficacy .................................................................50 
5.11. Analysis of Biomarker Data...........................................................................................51 
6. 
DATA CONVENTIONS ...............................................................................................53 
6.1. Definition of Baseline for Efficacy/Safety Variables ....................................................53 
6.2. General Data Handling Conventions .............................................................................53 
6.3. Data Handling Convention Missing Data ......................................................................53 
6.4. Analysis Visit Window ..................................................................................................55 
6.5. Statistical Technical Issues ............................................................................................58 
7. 
Interim analysis ..............................................................................................................58 
8. 
Software .........................................................................................................................58 
9. 
References ......................................................................................................................59 
Appendix 1. 
Prohibited and Rescue Medications .......................................................................61 
Appendix 2. 
List of Analysis ......................................................................................................62 
Appendix 3. 
Schdule of Events for the Screening, Treatment, and Follow-Up Period (Part B) 67 
Appendix 4. 
AESI  and  other AEs Criteria................................................................................88 
Appendix 5. 
PCSV Criteria ........................................................................................................91 
Appendix 6. 
Rescue Treatments ...............................................................................................102 
 
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Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 5 of 104 
LIST OF TABLES 
Table 1: Assignment of “as-treated” arms ...................................................................................16 
Table 2: Analysis Visit Window for Efficacy Endpoints CDLQI, IDQOL, DFI, POEM, 
CMW, CGID, CGIC ......................................................................................................56 
Table 3: 
Analysis Visit Window for PASQ ..............................................................................57 
Table 4: 
Analysis Visit Window for Safety labs, Vitals, PK and Biomarkers .........................57 
 
LIST OF FIGURES 
Figure 1: 
Overall Design ............................................................................................................12 
Figure 2 
Randomization Scheme for Part B .............................................................................13 
Figure 3: 
Study Flow Diagram ...................................................................................................15 
  
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Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 6 of 104 
List of abbreviations and definition of terms 
AD 
 
Atopic dermatitis 
ADA 
Anti-Drug Antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT (SGOT) 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST (SGPT) 
Aspartate aminotransferase 
BAS 
Biomarker analysis set 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CDLQI 
Children's Dermatology Life Quality Index 
CGIC 
Caregiver Global Impression of Change 
CGID 
Caregiver Global Impression of Disease 
CMH 
Cochran-Mantel-Haenszel 
CNSQ 
Caregiver-Reported Nasal Symptom Questionnaire 
CRF 
Case report form 
DFI 
Dermatitis Family Index 
EASI 
Eczema area and severity index 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
EU 
European Union 
FAS 
Full analysis set 
GISS 
Global Individual Signs Score 
HADS 
Hospital Anxiety and Depression Scale 
HLT 
High Level Term 
ICF 
Informed consent form 
ICH 
International conference on harmonisation 
IDQOL 
Infants’ Dermatology Quality of Life Index 
IGA 
Investigator global assessment 
IL 
Interleukin 
IgE 
Immunoglobulin E 
LDH 
Lactate dehydrogenase  
LOCF 
Last observation carried forward 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 7 of 104 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
NAb 
Neutralizing antibody 
PASQ 
Pediatric Asthma Symptom Questionnaire 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
POEM 
Patient Oriented Eczema Measure 
PPS 
Per protocol set 
PT 
Preferred term 
QW 
Weekly 
Q2W 
Once every 2 weeks 
Q4W 
Once every 4 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SCORAD 
SCORing atopic dermatitis 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System organ class 
TARC 
Thymus and activation-regulated chemokine 
TCI 
Topical calcineurin inhibitors 
TCS 
Topical corticosteroids 
TEAE 
Treatment emergent adverse event 
WHODD 
World health organization drug dictionary 
 
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R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 8 of 104 
1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying statistical approaches for the analysis of the study data. This SAP is intended to 
be a comprehensive and detailed description of strategy and statistical techniques to be used to 
perform the analysis of data for Part B of the R668-AD-1539 study (R668-AD-1539B). Note that 
a separate SAP was developed and finalized for the Part A of this study (R668-AD-1539A).  
This plan includes only Part B based on protocol amendment 4 and may be revised during the 
study to accommodate protocol amendments and to adapt to unexpected issues in study execution 
or data that affect planned analyses. This plan will be finalized prior to the database lock planned 
when all patients have completed end of treatment, which will be used to conduct the primary 
analysis of this study 
1.1. 
Background and Rationale 
Atopic dermatitis (AD), also known as atopic eczema, is a pruritic skin condition characterized by 
a chronic, relapsing form of skin inflammation, a disturbance of the epidermal-barrier function 
associated with immune changes in the skin, and a high prevalence of immunoglobulin E 
(IgE)-mediated sensitization to food and environmental allergens. 
Atopic dermatitis is one of the most common skin disorders in infants and children.  The disease 
affects over 20% of children in many industrialized countries.  A total of 45% of all cases of AD 
begin within the first 6 months of life, 60% begin during the first year, and 85% begin before 5 
years of age.  
The prevalence of AD has been estimated at a comparable 15–38% of children aged <5 years in 
the US (Al-Naqeeb 2019) and 21.5% of German children under age 2 (Illi 2004).  
The clinical pattern of AD varies with age. Infants typically present with erythematous papules 
and vesicles on the cheeks, forehead, or scalp, which are exudative and intensely pruritic. The 
childhood phase typically occurs from 2 years of age to puberty. Children present with lichenified 
papules and plaques representing the more chronic disease involving the hands, feet, wrists, ankles, 
and antecubital and popliteal regions. 
The disease has been shown to have a marked impact on the quality of life (QOL) of pediatric 
patients, greater than that seen in other common skin disorders like psoriasis and urticaria (Beattie 
2006). A study comparing the impact on the QOL of family members of children suffering from 
eczema and type 1 diabetes found that all families of children with moderate-to-severe eczema had 
significantly higher impact scores than those of diabetic children (Su 1997). 
Of particular interest in younger children is the phenomenon of “Atopic March” which is 
characterized by a typical sequence of progression of clinical signs of atopic disease. In general, 
the clinical signs of AD and of food allergies predate the development of asthma and allergic 
rhinitis, suggesting that AD is an “entry point” for subsequent allergic disease (Spergel 2003). 
Type 2 inflammation (including Th2 responses) and the dysregulated activation of Th2 cells have 
been recognized as the key underlying disease drivers of AD and other associated atopic/allergic 
diseases. Targeting the key type 2 cytokines, IL-4 and IL-13, has the potential for treating the 
pathology of AD as well as other associated atopic/allergic diseases. A study was recently 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 9 of 104 
conducted with the aim of identifying differences and similarities between cutaneous lymphocyte 
antigen (CLA) +ve, polarized T-cell subsets in children versus adults with AD. In this study, 
peripheral blood from children less than 5 years old was compared with that of adults with well-
characterized moderate-to-severe AD, using flow cytometry. The study concluded that Th2 
activation within skin-homing T cells might drive AD in children. Moreover, the spreading to 
additional Th subsets, particularly Th22, is seen in adults but not in children (Czarnowicki 2015).  
There is currently a high unmet medical need for an effective therapy for AD with an acceptable 
safety profile in infants and young children who suffer with moderate-to-severe AD.  
Nonpharmacological management of AD, which includes environmental control measures 
(eg, avoidance of antigen and skin irritants) and skin care measures (eg, maintaining the hydration 
of the skin through the use of emollients) play a supportive role, especially in children with 
moderate-to-severe disease.  Pharmacological management of AD in children is mainly limited to 
topical therapy with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs).  
However, long-term use of TCS in children is not recommended because of the risk of irreversible 
skin atrophy, dyspigmentation, acneiform eruptions, and risks associated with systemic absorption 
(eg, growth retardation, hypothalamic pituitary axis effects, etc).  Topical calcineurin inhibitors, 
such as tacrolimus and pimecrolimus, are also used in AD as an alternative to or in combination 
with TCS.  However, both tacrolimus and pimecrolimus are not indicated for use in children <2 
years of age.  Moreover, the use of TCI is frequently associated with skin irritation.  Furthermore, 
a possible increased risk of malignancy (lymphoma and skin cancers) has been noted for TCIs. 
Systemic agents are used off-label in children (cyclosporine, systemic steroids, methotrexate, 
azathioprine, and mycophenolate mofetil). A recent survey conducted in Europe, “European 
Treatment of Severe Atopic Eczema in Children Taskforce (TREAT)” found that approximately 
70% of respondents initiated systemic therapy for children with severe AD (Proudfoot 2013). All 
of these systemic agents have significant side effects in children, including stunted growth, 
diabetes, hypertension, and osteoporosis (corticosteroids), myelosuppression and hepatotoxicity 
(methotrexate), nephrotoxicity and hypertension (cyclosporine), and gastrointestinal disturbances 
and leucopenia (azathioprine). Moreover, a high proportion of patients in which disease is initially 
controlled by systemic agents suffer from relapse soon after therapy is discontinued 
(Schmitt 2009). 
Dupilumab is a novel targeted immunoregulatory agent that selectively and simultaneously inhibits 
IL-4 and IL-13 signaling through the IL-4 receptor alpha subunit (IL-4Rα) by binding to the 
obligate shared component (IL-4Rα) of the IL-4/IL-13 receptor complex. It is intended to inhibit 
key disease drivers to achieve clinical benefit without the side effects commonly observed with 
existing non-selective systemic immunosuppressants. Dupilumab, given subcutaneously (SC), is 
currently in clinical trials for multiple indications, including treatment of uncontrolled severe AD 
in pediatric patients. Dupilumab has been approved for marketing in the US and EU for treatment 
of moderate to severe AD in adults and adolescents as well as for children 6-11 yrs. old with 
moderate to severe AD in the US, and for children 6-11 yrs. old with severe disease in the EU. 
Additional detailed background information can be found in the study protocol. 
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R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 10 of 104 
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
The primary objective of Part B of the study is to demonstrate the efficacy of multiple doses of 
dupilumab over 16 weeks of treatment when administered concomitantly with TCS in pediatric 
patients, 6 months to less than 6 years of age, with moderate-to-severe AD. 
1.2.2. 
Secondary Objectives 
The secondary objective of Part B of the study is to assess the safety and immunogenicity of 
multiple doses of dupilumab over 16 weeks of treatment when administered concomitantly with 
TCS in patients 6 months to less than 6 years of age with moderate to severe AD. 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
The following modifications have been implemented in this SAP.  
Item 
Change from the Protocol 
Reasons 
Per protocol set 
(PPS) population 
There will be no analysis using PPS population. 
Not required by ICH. 
Imputation for 
binary responses 
Missing data due any reasons other than rescue 
treatment, AE, lack of efficacy (LOE) or 
withdrawn consent from study will be imputed by 
multiple imputation (MI).  
Consistent with 
imputation method 
for continuous 
endpoints. 
Imputation for 
continuous 
responses 
Patients with missing values at week 16 due to 
rescue treatment, withdrawn consent, AE, and lack 
of efficacy will be imputed by postbaseline worst-
observation-carried-forward (WOCF) if there is at 
least one non-missing postbaseline value or by 
baseline value if there is no postbaseline value. 
Clarify WOCF and 
add that missing due 
to withdrawn consent 
should be imputed by 
WOCF.  
 
Onset of action 
analysis in 
percent change 
from baseline 
weekly average 
of daily worst 
scratch/itch NRS 
score,  
proportion of 
NRS≥3,  
Add the following analysis: Onset of action in 
percent change from baseline weekly average of 
daily worst scratch/itch NRS score can be assessed 
by providing a nominal p-value at each assessment 
visits. The analysis will be carried out on the FAS 
population only. Using this analysis, the first 
assessment visit at which p <0.05 for the difference 
from placebo in the weekly average of daily worst 
scratch/itch NRS score that remains p < 0.05 at 
subsequent weekly measurements through week 16 
 
To assess the onset of 
effect on these 
endpoints. 
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R668-AD-1539 Part B 
Statistical Analysis Plan 
 
April 28, 2021 
 
CONFIDENTIAL 
Page 11 of 104 
NRS≥4,  
IGA 0/1, and  
EASI-75 
can be identified. The similar analysis will be 
carried out on the following binary responses:  
• IGA 0/1  
• EASI-75 
• Improvement (reduction) of weekly average of 
daily worst itch NRS score ≥3 from baseline 
• Improvement (reduction) of weekly average of 
daily worst itch NRS score ≥3 from baseline 
 
Additional 
endpoint for TCS 
use 
• Mean weekly dose of medium and/or high 
potency TCS through week 16 
 
This endpoint 
measures the steroid 
sparing effect of 
study drug on 
medium or high 
potency TCS, which 
is considered to be 
clinically relevant. 
 
1.2.4. 
Revision History for SAP Amendments 
None. 
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2. 
INVESTIGATIONAL PLAN 
2.1. 
Study Design and Randomization 
The study, R668-AD-1539 is being conducted in two parts.  
Figure 1: Overall Design  
 
The Part A of AD-1539 has been completed. The CSR has been finalized and approved in 
Dec 2020. This document focuses on Part B of the study only.  
AD-1539 B is a randomized, double-blind, placebo-controlled, parallel-group study to investigate 
the efficacy and safety of SC dupilumab when administered concomitantly with TCS in pediatric 
patients, ≥6 months to <6 years of age, with moderate-to-severe AD. Approximately 160 patients 
are planned to be randomized in the study. The number of patients with moderate AD (IGA=3) is 
capped at approximately 40 patients. Figure 1 shows the overall design of AD-1539 (Parts A and 
B). 
Part B consists of the following 3 periods: a screening period of up to 56 days (including 2 weeks 
of TCS standardization), a treatment period of 16 weeks, and a follow-up period of 12 weeks 
(Figure 3).  Patients who enrolled in Part A of the study are not eligible to participate in Part B. 
Patients who continue to meet eligibility criteria at baseline undergo day 1/baseline assessments. 
Patients are randomized in a 1:1 ratio stratified by baseline body weight (≥5-<15 kg and ≥15-
<30 kg), baseline disease severity (IGA=3 and 4), and region/country (North America and 
Europe). Approximately 160 patients are randomized to 1 of the following 2 treatment regimens 
(Figure 2): 
• dupilumab Q4W tiered fixed-dose (200 mg or 300 mg) treatment regimen:   
− Patients with baseline weight ≥5 to <15 kg receive an SC injection of 200 mg dupilumab 
(1.14 mL of a 175 mg/mL solution) on day 1 and then 200 mg Q4W from week 4 to 
week 12.   
− Patients with baseline weight ≥15 to <30 kg receive an SC injection of 300 mg 
dupilumab (2 mL of a 150 mg/mL solution) on day 1 and then 300 mg Q4W from week 4 
to week 12.  
• placebo Q4W treatment regimen:  patients receive matching placebo on day 1 and then Q4W 
from week 4 to week 12.   
− In the ≥5 to <15 kg weight stratum, patients randomized to placebo receive Q4W 
injections of placebo (1.14 mL) matching 200 mg dupilumab.   
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− In the ≥15 to <30 kg weight stratum, patients randomized to the placebo group receive 
Q4W SC injections of placebo (2 mL) matching 300 mg dupilumab.  
 
Figure 2 Randomization Scheme for Part B 
 
Note: Randomization will be stratified by baseline weight (≥5-<15 kg and ≥15 to <30 kg), baseline disease severity 
(IGA=3, 4), and region/country (North America and Europe\). 
2.2. 
Statistical Hypothesis 
For the comparison of the dupilumab treatment group to placebo, the following hypotheses of the 
primary endpoint will be tested, where pd is the true proportion of patients achieving IGA 0 or 1 
at week 16. 
Proportion of patients achieving IGA 0 or 1 at week 16 
− Null hypothesis (H0): pp = pd, i.e., the proportion of patients achieving IGA 0 or 1 at week 
16 is the same between the dupilumab group and the placebo group.  
− Alternative hypothesis (H1): pp ≠ pd, i.e., the proportion of patients achieving IGA 0 or 1 
at week 16 is different between the dupilumab group and the placebo group. 
The following co-primary endpoints (only in the European Union [EU] and EU Reference 
Market Countries) will be tested: 
Proportion of patients achieving IGA 0 or 1 at week 16 
− Null hypothesis (H0): pp = pd, i.e., the proportion of patients achieving IGA 0 or 1 at week 
16 is the same between the dupilumab group and the placebo group.  
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− Alternative hypothesis (H1): pp ≠ pd, i.e., the proportion of patients achieving IGA 0 or 1 
at week 16 is different between the dupilumab group and the placebo group. 
Proportion of patients with EASI-75 (≥75% improvement from baseline) at week 16 
− Null hypothesis (H0): 𝑝𝑝
′  = 𝑝𝑑
′ , i.e., the proportion of patients with EASI-75 at week 16 is 
the same between the dupilumab group and the placebo group.  
− Alternative hypothesis (H1): 𝑝𝑝
′  ≠ 𝑝𝑑
′ , i.e., the proportion of patients with EASI-75 at week 
16 is different between the dupilumab group and the placebo group. 
2.3. 
Sample Size and Power Considerations (Part B) 
It is estimated that a sample size of 160 patients (80 patients per treatment group), at the 2-sided 
5% significance level using Fisher's exact test, will provide the following: 
• 88% power to detect a difference of 21.4% between the dupilumab and placebo groups in the 
percentage of patients who achieve an IGA score of 0 to 1 at week 16, assuming that the 
percentages are 32.8% and 11.4% for the dupilumab and placebo groups, respectively. 
• 99% power to detect a difference of 42.9% in the percentage of patients who achieve an EASI-
75 response at week 16, assuming the percentages are 69.7% and 26.8% for the dupilumab and 
placebo groups, respectively. 
The assumptions used for the above power calculations were based on results from patients in the 
R668-AD-1652 study (phase 3 combination study for patients ≥6 to <12 years of age with severe 
AD).  The tiered fixed-dose regimen (200 mg Q4W in patients ≥5-<15 kg, 300 mg Q4W in patients 
≥15-<30 kg) is expected to provided exposure comparable to that seen with 300 mg Q4W in 
patients ≥6 to <12 years of age or 300 mg Q2W in adult patients. 
Further justification for the sample size comes from the results from the R668-AD-1224 study (a 
phase 3 combination [with TCS] study for adult patients with moderate-to-severe AD). In this 
study, the proportions of patients who achieved an IGA score of 0 to 1 at week 16 were 38.7% and 
12.4% for dupilumab and placebo, respectively. The proportions of patients who achieved an 
EASI-75 response at week 16 were 23.3% and 68.9% for dupilumab and placebo, respectively. 
The study will have a power of 96% on both the co-primary endpoints based on the results from 
the R668-AD-1224 study. Additional support for the sample size comes from the R668-AD-1526 
study (a phase 3 study for adolescent patients with moderate-to-severe AD).  
The sample size calculations were done using nQuery (7.0). 
2.4. 
Study Plan (Part B) 
The study consists of the following periods (Figure 3):  
1. Screening of up to 56 days, including TCS standardization period of 2 weeks 
2. Treatment period of 16 weeks, and   
3. Follow-up of 12 weeks (for patients who do not enter the OLE study, R668-AD-1434)  
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Figure 3: Study Flow Diagram 
 
Screening 
 
Treatment Period 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TCS Std 
Moisturizer 
Baseline 
Dosing 
End of Treatment 
Part B 
End of 
Study 
Part B 
(Day  
–56) 
(Day  
–14) 
(Day  
–7) 
(Day  
–1) 
(Day 1) 
 
(Days 1, 29, 57, 85) 
(Day 113) 
(Day 197) 
 
TCS Std: topical corticosteroid standardization 
Note:  The length of the screening period is not fixed but must not exceed 56 days (including TCS standardization).  
The length of the TCS standardization period is fixed at 14 days.  Moisturizers are to be applied at least twice daily 
during the 7 consecutive days prior to randomization (not including day of randomization) and are to be used 
throughout the study.  At least 11 of the 14 total applications of moisturizers prior to randomization must be applied 
for the patient to remain eligible for the study.   
Starting on day -14, all patients will be required to initiate treatment with low potency TCS using 
a standardized regimen (see Section 5.2 for details). 
During the treatment period, patients will have in-clinic visits at baseline, week 1, week 2, and 
week 4, then monthly in-clinic visits through week 16 with weekly telephone visits in between the 
clinic visits. 
Safety and laboratory assessments, samples for dupilumab concentration and ADA response to 
dupilumab, and efficacy assessments will be performed or collected at specified time points 
throughout Part B of the study according to the schedule described in study protocol. The end of 
treatment period visit will occur at week 16, 4 weeks after the last dose of study drug. The primary 
endpoint (and co-primary endpoint for EU and EU Reference Market Countries only, proportion 
of patients with an EASI-75, which is a key secondary endpoint for US) will be assessed at this 
visit.  
An OLE study (R668-AD-1434) in patients aged 6 months to <18 years old is currently ongoing.  
Patients who complete the treatment period in Part B may subsequently be eligible to participate 
in the OLE study (refer to R668-AD-1434 Protocol).  
Patients who decline to participate in the OLE will enter a follow-up period of 12 weeks.  Follow 
up visits will occur every 4 weeks from week 20 through week 28.  During the follow-up period, 
patients will be monitored for safety and tolerability and have laboratory and clinical assessments  
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3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (1998), the following populations of analysis will be used 
for all statistical analyses. 
3.1. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients. Efficacy analyses will be based on 
the treatment allocated at randomization (as randomized).  All efficacy variables will be evaluated 
in the FAS, which will be the primary analysis set.  
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who receive at least one dose of 
study drug and will be analyzed as treated. Treatment compliance/administration and all clinical 
safety variables will be summarized based on the SAF. 
The “as treated” assignments will be made as follows:  
Table 1: Assignment of “as-treated” arms 
Randomized to 
Treatment Received 
Treatment Assignment 
Dupilumab  
All placebo 
Placebo 
Dupilumab  
≥ 1 Dupilumab dose 
Dupilumab 
Placebo 
>=1 Dupilumab dose 
Dupilumab  
In addition:  
• Nonrandomized but treated patients will not be part of the safety population (SAF); however, 
their safety data will be presented separately. 
• Randomized patients for whom it is unclear whether they took the study drug will be included 
in the safety population as randomized. 
For safety summaries, three analysis periods are defined as follows:  
•  16-week treatment period is defined as  
− Day 1 to the study completion date of the planned Week 16 visit (or study day 113 
starting from the first dose of study drug if the date of the Week 16 treatment visit is 
unavailable) for those patients who completed the 16-week treatment period  
− Day 1 to the date of early termination visit, for those patients who did not complete the 
16-week treatment period  
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• Follow-up period is defined as the date after the week 16 visit date (or study day 113 starting 
from the first dose of study drug if the date of Week 16 treatment visit is unavailable) to the 
date of the end of study visit 
• Overall study Period is defined as Day 1 to the date of the end of study (EOS) visit  
The SAF will be the basis for the analyses for the treatment period and overall study period; 
however, for the analyses for the follow-up period, only a subset of the SAF will be included, 
which is defined as the patients who entered the follow-up period and had at least one visit after 
the week 16 treatment visit (EOT).  
3.3. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK analysis set includes all randomized patients who received any study drug and who had at 
least one non-missing drug concentration result following the first dose of study drug. 
3.4. 
The Immunogenicity Analysis Set  
The ADA analysis set (AAS) will consist of all patients who received any study drug and who had 
at least one non-missing ADA result after the first dose of the study drug. Patients will be analyzed 
according to the treatment they actually received.  
The neutralizing antibody (NAb) analysis set (NAS) includes all patients who received any study 
drug and who tested negative at all ADA sampling times or tested positive for ADA with at least 
one non-missing result in the NAb assay after the first dose of the study drug; note that, patients 
who are ADA negative are set to negative in the NAb analysis set. Patients will be analyzed 
according to the treatment they actually received.  
3.5. 
Subgroups 
Subgroups are defined by key baseline factors recorded on the eCRF (unless otherwise specified) 
and listed as follows. The analysis for the subgroups defined may not be performed if the number 
of patients within the subgroup is small, e.g. <10 patients per treatment arm. No subgroup analysis 
will be performed if the study fails to meet its primary objective. 
Subgroups to be considered for both efficacy and safety analyses: 
• Age group (>6months- <2years, 2years-<6years)  
• Sex (Male, Female) 
• Ethnicity: Hispanic or Latino (no/yes) 
• Race (White, Black, Asian, Other) 
• Duration of AD (< 3 years, ≥3 years) 
• Baseline BMI (overweight: >= 85 percentile of BMI for >=2 years based on age and gender, 
>= 95 percentile of weight based on length (height), age and gender for < 2 years,  Not 
overweight: not meeting the criteria of overweight ) [based on CDC (Center for Disease 
control and Prevention) chart] 
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• Baseline weight group (>=5- <15kg, >=15-<30kg) 
 
Subgroups listed for primary and key secondary efficacy endpoints: 
• Age of disease onset (<2 years, ≥2years) 
• Family history of atopic disease (Yes/No) 
• Region (North America, Europe) 
• Baseline EASI (<25, >=25) 
• Baseline worst scratch/itch scale (<7, ≥7) 
• Body Surface Area (BSA) (≥10%-<30%, ≥30%-<50%, ≥50%) 
• Baseline SCORAD score (<50, ≥50) 
• Previous usage of ciclosporin (CsA) (Yes, No) 
• Previous use of systemic immunosuppressants (Systemic Corticosteroid and Systemic Non-
Steroidal Immunosuppressant) for AD (Yes, No) 
• History of asthma (Yes, No) 
• History of allergic rhinitis (Yes, No) 
• History of food allergies (Yes, No)  
In addition, for analysis of conjunctivitis TEAEs, sub-group analysis based on medical history of 
conjunctivitis (yes/no) may be performed. TEAE and overall AE summary will be provided by 
history of food allergies subgroup. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized: 
• Demographic variables: Age at screening (year), Age group (>6m-<2Y, 2Y-<6Y), Sex (Male, 
Female), Ethnicity (Hispanic or Latino, Not-Hispanic or Latino), Race (White, Black or 
African American, Asian, Other), Region (North America, EU), Baseline weight (kg), Baseline 
weight  with grouping (>5-15 kg,  >15-30 kg), height (m), BMI [for >= 2 years, BMI will use 
weight/ height^2 formula;  for <2 yrs., BMI will use weight for length formula 
(weight/length)], BMI with grouping (overweight, not overweight) [using the separate formula 
by age as described previously]  
• Baseline characteristics: Duration of AD disease with grouping (< 3 years, >=3 years), worst 
scratch/itch NRS score, Investigator’s Global Assessment (IGA) score [IGA = 3, 4], Eczema 
Area and Severity Index (EASI) score, SCORing Atopic Dermatitis (SCORAD) score, Body 
Surface Area (BSA) affected by Atopic Dermatitis, Caregiver global impression of disease 
(CGID), Patient Oriented Eczema Measure (POEM), Children's Dermatology Life Quality 
Index (CDLQI for patients >=4 years of age), Infants’ Dermatology Quality of Life Index 
(IDQOL for patients <4 years of age), Global Individual Signs score (GISS), Dermatitis Family 
Index (DFI), NRS Skin Pain, NRS Sleep, Patients with inadequate response to topicals 
(Yes/No), Pediatric Asthma Symptom Questionnaire (PASQ, only for patients with ongoing 
asthma), Caregiver-Reported Nasal Symptom Questionnaire (CNSQ, only for patients with 
allergic rhinitis) 
4.2. 
Medical History and Atopic Disease Medical History 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). Information on conditions related to AD including diagnosis of AD and AD treatment 
history, personal and/or family history of asthma, allergic conjunctivitis, allergic rhinitis, chronic 
rhinosinusitis, nasal polyps, eosinophilic esophagitis, food allergy, hives and other allergies due to 
medications, animals, plants, mold, dust mites, etc. are collected. Recent AD topical treatments 
history within 6 months before the screening visit is also collected. History of treatment with 
systemic immunosuppressants for AD (cyclosporine, systemic corticosteroids, methotrexate, 
azathioprine and other treatments) during the last 6 months will also be collected. 
4.3. 
Prior / Concomitant Medications and Procedures 
Medications/Procedures will be recorded from the day of informed consent until the end of study 
(EOS) visit. Medications will be coded using WHO Drug Dictionary (WHODD). If a patient takes 
more than one medication within the same medication class, this patient will be counted only once 
in the summary. Procedures will be coded using MedDRA. 
Prior medications/procedures: medications taken, or procedures performed prior to 
administration of the first dose of study drug. 
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Concomitant medications/procedures (CMs/CPs): medications taken, or procedures performed 
following the first dose of study drug through the EOS visit.  
• Concomitant medications/procedures during the 16-week treatment period are 
medications/procedures taken after the first dose up to the week 16 visit date or date of study 
day 113 if the week 16 visit date is missing. Medications/procedures taken during the 16-
week treatment period and continued afterwards into the follow-up period will be counted 
only once as concomitant medications/procedures during the 16 week treatment period. 
• Concomitant medications/procedures during the follow-up period are medications/procedures 
taken after the week 16 visit date to end of study. 
Prohibited concomitant medications/procedures: Treatment with the following concomitant 
medications is prohibited during the study: 
• Treatment with a live (attenuated) vaccine (e.g. Chickenpox (Varicella), Mumps) 
• Treatment with an investigational drug (other than dupilumab) 
• Treatment with immunomodulating biologics 
• Treatment with systemic nonsteroidal immunosuppressant (e.g. cyclosporine, methotrexate) 
[may be used as rescue] 
• Treatment with crisabarole (may be used as rescue) 
• Treatment with medium potency, high-potency or very high potency TCS, (medium or high 
potency TCS may be used as rescue) 
• Treatment with TCI (may be used as rescue) [Note: The use of TCI is prohibited during the 
2-week screening period leading up to the baseline visit, and the treatment and follow-up 
periods] 
• Initiation of treatment of AD with prescription moisturizers 
 
The following concomitant procedures are prohibited during study participation: 
− Major elective surgical procedures 
− Phototherapy (ultraviolet A and/or ultraviolet B) 
 
For details of permitted and prohibited medications, see Appendix 1. 
 
Rescue treatments (i.e. both medications and procedures):  
If medically necessary (i.e. to control intolerable AD symptoms), rescue treatment for AD may be 
provided to study patients at the discretion of the investigator. The use of rescue treatment is only 
allowed after day 14 of the study. Investigators will be required to perform an IGA assessment 
prior to starting rescue treatment and initiate rescue treatment only in patients who either have an 
IGA score >= 3 or have intolerable symptoms.  If possible, investigators are encouraged to consider 
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rescue initially with topical treatment (e.g., high potency TCS) and to escalate to systemic 
medications only for patients who do not respond adequately after at least 7 days of topical 
treatment. Patients may continue study treatment if rescue consists of topical medications. Patients 
who receive systemic corticosteroids or systemic non-steroidal immunosuppressive drugs (e.g., 
cyclosporine, methotrexate, mycophenolate-mofetil, azathioprine, etc.) as rescue medication 
during the study will be discontinued permanently from the study drug.  All patients will be asked 
to complete the scheduled study visits and assessments whether or not they complete study 
treatment and whether or not they receive rescue treatment for AD.  Investigators should make 
every attempt to conduct efficacy and safety assessments (e.g., disease severity scores, safety 
laboratory tests) immediately before administering any rescue treatment.  An unscheduled visit 
may be used for this purpose, if necessary. For the purpose of efficacy analysis, patients who 
receive rescue treatment during the study will be considered treatment failures. 
For the purpose of the efficacy responder analysis, a pre-specified algorithm will be used to classify 
rescue (details in Section 5.6.1). In addition, a blinded review of all post-baseline medications to 
adjudicate rescue treatment, based on medical judgement, will be performed to adjudicate rescue. 
Patients who receive rescue treatment as per this adjudication during the study will be considered 
as treatment failures. 
4.4. 
Efficacy Variables 
4.4.1. 
Primary Efficacy Variable 
The primary endpoint in the study is: 
• Proportion of patients with IGA 0 or 1 (on a 5-point scale) at week 16 
For the EU and EU Reference Market Countries only, the co-primary endpoints are: 
• Proportion of patients with EASI-75 (≥75% improvement from baseline) at week 16 
• Proportion of patients with IGA 0 or 1 (on a 5-point scale) at week 16 
 
Investigator’s Global Assessment (IGA) 
The IGA is a static 5-point assessment instrument to rate AD disease severity globally in clinical 
studies. The ratings (0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe) are an overall 
assessment of AD skin lesions based on erythema and papulation/infiltration. IGA score will be 
assessed at the scheduled and unscheduled clinic visits according to  Appendix 3 . 
Eczema Area and Severity Index (EASI) 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin 2001). The EASI score calculation is based upon the Physician’s 
Assessment of Individual Signs [erythema (E), induration/papulation (I), excoriation (X), and 
lichenification (L)], where each sign is scored as 0 = Absent, 1 = Mild, 2 = Moderate, or 3 = Severe, 
and also upon the Area Score [based on the % (BSA) affected] where 0 = 0% BSA, 1 = 1-9% BSA, 
2 = 10-29% BSA, 3 = 30-49% BSA, 4 = 50-69% BSA, 5 = 70-89% BSA, 6 = 90-100% BSA. 
For each of major section of the body (head, upper extremities, trunk and lower extremities), EASI 
score = (E+I+X+L) x Area Score. The total EASI score is the weighted total of the section EASI 
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using the weights as follows: the head and neck (H), upper extremities (U), trunk (T), and lower 
extremities (L) are assigned proportionate body surface areas of 20% (H), 20% (U), 30% (T), and 
30% (L), roughly consistent with the ‘rule of nines”. The minimum possible EASI score is 0 and 
the maximum possible EASI score is 72 where a higher score indicates increased extent and 
severity of atopic dermatitis. The EASI score of each sign (E, I, X and L) can be calculated in a 
similar way, for example, the EASI score of erythema = weighted sum of E x Area Score at each 
section.  
The EASI will be collected at the scheduled and unscheduled clinic visits according to 
Appendix 3. 
4.4.2. 
Secondary Efficacy Variables 
The key secondary endpoints: 
• Proportion of patients with EASI-75 (≥75% improvement from baseline) at week 16 (not 
applicable for EU or EU Reference Market Countries) 
• Percent change in EASI score from baseline to week 16 
• Percent change from baseline to week 16 in weekly average of daily worst scratch/itch NRS 
score 
Pruritus (worst scratch/itch) NRS score 
Itch will be measured using a worst scratch/itch NRS that was developed and tested for the 
study-relevant age group.  This is an 11-point scale (0 to 10) in which 0 indicates no 
scratching/itching while 10 indicates worst scratching/itching possible. The parents/caregivers will 
be asked to:  
“Answer the question below based on what you observe and what your child tells you (if 
applicable):” 
“How would you rate your child’s scratching/itching at its worst in the past 24 hours?” 
Pruritus will be assessed by the parent/caregiver on a daily basis using an e-diary throughout the 
entire study (i.e., screening, treatment, and follow-up periods). 
Parents/caregivers will be instructed on using the scale to record their child’s pruritus score at the 
screening visit.  Using the e-diary, parents/caregivers will complete the rating scale DAILY 
through the entire study (screening, treatment, and follow-up periods).  Clinical sites will check 
parent/caregiver data, collected using the e-diary, for protocol compliance and remind 
parents/caregivers to complete the e-diary throughout the study. 
The baseline worst scratch/itch scale score is defined as the prorated average of the worst 
scratch/itch scale scores reported continuously for 7 days right before the baseline visit (i.e. study 
day -7 to day -1). For post-baseline worst itch scale score, the weekly mean of daily worst 
scratch/itch score is calculated as the average of the available reported daily worst scratch/itch 
score within the week. For example, if there are 3 scores in a week, the prorated average = (score1 
+ score2 + score3)/3.  
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Other secondary efficacy endpoints: 
• Proportion of patients with EASI-50 at week 16 
• Proportion of patients with EASI-90 at week 16 
• Change from baseline to week 16 in percent BSA affected by AD 
• Percent change from baseline to week 16 in SCORAD 
• Change from baseline to week 16 in weekly average of daily worst scratch/itch NRS score 
• Proportion of patients with improvement (reduction) of weekly average of daily worst itch 
score ≥4 from baseline at week 16  
• Proportion of patients with improvement (reduction) of weekly average of daily worst itch 
score ≥3 from baseline to week 16   
• Change from baseline to week 16 in skin pain NRS 
• Change from baseline to week 16 in patient’s sleep quality NRS 
• Change from baseline to week 16 in caregiver’s sleep quality NRS 
• Change from baseline to week 16 in health-related quality of life, as measured by CDLQI 
score (patients ≥4 years of age)  
• Change from baseline to week 16 in health-related quality of life, as measured by IDQOL 
score (patients <4 years of age) 
• Change from baseline to week 16 in Dermatitis Family Index, DFI score 
• Change from baseline to week 16 in POEM score 
• Topical treatment for AD – proportion of TCS medication-free days from baseline to week 
16 
• Mean weekly dose of low potency TCS through week 16 
• Mean of caregiver missed workdays (CMW) from baseline to week 16 
Secondary endpoints for safety: 
• Incidence of skin infection TEAEs (excluding herpetic infections) through week 16* 
• Incidence of SAEs through week 16 
*Adjudicated by study medical director. 
Additional secondary efficacy endpoints (that are not in protocol): 
• Mean weekly dose of medium or high potency TCS through week 16 
Skin Pain NRS 
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Skin pain will be assessed by the parent/caregiver at time points during Part B according to 
Appendix 3.  Skin pain will be measured during Part B using a skin pain NRS that was developed 
and tested for the study-relevant age group.  This is an 11-point scale (0 to 10) in which 0 indicates 
no pain while 10 indicates worst pain possible.  The parents/caregivers will be asked to: 
“Think about all the areas of your child's skin with eczema.  Answer the question below based on 
what you observe and what your child tells you (if applicable).” 
“How would you rate your child's skin pain at its worst in the past 24 hours?” 
Clinical sites will check and remind the parent/caregiver to complete the scale according to the 
time points in Appendix 3. Parents/caregivers will be instructed on using the scale to record their 
child’s skin pain score at the screening visit.  Parents/caregivers will complete the rating scale 
DAILY for the 14 days prior to the baseline visit, for the 7 days prior to the week 2 visit, for the 7 
days prior to the week 4 visit, for the 7 days prior to the week 16 visit, and for the 7 days prior to 
the week 28 visit.  Clinical sites will check parent/caregiver data collected using an e-diary for 
protocol compliance and remind parents/caregivers to complete their e-diary throughout the study. 
Higher score indicates worse condition. 
The baseline Skin Pain NRS score is defined as the prorated average of the Skin Pain scores 
reported continuously for 7 days right before the baseline visit (i.e. study day -7 to day -1). For 
post-baseline Skin Pain NRS score, the weekly mean of daily Skin Pain score is calculated as the 
average of the available reported skin pain score within the week. For example, if there are 3 scores 
available in a week, the prorated average = (score1 + score2 + score3)/3.  
Sleep Quality NRS 
A sleep diary will be completed by the parent/caregiver at time points during Part B according to  
Appendix 3. The sleep diary includes 2 questions assessing the caregiver’s sleep, and 6 questions 
assessing the child’s sleep based on caregiver observation.  Sleep diary items, either alone or in 
combination will serve as subjective measures of sleep quality, difficulty falling asleep, nighttime 
awakenings, and sleep duration. Sleep quality will be measured using an 11-point NRS (0 to 10) 
in which 0 indicates worst possible sleep while 10 indicates best possible sleep.  The 
parents/caregivers will be instructed to complete the questions about the child’s sleep upon 
awakening for the day as well as to complete the questions about their own sleep.  
Clinical sites will check and remind the parent/caregiver to complete the diary according to the 
time points in Appendix 3. Parents/caregivers will be instructed on using the diary to record their 
child’s sleep quality score at the screening visit.  Parents/caregivers will complete the diary DAILY 
for the 14 days prior to the baseline visit, for the 7 days prior to the week 1 visit, for the 7 days 
prior to the week 2 visit, for the 7 days prior to the week 4 visit, for the 7 days prior to the week 
16 visit, and for the 7 days prior to the week 28 visit.  Clinical sites will check parent/caregiver 
data collected using an e-diary for protocol compliance and remind parents/caregivers to complete 
their e-diary throughout the study. Higher score indicates better condition. 
The baseline Sleep Quality NRS score is defined as the prorated average of the sleep quality NRS 
scores reported continuously for 7 days right before the baseline visit (i.e. study day -7 to day -1). 
For post-baseline Sleep quality NRS score, the weekly mean of daily sleep quality score is 
calculated as the average of the available reported daily sleep quality score within the week. For 
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example, if there are 3 scores available in a week, the prorated average = (score1 + score2 + 
score3)/3.  
Body Surface Area (BSA) Involvement of Atopic Dermatitis 
Body surface area affected by AD will be assessed for each section of the body (head, trunk, 
arms, and legs) and will be reported as a percentage of all major body sections combined. The 
possible highest score for each region is:  
Age 
Head 
Torso 
Lower Extremities 
Upper Extremities 
Genitals 
6 months - <2 years 18% 
36% 
28% 
18% 
0% 
2 - <3 years 
17% 
36% 
29% 
18% 
0% 
3 - <4 years 
16% 
36% 
30% 
18% 
0% 
4 - <5 years 
15% 
36% 
31% 
18% 
0% 
5 - < 6 years 
14% 
36% 
32% 
18% 
0% 
Total BSA will be the sum of all individual body areas. Patients will undergo this assessment at 
the scheduled and unscheduled clinic visits according to Appendix 3.  
SCORing Atopic Dermatitis (SCORAD) 
The SCORAD is a validated tool used in clinical research and clinical practice that was developed 
to standardize the evaluation of the extent and severity of AD (Dermatology 1993). The extent of 
AD is assessed by the Investigator as a percentage of each defined body area and reported as the 
sum of all areas, with a maximum score of 100% (assigned as “A” in the overall SCORAD 
calculation). The severity of 6 specific symptoms (erythema, oedema / papulation, excoriations, 
lichenification, oozing / crusts and dryness) of AD is assessed by the Investigator using the 
following scale: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, 
assigned as “B” in the overall SCORAD calculation). Subjective assessment of itch and 
sleeplessness is recorded for each symptom by the patient or relative on a visual analogue scale 
(VAS), where 0 is no itch (or sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), 
with a maximum possible score of 20. This parameter is assigned as “C” in the overall SCORAD 
calculation. The SCORAD is calculated as A/5 + 7B/2 + C. The maximum SCORAD score is 103. 
The objective SCORAD is calculated as A/5 + 7B/2. The maximum objective SCORAD score is 
83. Higher score indicates worse condition. 
Patients will undergo this assessment at the scheduled and unscheduled clinic visits according to 
Appendix 3. 
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Children’s Dermatology Life Quality Index (CDLQI) 
The CDLQI is a validated questionnaire designed to measure the impact of skin disease on the 
QOL in children ≥4 years of age (Lewis-Jones 1995).  The aim of the questionnaire is to measure 
how much a patient’s skin problem has affected the patient over a recall period of the past week. 
In this study, a cartoon version of the CDLQI will be administered to patients 4 to 5 years of age, 
with the assistance of a parent or adult “as necessary”.  If assistance of parent or adult caregiver is 
required, it is recommended that the same person assist the patient throughout the study.  The 
cartoon version of the CDLQI uses the same text and scoring system as the original CDLQI but 
includes 10 color drawings of a dog illustrating the theme of each question. 
To complete the questionnaire, patients need to provide responses to 10 questions (the questions 
focus on domains such as symptoms feelings associated with disease, the impact of the disease on 
leisure, school or holidays, personal relationships, sleep, and side effects of treatment for the skin 
disease.  The instrument has a recall period of 7 days.  Nine of the 10 questions are scored as 
follows: 
• Very much = 3  
• Quite a lot = 2  
• Only a little = 1  
• Not at all = 0  
• Question unanswered = 0  
Question 7 has an additional possible response (prevented school), which is assigned a score of 3. 
Overall scoring ranges from 0 to 30; a high score is indicative of a poor QOL. The CDLQI will be 
assessed at the scheduled and unscheduled clinic visits according to Appendix 3. 
Handling missing items from CDLQI: 
i. 
If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. 
ii. 
If two or more questions are left unanswered the questionnaire is not scored. 
iii. 
If two or more response options are ticked for one question, the response option with 
the highest score should be recorded. 
iv. 
The CDLQI sub-scores may be analyzed by calculating the score for each of its six sub-
scales. When using sub-scales, if the answer to one question in a sub-scale is missing, 
that sub-scale will not be scored:  
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Sub-scales 
Questions 
Maximum Score 
Symptoms and feelings 
Questions 1,2  
6 
Leisure 
Questions 4, 5 and 6 
9 
School or holidays 
Question 7 
3 
Personal relationships 
Questions 3 and 8  
6 
Sleep 
Question 9 
3 
Treatment 
Question 10 
3 
Infants’ Dermatology Quality of Life Index (IDQOL) 
The IDQOL is a validated questionnaire developed to measure the impact of skin disease on the 
QOL of infants and preschool children <4 years of age (Lewis-Jones 2001). The IDQOL is to be 
completed by the child’s parent or caregiver.  It is recommended that the same person complete 
the questionnaire on behalf of the patient throughout the study.  The questionnaire consists of 
10 questions related to itching and scratching; mood of the child; how long it takes for the child to 
get to sleep; whether the eczema has interfered with the child’s playing, swimming or participation 
in other family activities; problems during mealtimes; problems caused by treatment; level of 
comfort while dressing or undressing the child; and problems during bathing.  Each question asks 
about the impact over the previous week and is scored on a scale of 0 (minimum impact) to 3 
(maximum impact). A high score is indicative of a poor QOL 
The IDQOL for a patient is the sum of the score of each question with a maximum of 30 and a 
minimum of 0.  The higher the score, the greater the impact is on the QOL.  The IDQOL can also 
be expressed as a percentage of the maximum possible score of 30. Handling missing items from 
IDQOL will be same as that of CDLQI. The IDQOL sub-scores may be analyzed by calculating 
the score for each of its sub-scales, as appropriate. When using sub-scales, if the answer to one 
question in a sub-scale is missing, that sub-scale will not be scored. 
This assessment will be performed in Part B at time points according to Appendix 3. 
Sub-scales 
Questions 
Maximum Score 
Symptoms (1 item) 
Question 1 
3 
Difficulties with mood (1 item) 
Question 2 
3 
Sleep (2 items) 
Questions 3, 4 
6 
Play (1 item) 
Question 5 
3 
Family activities (1 item) 
Question 6 
3 
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Mealtimes (1 item) 
Question 7 
3 
Treatments (1 item) 
Question 8 
3 
Dressing (1 item) 
Question 9 
3 
Bathing (1 item) 
Question 10 
3 
Patient Oriented Eczema Measure (POEM) 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults with atopic eczema (Charman 2004). The format is patient 
response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based 
on symptom frequency during the past week (i.e., 0 = ‘no days’, 1 = ‘1 to 2 days’, 2 = ‘3 to 4 days’, 
3 = ‘5 to 6’ days, and 4 = ‘every day’). The total score is the sum of the 7 items which is ranged 
from 0 to 28; a high score is indicative of a poor QOL. The following POEM banding scores have 
been established (Charman 2004): 0 to 2 = Clear or almost clear; 3 to 7 = Mild eczema; 8 to 16 = 
Moderate eczema; 17 to 24 = Severe eczema; 25 to 28 = Very severe eczema. If two or more 
response options are selected for a question, then the response option with the highest score is 
recorded. If one question of the seven is left unanswered, then that question is scored as 0 and the 
scores are summed and expressed as usual out of a maximum of 28. If two or more questions are 
left unanswered, then the questionnaire is not scored and is set to missing. If two or more response 
options are ticked for one question, the response option with the highest score should be recorded. 
Higher score indicates worse condition.  
This questionnaire asks the caregiver to report their perception of the patient’s AD symptoms. It 
is therefore completed by the caregiver. It is recommended that the same person complete the 
questionnaire on behalf of the patient throughout the study. 
Caregiver Assessment of Missed Workdays (CMW)  
Caregivers who are employed will be asked to report the number of sick-leave days since the last 
study assessment. Caregivers will undergo this assessment at the time points according to  
Appendix 3. 
Dermatitis Family Index (DFI) 
The impact on family life has been documented in families of children with very severe AD.  The 
DFI was the first instrument assessing the impact of having a child with AD on family QOL 
(Lawson 1998).  The 10-item disease specific questionnaire was formed after ethnographical 
interviews and focus groups revealed the areas of family QOL affected by AD.  The 
self-administered instrument is completed by an adult family member of a child affected by 
dermatitis.  The items inquire about housework, food preparation, sleep, family leisure activity, 
shopping, expenditure, tiredness, emotional distress, relationships and the impact of helping with 
treatment on the primary caregiver’s life.  The DFI questions are scored on a four-point Likert 
scale ranging from 0 to 3, so that the total DFI score, which is calculated as sum of all 10 questions, 
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ranges from 0 to 30. The time frame of reference is the past week.  A higher DFI score indicates 
greater impairment in family QOL as affected by AD. The DFI will be assessed at time points 
according to Appendix 3. Note that, DFI is also called as Dermatitis Family Impact. 
Handling missing items from DFI: 
v. 
If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. 
vi. 
If two or more questions are left unanswered the questionnaire is not scored. 
vii. 
If two or more response options are ticked for one question, the response option with 
the highest score should be recorded. 
 
4.4.3. 
Exploratory Efficacy Variable(s) 
Exploratory efficacy endpoints include: 
• Proportion of patients with SCORAD-50 (>=50% reduction in SCORAD from baseline) 
response at week 16 
• Proportion of patients with SCORAD-75 (>=75% reduction in SCORAD from baseline) 
response at week 16 
• Proportion of patients with SCORAD-90 (>=90% reduction in SCORAD from baseline) 
response at week 16 
• Caregiver global impression of disease (CGID):  
− Proportion of patients with No symptoms at week 16  
− Proportion of patients with No symptoms or Mild symptoms at week 16 
• Caregiver global impression of change (CGIC):  
− Proportion of patients who rate their eczema symptoms as “Much better” at week 16 
− Proportion of patients who rate “Much better” or “Moderately better” at week 16 
• Proportion of patients who achieve reduction of IGA score by ≥2 from baseline to week 16 
• Proportion of patients who achieve an IGA score of 2 (mild disease) or less at week 16 
• Change from baseline to week 16 in GISS (erythema, infiltration/papulation, excoriations, 
lichenification) 
• Proportion of patients with IGA score 0 or 1 or EASI-90 at week 16 
• Change from baseline in PASQ score at week 16 (for patients with Asthma) 
• Change from baseline in CNSQ score at week 16 (for patients with medical history of 
allergic rhinitis) 
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Caregiver Global Impression of Disease (CGID)  
The CGID is an assessment instrument used by the parent/caregiver in clinical studies to rate their 
child’s eczema symptoms during the past 7 days.  An appropriate version of the CGID was being 
developed and tested for the study-relevant age group.   
Parents/caregivers will rate their child’s disease based on the 5-level scale as follows: 
“Overall, how would you rate your child’s eczema symptoms during the past 7 days?” 
− No symptoms 
− Mild 
− Moderate 
− Severe 
− Very severe 
The CGID score will be assessed at time points according to Appendix 3. 
Caregiver Global Impression of Change (CGIC) 
Caregiver global impression of change will be measured using a caregiver administered tool that 
is currently being developed and tested for the study-relevant age group. 
Parents/caregivers will respond to the following question based on the 7-level scale as follows:  
“Compared to before your child started the study, how would you rate his or her eczema now?” 
− Much better 
− Moderately better 
− A little better 
− No change 
− A little worse 
− Moderately worse 
− Much worse  
The CGIC is an instrument used by the parent/caregiver in clinical studies to compare their child’s 
eczema symptoms from the beginning of the study to when they completed the assessment.   
The CGIC score will be assessed at time points according to Appendix 3. 
Global Individual Signs Score (GISS) 
Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and 
lichenification) will be rated globally by the Investigator (i.e., each assessed for the whole body, 
not by anatomical region) on a 4-point scale (0=none, 1=mild, 2=moderate and 3=severe) using 
the EASI severity grading criteria. The cumulative score is the sum of the four components, which 
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will be ranged from 0 to 12. A higher GISS score indicates worse AD lesions of the patient. 
Handling missing items from GISS: 
i. 
If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 12. 
ii. 
If two or more questions are left unanswered the questionnaire is not scored. 
iii. 
If two or more response options are ticked for one question, the response option with 
the highest score should be recorded. 
The GISS will be assessed at the scheduled and unscheduled clinic visits according to 
Appendix 3. 
Pediatric Asthma Symptom Questionnaire (PASQ) 
The PASQ is a questionnaire developed by the sponsor to monitor asthma control in preschool 
children in clinical trial settings. The advantage of the PASQ is the much shorter recall period for 
various items to fit the schedule of clinical trials and improvement in ability to recall as compared 
to existing instruments. The questionnaire consists of 6 questions related to asthma control. 
The questionnaire will be completed only for the subset of patients with ongoing asthma. It is to 
be completed by the child’s parent or caregiver who fluently speaks a language in which the 
questionnaire is presented, at time points according to Appendix 3. It is recommended that the 
same person complete the questionnaire on behalf of the patient throughout the study. Questions 
4, 5, and 6 will only be answered if the answer to Question 3 is > 0 days. Higher score indicates 
worse condition (asthma severity). 
The following algorithm will be implemented to calculate PASQ score. 
• Questions 1 & 2 should still be calculated and summarized separately.  
• For questions 3 to 6 (ranged from 0 to 4), total score, which can be termed as PASQ 
score. will be calculated.  
- 
If answer to question 3 is 0, then the total score is 0, regardless of answers to 
questions 4-6; 
- 
If answer to question 3 is non-zero and answers to questions 4 to 6 are all 0, then 
the total score will be equal to the score for question 3;  
- 
If answer to question 3 is non-zero and answers to questions 4 to 6 are also non-
zero values, then the total score is calculated by adding the scores for questions 4 
to 6; Also ignore the score in question 3.  
Handling missing items from PASQ: 
If answer to question 3 is missing and answers to questions 4-6 are non-missing, then the total 
score is calculated by adding the scores for questions 4 to 6; if one item from questions 4 to 6 is 
missing, set the score of the missing item as the average of the other two non-missing items from 
questions 4-6 and calculate total score. If two or more items from questions 4-6 are missing, then 
set the total score as missing. 
If answer to question 3 is non-missing and non-zero,  and if one item from questions 4-6 is 
missing, set the score for the missing item as the average of the other two non-missing items from 
questions 4-6 and calculate total score. If two or more items from questions 4-6 are missing, then 
set the total score as missing. 
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Caregiver-Reported Nasal Symptom Questionnaire (CNSQ):  
The CNSQ will be used to assess the effect of study drug on symptoms of allergic rhinitis. The 
summed score will include the following 4 symptoms: runny nose, nasal congestion, nasal itching, 
and sneezing, each rated on a 0 to 3 scale of severity. The questionnaire will be completed only 
for the subset of patients with a medical history of allergic rhinitis. It is to be completed by the 
child’s parent or caregiver who fluently speaks a language in which the questionnaire is presented 
(based on availability of translations in participating countries). Total score is the sum of all 
symptom scores. If there is one symptom score missing, the total score is set to missing. The 
minimum and maximum possible values of the total CNSQ score are 0 and 12. Higher score 
indicates worse condition. 
Caregivers will be instructed on using the e-diary to record the CNSQ during the screening 
period (for the 14 days before baseline/day 1) and for the 7 days preceding visits  for weeks 4, 
16, and 28 as described in Appendix 3. 
The baseline CNSQ score is defined as the average of the CNSQ scores reported continuously 
for 7 days right before the baseline visit (i.e. study day -7 to day -1). The weekly average CNSQ 
score (post-baseline) will be calculated as the average of the available reported daily CNSQ 
score within 7 days prior to the visit. For example, if there are 3 scores available in a week, the 
average = (score1 + score2 + score3)/3. 
4.5. 
Safety Variables  
4.5.1. 
Adverse Events and Serious Adverse Events Variables 
Adverse events and serious adverse events (SAE) will be collected starting from the time of 
informed consent signature and at each visit until the end of the study. All adverse events are to 
be coded to a “Preferred Term (PT)”, “High Level Term (HLT)” and associated primary “System 
Organ Class (SOC)” according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The criteria for determining whether an abnormal laboratory, vital sign or ECG finding should be 
reported as an AE are as follows: 
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
• Test result leads to a change in dosing (outside of protocol-stipulated dose adjustments) or 
discontinuation from the study, significant additional concomitant drug treatment, or other 
therapy 
The pre-treatment period is defined as the period from the patient providing informed consent up 
to the first dose of study drug. The treatment and follow-up period is defined as the period from 
the administration of first study dose to the EOS visit. 
Pre-treatment AEs and treatment emergent AEs (TEAEs) are defined as follows:  
• Pre-treatment AEs are AEs that developed or worsened in severity during the pre-treatment 
period. 
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• Treatment-emergent AEs (TEAEs) are AEs that developed or worsened in severity compared 
to the baseline during the treatment and follow-up period. As only worsening pre-existing 
AEs and new AEs reported during the treatment and follow-up period will be collected in the 
study, all AEs collected during the treatment and follow-up period are considered TEAEs. 
• TEAEs during the 16 week treatment period are AEs with onset after the first dose up to the 
week 16 visit date (study day 113 if the week 16 visit date is missing) or early termination 
visit, whichever is earlier. TEAEs that have an onset during the 16 week treatment period and 
continued afterwards into the follow-up period will be counted only once as TEAEs during 
the 16 week treatment period. 
• TEAEs during the follow-up period are AEs with onset after the week 16 visit date up to the 
end of the study. 
AEs of Special Interest (AESI):   
The following AESIs will be analyzed:  
• Anaphylactic reactions 
• Systemic hypersensitivity reactions 
• Helminthic infections  
• Any severe type of conjunctivitis or blepharitis 
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms) 
Other AEs: 
Skin Infections (with adjudication by clinical), Herpes Infections and Injection Site Reactions 
will be analyzed.  
Additionally other AEs such as Narrow and Broad Conjunctivitis CMQ will be analyzed. 
• Narrow conjunctivitis CMQ is defined as the following PT terms 
− Conjunctivitis 
− Conjunctivitis allergic 
− Conjunctivitis bacterial 
− Conjunctivitis viral 
− Atopic Keratoconjunctivitis 
• Broad conjunctivitis CMQ is defined as the following PT terms 
− Conjunctivitis 
− Conjunctivitis allergic 
− Conjunctivitis bacterial 
− Conjunctivitis viral 
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− Atopic Keratoconjunctivitis 
− Blepharitis 
− Dry eye 
− Eye irritation 
− Eye pruritus 
− Lacrimation increased 
− Eye discharge 
− Foreign body sensation in eyes 
− Photophobia  
− Ocular hyperaemia 
− Conjunctival hyperaemia 
− Xerophthalmia 
Note that, Appendix 4 provides a list of AESIs search criteria. 
4.5.2. 
Laboratory Safety Variables 
Hematology, and chemistry samples will be analyzed by a central laboratory.  
Samples for laboratory testing will be collected according to visit schedule (Appendix 3). Tests 
will include 
 Serum Chemistry 
Sodium 
Total protein, serum 
Total bilirubin1 
Potassium 
Creatinine 
Total cholesterol2 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
AST 
Uric acid 
Calcium 
ALT 
CPK3 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
1 Direct and indirect bilirubin will be measured when the total bilirubin is above the ULN 
2 Low-density lipoprotein and high-density lipoprotein 
3 CPK isoenzymes will be measured when CPK >5× the ULN 
 
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Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
 
 
Other Laboratory Tests 
The following tests will be performed at screening: HIV, HBsAg, HBsAb, HBcAb, hepatitis C 
antibody, tuberculosis (will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ethics boards). Serum samples for vaccination 
response will be collected at time points as described in Appendix 3. 
4.5.3. 
Vital Sign Variables 
The following vital signs parameters will be collected: 
• Respiratory rate (bpm) 
• Heart rate (beats/min) 
• Sitting systolic and diastolic blood pressures (mmHg) 
• Body temperature (oC) 
Patients will be monitored at the study site at certain dosing visits for a minimum of 2 hours after 
study drug administration. Vital signs (systolic and diastolic blood pressure, heart rate, respiration, 
and temperature) will be performed at 30 minutes (±10 minutes) and 2 hours (±15 minutes) post-
injection. See Appendix 3 for assessment time points. 
4.5.4. 
Body Weight and Height 
Body weight and height will be measured at time points according to Appendix 3. 
4.5.5. 
Physical Examination Variables 
The physical examination variable values are dichotomized to normal and abnormal. A thorough 
and complete physical examination will be performed at time points according to the schedule 
described in Appendix 3. 
4.5.6. 
12-Lead Electrocardiography (ECG) Variables 
Standard 12-Lead ECG parameters include: Ventricular HR, PR interval, QRS interval, corrected 
QT interval (QTc Fridericia [QTcF] =QT/[RR0.33]) ECG status: normal, abnormal not clinical 
significant or abnormal clinical significant. See Appendix 3 for assessment time points. 
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4.6. 
Pharmacokinetic (PK) Variables  
Serum samples for measuring functional dupilumab concentrations will be collected at time points 
according to Appendix 3. PK parameters may include, but are not limited to Ctrough and Ctrough,SS. 
4.7. 
Immunogenicity Variables   
The immunogenicity variables are ADA status, titer, NAb status and time-point/visit. Serum 
samples for anti-dupilumab antibody testing will be collected at time points according to the visit 
schedule described in  Appendix 3. Samples positive in the ADA assay will be analyzed for the 
presence of neutralizing antibody in the NAb assay.  
- 
ADA Negative, defined as ADA negative response in the dupilumab ADA assay at all 
timepoints, regardless of any missing samples. 
- 
Pre-existing immunoreactivity, defined as either an ADA positive response in the 
dupilumab ADA assay at baseline with all post first dose ADA results negative, OR a 
positive response at baseline with all post first dose ADA responses less than 4-fold 
of baseline titer levels. 
- 
Treatment-emergent response, defined as an ADA positive response in the dupilumab 
ADA assay post first dose when baseline results are negative or missing. The 
treatment-emergent responses may be further characterized as Persistent, 
Indeterminate or Transient.   
- 
Persistent Response – Treatment-emergent ADA positive response with two or more 
consecutive ADA positive sampling time points, separated by at least 12-week period 
(based on nominal sampling time), with no ADA negative samples in between, 
regardless of any missing samples. 
- 
Indeterminate Response –Treatment-emergent ADA positive response with only the 
last collected sample positive in the ADA assay, regardless of any missing samples. 
- 
Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
- 
Treatment-boosted response, defined as a positive response in the dupilumab ADA 
assay post first dose that is greater than or equal to 4-fold over baseline titer levels, 
when baseline results are positive. 
Maximum Titer categories (Maximum titer values) are provided below. 
Low (titer <1,000) 
Moderate (1,000 ≤ titer ≤ 10,000) 
High (titer >10,000) 
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4.8. 
 Biomarkers Variables  
Biomarkers to be analyzed in this study are:  
• TARC  
•  Total serum IgE  
• Immunoglobulin profiling 
• Antigen-specific IgE 
• Lactate dehydrogenase (LDH) [which will be measured as part of the blood chemistry] 
Serum samples for measurements of biomarkers to study the PD activity of dupilumab in 
pediatric AD patients will be collected at time points according to Appendix 3.  
5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, first quartile (Q1), third quartile 
(Q3), minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
All data will be summarized by 2 treatment groups (i.e., dupilumab 200/300 mg Q4W and 
placebo).  
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group for the FAS.  
5.2. 
Medical and AD History 
Medical history will be summarized by primary SOC and PT for each treatment group. The table 
will be sorted by decreasing frequency of SOC, followed by PT, based on the overall incidence 
across treatment groups. Medical history will be listed, sorted by treatment groups. 
Information on conditions related to AD will be summarized and includes diagnosis of AD and 
AD treatment history, asthma, allergic conjunctivitis, allergic rhinitis, chronic rhinosinusitis, nasal 
polyps, eosinophilic esophagitis, food allergy hives and other allergies due to medications, 
animals, plants, mold, dust mites, etc.. 
All analyses will be based on the SAF population. 
5.3. 
Prior/Concomitant Medications/Procedures 
The number and proportion of patients taking prior/concomitant medications, prohibited 
medications and rescue medications will be summarized, sorted by decreasing frequency of ATC 
Level 2 and ATC level 4, based on the overall incidence for the combined dupilumab treatment 
group. Patients will be counted only once for each medication class (ATC level 2 and 4) linked to 
the medication. 
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The number and proportion of patients taking prior/concomitant procedures, prohibited procedures 
and rescue procedures will be summarized, sorted by decreasing frequency of SOC and PT based 
on the overall incidence for the dupilumab treatment group. Patients will be counted only once for 
each SOC and PT linked to the procedure.  
The number and proportion of patients taking adjudicated rescue treatment (concomitant topical 
treatments (medium to high potency TCS/TCI), systemic immunosuppressants) and/or other 
treatments (emollients/ antihistamines) will also be summarized separately. 
The compliance with protocol requirements for application of moisturizers (emollients) used from 
7 days before the baseline visit to end of study, which is defined as the (number of days 
moisturizers used during the period) / (number of days within the period) x 100%, will be 
summarized by treatment group 
In addition, the summary of prior/concomitant medications/procedures may be provided for 
subjects who were impacted by the COVID-19 pandemic and not impacted by COVID-19 
pandemic in each study period. The summary will be performed for pre-, during, and post-COVID-
19 periods for subjects impacted by COVID-19, if deemed appropriate. The COVID-19 periods 
are consisting of ‘Pre COVID-19 period’, ‘Post COVID-19 period’ and ‘During COVID-19 
period’ using start date and end date of being affected by COVID-19 for each patient who are 
affected by COVID-19.  
Kaplan Meier curves for time to first rescue use will be generated. 
5.4. 
Subject Disposition 
The following summaries will be provided for each treatment group and study total (unless 
otherwise specified): 
• The total number of screened patients who signed ICF, along with reasons for screen failure 
(for study total only) 
• The total number of randomized patients (patients who received a randomization number) 
• The total number of patients in each analysis set 
• The total number of patients who completed the study and discontinued the study with the 
reason of discontinuation (including COVID-19 related reasons) 
• The total number of patients who completed the study treatment and discontinued the study 
treatment with the reason of discontinuation (including COVID-19 related reasons) 
• The total number of patients who continued on to the pediatric open label extension study 
• The total number of patients who entered into the follow-up period and their study 
completion status, with reason of discontinuation (including COVID-19 related reasons), if 
applicable 
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5.5. 
Extent of Study Treatment Exposure and Compliance 
5.5.1. 
 Measurement of Compliance  
The compliance with protocol-defined study drug administration will be calculated as follows: 
Treatment Compliance= (Number of study drug injections during exposure period) / (Number of 
planned study drug injections during exposure period) x 100% 
The summary of study drug administration will include the number of study drug doses 
administered and treatment compliance. The treatment compliance will be presented by the 
following specific ranges for each treatment group: <80%, and ≥80%. 
5.5.2. 
Exposure to Study Drug and Observation Period 
The duration of treatment (Q4W dosing) exposure during the study in day is calculated as: 
(Date of last study drug injection – date of first study drug injection) + 28 days 
The calculations do not take into account temporary dosing interruption including due to COVID-
19. The summary of exposure to study drug will include the number of study drug doses 
administered and the duration of exposure. Duration of exposure will be summarized for each 
treatment group using the number of patients, mean, SD, minimum, median, Q1, Q3, and 
maximum. 
In addition, the duration of exposure will be summarized categorically by counts and percentages 
for each of the following categories cumulatively by these categories: ≥ 28 days, ≥ 56 days, ≥ 84 
days, and ≥ 112 days with an increment of 4 weeks for each subsequent category. 
The duration of observation period during the study in days is calculated as: 
(Date of the last visit – date of the first study drug injection) +1. 
The duration of observation period will be summarized descriptively using number of 
patients, mean, SD, median, Q1, Q3, minimum and maximum. In addition, the number (%) of 
subjects with observation periods will be presented by specific time periods. The time periods of 
interest are specified as: 
< 8 days, ≥ 8 days, ≥ 15 days, ≥ 22 days, ≥ 29 days, ≥ 57 days, ≥ 85 days,  ≥113 days, ≥141 days, 
≥169 days, and ≥197 days. 
5.6. 
Analyses of Efficacy Variables  
The analyses of efficacy variables are described in the subsections below and summarized in 
Appendix 2. The intercurrent events, strategies, and the corresponding missing data handling 
approaches for the estimands of interest for the co-primary endpoints (only in European Union 
[EU] and EU Reference Market Countries) and key secondary endpoints are provided below. 
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                                                       Estimands 
Endpoint 
Category 
Endpoints 
Population Intercurrent event(s) 
handling strategy and 
missing data handling 
Population-level 
summary/Analysis 
Method 
Co-primary 
(Proportion)  
• Proportion 
of patients 
with IGA 0 
or 1 (on a 
5-point 
scale) 
at 
week 16 
• Proportion 
of patients 
with EASI-
75 at week 
16 
 
FAS 
The intercurrent events 
will 
be 
handled 
as 
follows: 
• Discontinuation 
of 
study 
intervention: 
Data collected after 
the 
patient 
discontinued 
treatment 
will 
be 
included 
in 
the 
analyses 
(treatment 
policy strategy). 
• Initiation of rescue 
treatment: 
Patients 
will be considered as 
non-responders after 
such 
events 
(composite strategy). 
 
Missing data imputation 
rules: 
• Missing data due to 
withdrawn 
consent,  
AE, LOE will be 
imputed 
as 
non-
responder. 
• Missing data due to 
any 
other 
reason 
including COVID-19 
will be imputed using 
multiple 
imputation 
(MI) 
Proportion 
of 
response/ 
CMH test adjusted 
by 
randomization 
strata  
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                                                       Estimands 
Endpoint 
Category 
Endpoints 
Population Intercurrent event(s) 
handling strategy and 
missing data handling 
Population-level 
summary/Analysis 
Method 
Key 
Secondary 
(Continuous) 
• Percent 
change 
in 
EASI score 
from 
baseline to 
week 16 
• Percent 
change 
from 
baseline to 
week 16 in 
weekly 
average of 
daily worst 
scratch/itch 
NRS score 
 
FAS 
The intercurrent events 
will 
be 
handled 
as 
follows: 
• Discontinuation 
of 
study 
intervention: 
Data collected after 
the 
patient 
discontinued 
treatment 
will 
be 
included 
in 
the 
analyses 
(treatment 
policy strategy). 
• Initiation of rescue 
treatment: data after 
rescue treatment will 
be 
assigned 
by 
postbaseline 
worst- 
observation- carried- 
forward 
(WOCF) 
(hypothetical 
strategy). If there is no 
post-baseline 
assessment, 
the 
baseline value will be 
used 
(hypothetical 
strategy). 
Missing data imputation 
rules: 
• Missing data due to 
withdrawn consent, 
AE, or lack of 
efficacy will be 
imputed by 
postbaseline WOCF. 
If there is no post-
baseline assessment, 
Mean Change from 
baseline/ 
ANCOVA 
model 
with treatment and 
randomization 
strata  as covariates 
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                                                       Estimands 
Endpoint 
Category 
Endpoints 
Population Intercurrent event(s) 
handling strategy and 
missing data handling 
Population-level 
summary/Analysis 
Method 
the baseline value 
will be used. 
• Missing values due to 
other 
reasons 
including COVID-19 
will be imputed by MI 
approach 
5.6.1. 
Analysis of Primary/Co-Primary Efficacy Variable  
The Cochran-Mantel-Haenszel (CMH) test adjusted by randomization strata (baseline weight 
group: ≥5-<15 kg and ≥15-<30 kg), baseline disease severity (IGA=3 and 4), and region/country 
(North America, Europe)) will be used for the analysis of percentage of patients with IGA 0 or 1 
at week 16. Similar procedures will be used for percentage of patients with EASI-75 at week 16. 
At the time of this SAP, all patients for this study have been randomized. The smallest stratum 
(region = EU, baseline weight<15 kg, IGA=3) has 2 subjects only. All other strata have more than 
10 patients. In all statistical analysis utilizing stratification factors in CMH test, stratum (region = 
EU, baseline weight<15 kg, IGA=3) will be combined with the stratum (region = EU, baseline 
weight >= 15 kg, IGA=3). 
Handling of dropouts or adjudicated rescue treatment or missing value for the binary response 
variables as the primary analysis: 
• If a patient withdraws consent from the study or discontinues due to AE or lack of efficacy 
(LOE), this patient will be counted as a non-responder for the time points after withdrawal. 
• To account for the impact of rescue treatment on the efficacy effect: if rescue treatment is 
used (see Section 4.3, Appendix 1,  and Appendix 6 for rescue treatment), the patient will be 
specified as a non-responder from the time the rescue treatment is used. 
• If the patient has the missing value at week 16 due to any other reasons including COVID-
19, the data will be imputed using multiple imputation (MI) based on all observed values as 
described below:  
• The underlying continuous (e.g. EASI) or categorical variable (e.g. IGA) will be imputed 40 
times to generate 40 complete data sets by using the SAS procedure MI using the following 
steps. 
− Step 1: The monotone missing pattern is induced by Markov Chain Monte Carlo 
(MCMC) method in MI procedure using seed number 12345. The monotone missing 
pattern means that if a patient has missing value for a variable at a visit, then the values at 
all subsequent visits for the same variable are all missing for the patient. 
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− Step 2: The missing data at subsequent visits will be imputed using the regression 
method for the monotone pattern with seed number 54321 and adjustment for covariates 
including treatment groups, randomization strata (baseline weight group, baseline IGA 
and region), and relevant baseline variables. For the categorical variable, such as IGA, a 
logistic regression under monotone option will be used. 
Based on each imputed data, the response status (responder or non-responder) will be determined 
for each subject. 
Once imputations are made, the week 16 data (binary response) of each of the 40 complete datasets 
will be analyzed using CMH test. The SAS MIANALYZE procedure will be used to generate valid 
statistical inferences by combining results from the 40 analyses using Rubin’s formula. An 
appropriate transformation (such as Wilson-Hilferty transformation) of CMH test statistics can be 
used in Rubin’s formula (Ratitch et. al 2013). 
Sensitivity analyses: 
Sensitivity analysis on primary and co-primary efficacy endpoints will be performed using the 
Tipping-point analysis method.  
To assess the robustness of primary analysis results, a delta-adjusting pattern-mixture approach 
for tipping point analysis (2013, Ratitch) under MNAR (missing not at random) assumption, will 
be conducted for the co-primary endpoints. The impact from missing data on the comparisons in 
proportion of patients achieving IGA 0/1 (co-primary endpoint: EASI-75, only in European 
Union [EU] and EU Reference Market Countries) at week 16 between dupilumab and placebo 
control group will be examined as follows. 
− A sequence of analyses will be performed with the adjustment to artificially decrease the 
response rate in dupilumab group and increase the response rate in placebo group with a 
fixed and definite set of values for data imputation. 
− For each combination of increasing response rate in placebo and decreasing response rate 
in dupilumab, multiple imputed datasets will be generated and analyzed using CMH test. 
The results obtained from multiple imputed datasets will be combined to generate 
statistical inference, i.e. p-value and treatment difference between 2 treatment groups. 
− A “tipping point” will be identified while the result is no longer statistically significant 
(i.e. p-value >0.05). 
5.6.2. 
Analyses of Secondary Efficacy Variables 
All secondary endpoints will be evaluated based on the FAS population. 
The binary secondary efficacy endpoints will be analyzed using the same approaches used for the 
analysis of the primary endpoints as described in Section 5.6.1.  
The continuous endpoints (e.g. EASI, worst scratch/itch NRS score) will be analyzed using 
analysis of covariance (ANCOVA) model with treatment, randomization strata (baseline weight 
group: ≥5-<15 kg and ≥15-<30 kg), baseline disease severity (IGA=3 and 4), region/country 
(North America, Europe)) and relevant baseline value included in the model as the primary 
analysis method. The missing data for continuous endpoints will be imputed by the pattern-mixture 
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approach (MI-WOCF Method).  The WOCF approach will be used for data after rescue or missing 
due to withdrawn consent, AE, and lack of efficacy. To be specific, the missing data will be 
imputed by postbaseline worst-observation-carried-forward (WOCF) if there is at least one non-
missing postbaseline value or by baseline value if there is no postbaseline value. The multiple 
imputation (MI) approach will be used for the missing due to other reasons, including reasons due 
to COVID-19. The MI will be performed based on all observed data before the imputation by 
WOCF approach. To account for the uncertainty in the imputation, missing data from the FAS will 
be imputed 40 times to generate 40 complete data sets by using the SAS procedure MI following 
the 2 steps below: 
Step 1: The monotone missing pattern is induced by Markov Chain Monte Carlo (MCMC) method 
in MI procedure using seed number 12345. The monotone missing pattern means that if a patient 
has missing value for a variable at a visit, then the values at all subsequent visits for the same 
variable are all missing for the patient. 
Step 2: The missing data at subsequent visits will be imputed using the regression method for the 
monotone pattern with seed number 54321 and adjustment for covariates including treatment 
groups, randomization strata (baseline weight group, baseline IGA and region), and relevant 
baseline. 
Once imputations are made, the week 16 data of each of the 40 complete datasets will be analyzed 
using ANCOVA model with treatment, randomization strata (baseline weight group, baseline IGA 
and region), and relevant baseline included in the model, and the SAS MIANALYZE procedure 
will be used to generate valid statistical inferences by combining results from the 40 analyses using 
Rubin’s formula. 
The imputation model will include: 
• The covariates included in the ANCOVA model, including the treatment group, the baseline 
value and the randomization strata (baseline weight group, baseline IGA and region) 
• Measured endpoint values at every clinic visit (e.g. week 1, 2, 4, 8, 12 and week 16 for 
EASI) 
Mean weekly dose of low potency TCS 
The mean weekly dose of low potency TCS use during the treatment period endpoints will be 
analyzed using an ANCOVA model with treatment, randomization strata (baseline weight group, 
disease severity and region) and relevant baseline variables included in the model. 
Similar analysis will be carried out for medium and/or high potency TCS. 
Descriptive statistics will be provided for the mean of caregiver missed workdays (CMW) from 
baseline to week 16 for each treatment group. 
Onset of action analysis, 
Onset of action in percent change from baseline weekly average of daily worst scratch/itch NRS 
score can be assessed by providing a nominal p-value at each assessment visits. The analysis will 
be carried out on the FAS population only. Using this analysis, the first assessment visit at which 
p <0.05 for the difference from placebo in the weekly average of daily worst scratch/itch NRS 
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score that remains p < 0.05 at subsequent weekly measurements through week 16 can be identified. 
The similar analysis will be carried out on the following binary responses:  
- 
IGA 0/1  
- 
EASI-75 
- 
Improvement (reduction) of weekly average of daily worst itch NRS score ≥3 from 
baseline 
- 
Improvement (reduction) of weekly average of daily worst itch NRS score ≥3 from 
baseline. 
5.6.3. 
Adjustment for Multiple Comparison  
Multiplicity Considerations 
The following multiplicity adjustment approach, a hierarchical procedure, will be used to control 
the overall Type-1 error rate at 0.05 for the primary endpoint and the secondary endpoints of 
dupilumab versus placebo. Each hypothesis will be formally tested only if the preceding one is 
significant at the 2-sided 0.05 significance level. The hierarchical testing order is shown in below 
table (all comparisons are with the placebo).  
 
 
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Level 
Endpoints 
Testing 
Order  
Primary endpoint 
Proportion of patients with IGA 0 to 1 (on a 5-point 
scale) at week 16 
1 
Co-primary endpoint for EMA 
and EMA Reference Market 
Countries only, key secondary for 
US 
Proportion of patients with EASI-75 (>=75% 
improvement from baseline) at week 16 
2 
Secondary endpoints 
Percent change in EASI score from baseline to week 16 
3 
Percent change from baseline to week 16 in weekly 
average of daily worst scratch/itch score 
4 
Proportion of patients with improvement (reduction) of 
weekly average of daily worst itch score ≥4 from 
baseline 
5 
Proportion of patients with improvement (reduction) of 
weekly average of daily worst itch score ≥3 from 
baseline 
6 
Proportion of patients with EASI-50 at week 16 
7 
Proportion of patients with EASI-90 at week 16 
8 
Change from baseline in percent BSA affected by AD 
9 
Change from baseline to week 16 in POEM 
10 
Percent change from baseline to week 16 in SCORAD 
11 
Change from baseline in Patient’s sleep quality NRS 
12 
Change from baseline in Patient’s skin pain NRS 
13 
Change from baseline in DFI 
14 
Change from baseline to week 16 in CDLQI 
15 
Change from baseline to week 16 in IDQOL 
16 
5.6.4. 
Subgroup Analysis 
Subgroups for the primary endpoint (or co-primary endpoints for EU and EU reference countries) 
and key secondary endpoints will be analyzed based on the FAS. 
Primary endpoints (or co-primary endpoints for EU and EU reference countries) and secondary 
endpoints those are in the  hierarchical procedure (Section 5.6.3)  will be analyzed in a similar 
fashion as in the main analysis for the severe AD subgroup (IGA = 4). Nominal p-values will be 
provided.  
The analysis method for the subgroups will be the same as the primary analysis described in 
Section 5.6.1, and Section 5.6.2,  as appropriate. If for any reason such as due to small number of 
patients in a subgroup, the model-based inferential statistics cannot be computed, or deemed 
inappropriate, only descriptive statistics will be provided.  
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Forest plots of the co-primary and key secondary efficacy endpoints across subgroups will be 
provided.   
5.6.5. 
Analyses of Other Efficacy Variables 
The analyses of other efficacy variables (binary and continuous endpoints) will be conducted in a 
similar fashion as the primary analysis described in  Sections 5.6.1 and 5.6.2. unless otherwise 
noted in the individual descriptions of other efficacy variables or deemed inappropriate.  
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed based on the SAF.  
The safety analysis will be based on the reported AEs, clinical laboratory evaluations, physical 
examination, vital signs and 12-lead ECG. 
Thresholds for treatment-emergent Potentially Clinically Significant Values (PCSVs) in 
laboratory variables and vital signs are defined in Appendix 5. A treatment-emergent PCSV is any 
PCSV which developed or worsened in severity compared to baseline during the treatment and/or 
follow-up period.  The time interval to detect any event or abnormality is between the first injection 
of study medication and EOS. 
In addition, the summary of safety results (including TEAEs, clinical laboratory, vital signs and 
ECG) will be performed for subjects who were impacted by COVID-19 pandemic and not 
impacted by COVID-19 pandemic in each study part, respectively if deemed appropriate. The 
summary will be performed for pre-, during, and post-COVID-19 periods for patients impacted by 
COVID-19, if deemed appropriate.  
5.7.1. 
Adverse Events 
The number and proportion of patients reporting TEAEs will be summarized overall during the 
study, during the week 16 treatment period, and during the follow-up period separately, sorted by 
decreasing frequency of SOC and PT in the dupilumab group. 
AE incidence tables will be presented by treatment group for the SAF as well as for selected 
subgroups. TEAE summaries will present the number (n) and percentage (%) of subjects 
experiencing a TEAE by SOC and PT, sorted by decreasing frequency of SOC and PT for the 
dupilumab treatment group. Multiple occurrences of AEs of the same PT (or SOC) in the same 
subject will be counted only once for that PT (or SOC). For tables presenting severity of events, 
the worst severity will be chosen for subjects with multiple instances of the same event. The 
denominator for computation of percentage is the number of patients in each treatment group for 
the corresponding analysis period as specified in Section 3.2. 
An overall summary of TEAEs will be provided with number and proportions of patients with 
any: 
•  TEAE 
• Serious TEAE 
• TEAE of special interest (AESI) 
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• TEAE leading to death 
• TEAE leading to permanent treatment discontinuation 
Detailed summaries of TEAEs will include: 
• TEAEs 
− TEAEs by SOC/PT 
− TEAEs (for HLTs: Injection site reactions, Herpes viral infections) by SOC/HLT/PT  
− TEAEs by PT 
− Common TEAEs by SOC/PT (incidence with PT ≥5%) 
− TEAEs by severity by SOC/PT 
− Severe TEAEs by SOC/PT 
− TEAEs related to study medication as assessed by the investigator by SOC/PT 
− Severe TEAEs related to study medication as assessed by the investigator by SOC/PT  
• Serious TEAEs by SOC/PT 
− Serious TEAEs by SOC/PT 
− Serious TEAEs by SOC/PT 
− Serious TEAEs related to study medication as assessed by the investigator by SOC/PT  
• TEAEs leading to permanent discontinuation of study treatment by SOC/PT 
• Fatal TEAE by SOC/PT 
• AESI by AESI category (Appendix 4) and HLT/PT 
The time to first AESIs (TEAE category) will be assessed by Kaplan-Meier estimates (K-M plot). 
In order to detect any safety signals, the hazard ratio (HR) will be provided together with the 
corresponding 95% confidence interval (CI) for the selected adverse events during the treatment 
period only. Hazard ratios will be calculated using a Cox model including treatment group and 
randomization strata as factors. The time is defined as the date of first specific event – the date of 
first dose + 1. Patients without a specific event will be censored at the end of the treatment period. 
Graphs of cumulative incidence rate over time may be provided by treatment group for selected 
TEAEs leading to permanent discontinuation of study treatment. 
5.7.2. 
Analysis of Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to standard international units and US conventional units. Summaries of laboratory 
variables will include: 
• Descriptive statistics of laboratory result and change from baseline by visit 
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• The number (n) and percentage (%) of subjects with treatment emergent PCSVs. This summary 
will be provided based on all patients in the SAF as well as in the subgroup of SAF patients 
who did not meet the PCSV criterion at baseline. 
• Shift tables based on baseline normal/abnormal and other tabular and graphical methods may 
be used to present the results for parameters of interest  
5.7.3. 
Analysis of Vital Signs 
Summaries of vital sign variables will include: 
• Descriptive statistics of vital sign variable and change from baseline by visit 
• The number (n) and percentage (%) of patients with treatment-emergent PCSV  
• Shift tables based on baseline normal/abnormal and other tabular and graphical methods may 
be used to present the results for parameters of interest 
5.7.4. 
Analysis of 12-Lead ECG 
Summaries of 12-lead ECG parameters by treatment group will include: 
• Each ECG parameter and change from baseline 
• The number (n) and percentage (%) of subjects with PCSV, depending on data 
• ECG status (i.e. normal, abnormal) summarized by a shift table 
5.7.5. 
Analysis of Physical Exams 
The number (n) and percentage (%) of patients with abnormal physical exams will be 
summarized at baseline, end of treatment period and end of study by treatment group. Shift table 
for physical exams status will be provided. A summary of treatment-emergent abnormal findings 
will be provided, as appropriate. 
5.8. 
Analysis of Pharmacokinetic Data 
The following analyses will be conducted: 
• Descriptive statistics of functional dupilumab concentrations in serum at each sampling time 
by dose 
• Graphical presentations of median and mean (+/- SD) functional dupilumab concentration in 
serum vs nominal time profiles 
• Graphical presentations of individual functional dupilumab concentration in serum vs actual 
sampling time profiles  
• Assessment of the impact of anti-drug antibodies on functional dupilumab concentrations in 
serum. 
No formal statistical analysis will be performed. 
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5.9. 
Analysis of Immunogenicity Data 
5.9.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.7 will be summarized using descriptive 
statistics in the ADA analysis set.  
Immunogenicity will be characterized by ADA responses and titers observed in patients in the 
ADA analysis set.  
The following will be summarized by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative subjects  
- 
Number (n) and percent (%) of pre-existing immunoreactivity subjects 
• Number (n) and percent (%) of treatment-emergent ADA-positive patients 
- 
Number (n) and percent (%) of persistent treatment-emergent ADA positive patients 
- 
Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
- 
Number (n) and percent (%) of transient treatment-emergent ADA positive patients 
• Number (n) and percent (%) of treatment-boosted ADA-positive patients 
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
5.9.2. 
Analysis of Neutralizing Antibodies (NAb) 
Samples positive in the ADA assay will be further characterized for the presence of neutralizing 
antibodies (NAb) for dupilumab. The absolute occurrence (n) and percent of patients (%) with 
NAb status (positive or negative) will be provided for patients in the NAb analysis set.  
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.10.1. 
Association of immunogenicity with exposure 
Potential association between immunogenicity variables and systemic exposure to dupilumab 
will be explored by treatment groups. Plots of dupilumab concentration may be provided for 
analyzing the potential impact of treatment-emergent, persistent ADA response and titer (high, 
moderate or low) and NAb on PK profiles. 
5.10.2. 
Immunogenicity and Safety/ Efficacy 
Potential association between immunogenicity variables and safety events will focus on the 
following events: 
• Injection site reaction (serious or severe and lasting 24 hours or longer) 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
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•  Anaphylactic Reaction (SMQ: Anaphylactic Reaction [Narrow]) 
Potential association between immunogenicity variables and the co-primary efficacy endpoints 
may be explored (e.g. scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following ADA 
response categories: 
• ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response 
• ADA negative patients, that is patients with pre-existing immunoreactivity or negative in 
the ADA assay at all time points 
• Patients with persistent ADA response 
• NAb positive patients, that is patients who were positive in the NAb assay at any time 
point analyzed. 
• Maximum post-baseline titer level in treatment-emergent or treatment-boosted ADA 
positive patients: 
 
Low (titer <1,000), Moderate (1,000 ≤ titer ≤ 10,000), and High (titer >10,000) 
5.11. 
Analysis of Biomarker Data 
Descriptive statistics for the observed values, change from baseline and percent change from 
baseline values by treatment and visit will be provided for the following biomarker variables: 
• TARC  
• total serum IgE  
• Serum Immunoglobulin profile (IgG/IgM/IgA) 
• Lactate dehydrogenase (LDH)  
The Wilcoxon signed-rank test will be used to test if the change or percentage change from baseline 
value is significantly different from zero. P-value will be reported. 
Exploratory analyses for the difference between dupilumab groups and placebo of the change from 
baseline and percent change from baseline values will be performed using a rank-based ANCOVA 
model with treatment group as a fixed effect, and the relevant baseline values as covariate. Missing 
values will be imputed by LOCF method for visits between post-baseline and week 16. After week 
16, no imputation will be made. P-value for difference from placebo will be provided. 
Relationship of baseline TARC and baseline IgE with the following clinical endpoints will be 
explored using ANCOVA model. The model includes the below clinical endpoint as the dependent 
variable and the log10 based transformed baseline biomarker data, treatment group and their 
interaction as the predictor variables. Model coefficients and P-value will be provided. 
• Percent change from baseline to week 16 in EASI score 
• Percent change from baseline to week 16 in weekly average of daily worst scratch/itch NRS 
score  
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• Change from baseline to week 16 in percent BSA affected by AD 
• Percent change from baseline to week 16 in SCORAD 
Relationship of baseline TARC and baseline IgE with the following clinical endpoints will be 
explored using the logistic model. The model includes the responder/non-responder of the below 
clinical endpoints as the dependent variable and the log10 based transformed baseline biomarker 
data, treatment group and their interaction as the predictor variables. Model coefficients and P-
value will be provided to indicate significance of the correlation/association. 
• IGA 0-1 at week 16 
• EASI-75 at week 16 
• Improvement (reduction) of weekly average of worst scratch/itch scale ≥4 from baseline to 
week 16 
Association of positivity to at least one antigen-specific IgE with the following clinical endpoints 
may be explored using CMH test stratified by randomization strata. The risk ratio and P-value will 
be provided. 
− IGA 0-1 at week 16 
− EASI-75 at week 16 
− improvement (reduction) of weekly average of worst scratch/itch scale ≥4 from baseline 
to week 16 
All above analyses will be performed on the FAS for  
− All observed data, regardless if rescue treatment is used or data is collected after study 
drug withdrawal 
− All observed data with censoring after rescue treatment use  
The proportion of patients for whom biomarker concentrations “normalize” (shift from above 
normal to within the normal range) at Week 16 will also be evaluated.  
The additional analysis will be performed on the following biomarkers at week 16: 
− Serum total IgE  
− Serum LDH   
Serum total IgE and LDH have established clinical assays; the upper limit of normal (ULN) from 
the central lab reference range will determine the threshold for normal vs. elevated status.  
Summary tables with normal/elevated status for serum total IgE and LDH at baseline and each 
post-baseline visit (until end-of-study) will be provided by treatment group.  
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment of the study for all measurements will be the 
latest available valid measurement taken prior to the first administration of study drug. If any 
randomized patients are not treated, the baseline will be the last value on or prior to the 
randomization. The baseline of worst scratch/itch scale is defined in Section 4.4.2. 
The following rules specify the determination of baseline by both date/time information: 
1. For the AE, lab, PK and ADA data, both date and time of the measurement will be used to 
determine baseline by comparing with the first injection date and time. 
2. For other data except AE, lab, PK or ADA, only date of the measurement will be used to 
determine baseline by comparing with the first injection date. 
For the rescreened patients, all data from the same patient will be used to derive baseline 
regardless if the data is from the screen- failure subject ID or enrolled subject ID. 
6.2. 
General Data Handling Conventions 
For the laboratory safety variables data, if the data fall below the lower limit of quantification 
(LLOQ) / limit of linearity, half of the lower limit value (i.e., LLOQ/2) will be used for quantitative 
analyses. For data above the upper limit of quantification (ULOQ) / limit of linearity, the upper 
limit value (i.e., ULOQ) will be used for quantitative analyses. 
6.3. 
Data Handling Convention Missing Data 
Missing data will not be imputed in the listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAE. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
Adverse event start date  
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed, and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use the AE end 
date instead. Otherwise impute the AE start day using the first day of the month. If this leads to a 
date before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
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If AE start month is missing, and AE start year is not missing: If AE start year is less than the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month. If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE starting date imputation, in order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use end of follow 
up date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 
31 December as the day and month. If this leads to a date after end of study follow up date, use 
the end of follow up date instead. 
If AE end year is missing: Impute AE end date using the end of follow up date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment medication or concomitant medication or 
both, the missing medication start date is estimated as early as possible, and the missing medication 
end date is estimated as late as possible. If the medication start date is missing, the onset day will 
not be calculated in medication listings. 
Prior medication start date  
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’; 
If start month is missing, and start year is not missing: Impute the day and month using 01 January. 
Imputation flag is ‘M’. 
If start year is missing: Impute start date using 2 years before inform consent date. Imputation flag 
is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, in 
order to simplify the programming flow, the imputation is proposed in line with the protocol which 
specifies to collect up to 2 years of prior medication. Since the start date of prior medication will 
not be used in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
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If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date -
1 instead. Imputation flag is ‘M’ 
If end year is missing: Impute end date using the first dose intake date –1. Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use end of follow up date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the end of follow up 
date instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of follow up date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study DM and study MD. 
PCSV 
Patients who had a post-baseline PCSV but a missing baseline value will be regarded as having a 
treatment emergent PCSV. 
6.4. 
Analysis Visit Window 
Data analyzed by-visit-analysis (including efficacy, laboratory data, visit sign, ECG, ADA) will 
be summarized by the study scheduled visits described in the study protocol and SAP “Schedule 
of Events”. The analysis visit windows will be exhaustive so that all available values obtained 
from unscheduled visits, early termination (ET) visit have the potential to be summarized. No 
analysis visit windows will be applied for the study scheduled visits.  
The analysis visit windows are created per study Schedule of Events (SOE) table for each 
parameter and will be applied if the data from study scheduled visits are unavailable. The following 
general rules will be applied to unscheduled visit and/or early termination (ET) visit mapping for 
each parameter.  
1. If ET visit falls in an analysis window which already has no missing observed value of 
this parameter from the scheduled visit, ET will be mapped to the next scheduled visit.  
2. If both ET visit and unscheduled visit of the same parameter are available in the same 
analysis visit window, only ET visit will be mapped.  
3. If multiple unscheduled visits of the same parameter are available in the same analysis 
visit window, the unscheduled visits will be mapped using the following rules: 
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a. The closest unscheduled visit from the target day will be selected. 
b. If multiple unscheduled visits exist on the same day, the first unscheduled visit will 
be used.  
4. If mapping distance is greater than 2 weeks, the unscheduled visit will not be mapped.  
Unscheduled visits and early termination (ET) visit will be mapped per the following analysis visit 
windows based on the visit schedule of each parameter as per Appendix 3.  
Table 1A. Analysis Visit Window for Efficacy Endpoints IGA, EASI, SCORAD, 
BSA, GISS 
Visit from SOE 
Target Day 
Analysis Visit Window Based on Study day* 
Screening 
<1 
<1 
Baseline 
1 
1 
Week 1 
8 
[2,11]  
Week 2 
15 
 [12, 22] 
Week 4 
29 
 [23, 43] 
Week 8 
57 
[44, 71] 
Week 12 
85 
[72, 99] 
Week 16 
113 
[100, 127] 
Week 20 
141 
[128, 155] 
Week 24 
169 
[156, 183] 
Week 28 
197 
>=184 
* Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date +1) 
when date of assessment ≥ 1st injection date; otherwise study day = (date of assessment – 1st injection date). If 
patient never received any dose of study drug, randomization date will be used in place of 1st injection date. 
Table 2: Analysis Visit Window for Efficacy Endpoints CDLQI, IDQOL, DFI, 
POEM, CMW, CGID, CGIC 
Visit from SOE 
Target Day 
Analysis Visit Window Based on Study day* 
Screening 
<1 
<1 
Baseline 
1 
1** 
Week 2 
15 
 [2, 22] 
Week 4 
29 
 [23, 43] 
Week 8 
57 
[44, 71] 
Week 12 
85 
[72, 99] 
Week 16 
113 
[100, 127] 
Week 20 
141 
[128, 155] 
Week 24 
169 
[156, 183] 
Week 28 
197 
>=184 
* Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date +1) 
when date of assessment ≥ 1st injection date; otherwise study day = (date of assessment – 1st injection date). If 
patient never received any dose of study drug, randomization date will be used in place of 1st injection date. 
**Not applicable for CGIC. 
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Table 3: Analysis Visit Window for PASQ  
Visit from SOE 
Target Day 
Analysis Visit Window Based on Study day* 
Screening 
<1 
<1 
Baseline 
1 
1** 
Week 4 
29 
 [2, 71] 
Week 16 
113 
[72 155] 
Week 28 
197 
>=156 
* Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date +1) 
when date of assessment ≥ 1st injection date; otherwise study day = (date of assessment – 1st injection date). If 
patient never received any dose of study drug, randomization date will be used in place of 1st injection date. 
Table 4: Analysis Visit Window for Safety labs, Vitals, PK and Biomarkers  
Visit from SOE 
Target 
Study 
Day 
in Part B a 
Vital signs 
Physical 
examination
, ECG, 
Height, 
Weight 
Lab* 
PK, ADA 
TARC#,  
Serum 
Immunoglobulin 
profiling, antigen-
specific IgE 
Baseline 
1 
≤1 
≤1 
≤1 
≤1 
≤1 
Week 1 
8 
[2, 11] 
 
 
 
 
Week 2 
15 
[12, 22] 
 
 
 
 
Week 4 
29 
[23, 43] 
 
[2, 71] 
[2, 43] 
[2, 71] # 
Week 8 
57 
[44, 71] 
 
 
[44, 71] 
 
Week 12 
85 
[72, 99] 
 
 
[72, 99] 
 
Week 16 
113 
[100, 127] 
[2, 155] 
[72, 155]  
[100, 127] 
[72, 155]# 
[2, 155] 
Week 20 
141 
[128, 155] 
 
 
[128, 169] 
 
Week 24  
169 
[156, 183]   
 
 
 
Week 28  
197 
 >= 184 
>= 156 
>=156 
>= 170 
>= 156 
*Hematology and Blood Chemistry only. 
#Only for TARC which was collected at baseline, Day 29, Day 113/EOT and Day 197/EOS. 
Note that both scheduled and unscheduled measurements will be considered for determining abnormal/PCSV values 
for laboratory, vital signs or ECGs as well as the baseline values.  
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Rules for visit windows of ePRO data collected daily using eDiary: 
For the daily collected ePRO data (e.g. Pruritus worst scratch/itch NRS, skin pain NRS, sleep 
quality NRS [patient and caregiver], CNSQ), the analysis visit windows will be implemented 
following the procedure below: 
Step 1: Derive the study day,  
• If diary date ≥ 1st injection date, then diary study day=diary date – 1st injection date +1;  
• Otherwise diary study day=diary date – 1st injection date 
Step 2: Windows are defined as diary study day -7 to -1 = BL, 1 to 7 = week 1, 8 to 14 = week 2, 
etc, with 7 days interval between visit windows. 
6.5. 
 Statistical Technical Issues 
None. 
7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
The primary analysis may be performed when the last patient completes 16 weeks of treatment 
duration in order to expedite the submission to regulatory agencies. No changes in the conduct of 
the study will be made based on this primary analysis. The assessment of co-primary and secondary 
endpoints performed during the analysis will be the final analysis of the co-primary endpoint and 
secondary endpoints. Hence, there will be no need for alpha adjustment due to the primary analysis. 
In order to maintain study integrity (with respect to the post-treatment follow-up visits, safety 
visits, and analyses) in the event a decision is made to perform the primary analysis, a 
dissemination plan will be written. This plan will clearly identify the team (including the 
statistician) that will perform the primary analysis and all related activities, restrict other clinical 
team members and other sponsor personnel from access to individual patient treatment allocation 
and site level analysis results, and ensure that the dedicated team will not participate in the data 
review or data decisions for the following post treatment analyses. However, the dedicated team 
can participate in the analysis following the final database lock.  
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
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9. 
REFERENCES 
Al-Naqeeb J, Danner S, Fagnan LJ, et al. The Burden of Childhood Atopic Dermatitis in the 
Primary Care Setting: A Report from the Meta-LARC Consortium. J Am Board Fam Med. 
2019;32(2):191-200. 
Czarnowicki T, Esaki H, Gonzalez J, Malajian D, Shemer A, Noda S, Talasila S, et al. Early 
pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell 
imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets.  J Allergy Clin Immunol. 2015. 
ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of clinical study 
reports (E3). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for clinical 
trials (E8). International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. 
Hanifin JM, Thurston M, et al. The eczema area and severity index (EASI): assessment of 
reliability in atopic dermatitis. Exp Dermatol. 2001; 10: 11-18. 
Ileli S, von Mutius E, et al.  The natural course of atopic dermatitis from birth to age 7 years and 
the association with asthma. America Academy of Allergy, Asthma and Immunology. 2004; 
doi:10.1016/j.jaci.2004.01.778. 
Lawson V, Lewis-Jones MS, Finlay AY, Reid P, Owens, RG.  The family impact of childhood 
atopic dermatitis: the dermatitis family impact questionnaire. Br J Dermatol. 1998;138:107-13. 
Lewis-Jones MS, Finlay AY. The Childrens’ Dermatology Life Quality Index (CDLQI): initial 
validation and practical use. Br J Dermatol. 1995 Jun;132(6):942-9. PubMed PMID: 7662573. 
Proudfoot LE, Powell AM, Ayis S, Barbarot S, Torres EB, Deleuran M, et al. The European 
treatment of severe atopic eczema in children taskforce (TREAT) survey.  Br J Dermatol. 
2013;169:901-09. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York, NY: John Wiley & Sons, 
Inc., 1987. 
Ratitch Bohdana, Lipkovich, IIya et. al. Combining Analysis Results from Multiply Imputed 
Categorical Data, PharmaSUG 2013 - Paper SP03 
Schmitt J, Schakel K, et al. Prednisolone vs. ciclosporin for severe adult eczema. An investigator 
initiated double-blind placebo-controlled multicentre trial. Brit J Dermatol. 2009; journal 
compilation:1-8. 
Severity scoring of Atopic Dermatitis: The SCORAD index. Consensus report of the European 
Task Force on Atopic Dermatitis. Dermatol. 1993;186:23-31. 
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Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 
2003;112(6):S118-27. 
Su JC, Kemp AS, Varigos GA, Nolan TM.  Atopic eczema: its impact on the family and financial 
cost.  Arch Dis Child. 1997;76(2):159-62. 
Lawson V, Lewis-Jones MS, Finlay AY, Reid P, Owens, RG. The family impact of childhood 
atopic dermatitis: the dermatitis family impact questionnaire. Br J Dermatol. 1998;138:107-13. 
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APPENDIX 1. PROHIBITED AND RESCUE MEDICATIONS 
Low potency steroids (permitted) 
Medium potency steroids (permitted as rescue, prohibited otherwise) 
Hydrocortisone acetate 1% cream / Hydrocortisone 1% cream (provided to 
sites by sponsor) 
Desonide 0.05% cream 
Alclometasone dipropionate 0.05% cream 
Triamcinolone acetonide 0.1% ointment (provided to sites by sponsor)  
Triamcinolone acetonide 0.1% cream 
Fluticasone propionate 0.05% cream  
Fluocinolone acetonide 0.025% ointment 
High Potency steroids (permitted as rescue, prohibited otherwise) 
Very high potency steroids (prohibited) 
Mometasone furoate 0.1% ointment  
Triamcinolone acetonide 0.5% ointment 
Clobetasol propionate 0.05% ointment 
Betamethasone dipropionate 0.05% ointment 
This is a representative list of TCS to be used in the study based on the American Academy of Dermatology classification. Starting on 
day -14, all patients will be required to initiate treatment with a low potency TCS using a standardized regimen.  Based on investigator 
discretion, low/mild potency TCS may also be used on areas of thin skin (face, neck, intertriginous, and genital areas, areas of skin 
atrophy, etc.).  Hydrocortisone acetate 1% cream / hydrocortisone 1% cream should be used unless there are known side effects to these 
agents or due to non-availability due to any reason.  In those cases, other low potency TCS such as desonide 0.05% cream or 
alclometasone dipropionate 0.05% cream can be used.  The use of medium/high potency steroids should be reserved for rescue.  It is 
recommended that triamcinolone acetonide 0.1% ointment be used for rescue.  However, other medium or high potency TCS may be 
used as per investigator discretion. The use of very high potency steroids is not allowed during the study. 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 62 of 104 
APPENDIX 2. LIST OF ANALYSIS 
Efficacy Analysis: 
Parameter(s) 
 
Analysis 
Populations 
Endpoints  
Primary Statistical Method 
Supportive/Sens
itivity Statistical 
Method 
Subgroup 
Analysis 
Investigator’s 
Global Assessment 
(IGA) 
(Primary) 
 
 
FAS 
 
• 
IGA 0 to 1 (Categorical) 
 
• CMH test adjusted by randomization 
strata (IGA Severity, Region, and 
Baseline weight) 
Tipping point 
analysis  
Yes 
Eczema Area and 
Severity Index 
(EASI) 
 
(EASI-75 Co-
primary, for EU 
only) 
 
FAS 
Categorical: 
• 
EASI 75 
• 
EASI 50 
• 
EASI 90 
 
Continuous: 
• 
% change from baseline 
•Categorical: CMH test adjusted by 
randomization strata for categorical 
variables 
• Continuous: Multiple imputation 
(MI) using pattern mixture ((MI-
WOCF) ) with ANCOVA for 
continuous variables  
Tipping point 
analysis  
 for co-primary 
endpoint only. 
Yes; For 
EASI-75 
and % 
Change 
from 
baseline 
Pruritus worst 
scratch/itch score 
(NRS) 
 
FAS 
 
Categorical: 
• 
NRS score ≥3 
• 
NRS score ≥4 
Continuous:  
• 
% change from baseline 
• 
Change from baseline 
•Categorical: CMH test adjusted by 
randomization strata for categorical 
variables 
• Continuous: Multiple imputation 
(MI) using pattern mixture (MI-
WOCF) with ANCOVA for 
continuous variables  
No 
Yes for % 
change  
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 63 of 104 
Parameter(s) 
 
Analysis 
Populations 
Endpoints  
Primary Statistical Method 
Supportive/Sens
itivity Statistical 
Method 
Subgroup 
Analysis 
Skin Pain NRS 
FAS 
 
• 
Change from baseline 
 
Multiple imputation (MI) using 
pattern mixture (MI-WOCF) with 
ANCOVA for continuous variables 
No  
No 
Sleep quality NRS 
FAS 
• 
Change from baseline [Patient, 
Caregiver] 
Multiple imputation (MI) using 
pattern mixture (MI-WOCF) with 
ANCOVA for continuous variables 
 
No 
No 
Body Surface Area 
(BSA) Involvement 
of Atopic 
Dermatitis 
FAS 
• 
Change from baseline 
Multiple imputation (MI) using 
pattern mixture (MI-WOCF)  with 
ANCOVA 
No 
No 
 
 
SCORing Atopic 
Dermatitis 
(SCORAD) 
 
 
FAS 
 
Continuous: 
• 
% change from baseline 
 
Categorical: 
• 
SCORAD50 
• 
SCORAD75 
• 
SCORAD90 
• Multiple imputation (MI) using 
pattern mixture (MI-WOCF) with 
ANCOVA for continuous variables 
• CMH test adjusted by randomization 
strata for categorical variables 
 
No 
No 
Dermatitis Family 
Index (DFI)  
FAS 
• 
Change from baseline 
Multiple imputation (MI) using 
pattern mixture (MI-WOCF) with 
ANCOVA 
No 
No 
Global Individual 
Signs Score (GISS) 
FAS 
• 
Change from baseline 
Multiple imputation (MI) using 
pattern mixture (MI-WOCF) with 
ANCOVA for continuous variables 
No 
No 
Patient Oriented 
Eczema Measure 
(POEM) 
 
FAS 
• 
Change from baseline 
 
• Multiple imputation (MI) using 
pattern mixture (MI-WOCF) with 
ANCOVA for continuous variables 
No 
No 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 64 of 104 
Parameter(s) 
 
Analysis 
Populations 
Endpoints  
Primary Statistical Method 
Supportive/Sens
itivity Statistical 
Method 
Subgroup 
Analysis 
Children 
Dermatology Life 
Quality Index 
(CDLQI) (>= 4 
years of age) 
FAS 
• 
Change from baseline 
• Multiple imputation (MI) using 
pattern mixture (MI-WOCF) with 
ANCOVA for continuous variables 
No 
No 
Infants’ 
Dermatology 
Quality of Life 
Index (IDQOL) (< 
4 years of age) 
FAS 
• 
Change from baseline 
• Multiple imputation (MI using 
pattern mixture (MI-WOCF) with 
ANCOVA for continuous variables 
No 
No 
 
 
 
 
 
TCS 
 
FAS 
• 
Proportion of TCS medication-
free days from baseline to 
week 16 
• 
Mean weekly dose of TCS in 
grams for low potency TCS 
from baseline to week 16 
 
• CMH test adjusted randomization 
strata 
 
• ANCOVA for continuous variables 
No 
No 
Caregiver missed 
workdays (CMW) 
 
FAS 
• 
Mean of caregiver missed 
workdays  
 
• Descriptive statistics by visit/time 
No 
No 
Caregiver global 
impression of 
disease (CGID) 
FAS 
• 
Proportion of patients with No 
symptoms at week 16 
• 
proportion of patients with No 
symptoms or Mild at week 16 
CMH test adjusted randomization 
strata 
 
 
No 
No 
Caregiver global 
impression of 
change (CGIC) 
FAS 
• 
Proportion of patients with 
ratings = “Much better” at 
week 16 
• 
Proportion of patients with 
ratings = “Much better” or 
“Moderately better” at week 16 
CMH test adjusted randomization 
strata 
 
No 
No 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 65 of 104 
Parameter(s) 
 
Analysis 
Populations 
Endpoints  
Primary Statistical Method 
Supportive/Sens
itivity Statistical 
Method 
Subgroup 
Analysis 
PASQ 
(for patients with 
Asthma) 
 
FAS 
• 
PASQ total score based on 
questions 3-6 
 
Multiple imputation (MI using pattern 
mixture (MI-WOCF) with ANCOVA 
for continuous variables 
No 
No 
CNSQ  
(for patients with 
medical history of 
allergic rhinitis) 
 
FAS 
• 
Change from baseline in 
CNSQ score at week16  
Multiple imputation (MI using pattern 
mixture (MI-WOCF) with ANCOVA 
for continuous variables 
No 
No 
IGA 
 
FAS 
• 
Proportion of patients who 
achieve reduction of IGA score 
by ≥2 from baseline to week 
16 
CMH test adjusted randomization 
strata 
 
No 
No 
IGA and EASI 
 
FAS 
• 
Proportion of patients with 
IGA score 0 or 1 or EASI-90 at 
week 16 
CMH test adjusted randomization 
strata 
 
No 
No 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 66 of 104 
Safety Analyses: 
 
Analysis 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Populations 
Method 
Analysis 
Analysis 
Analyses 
 
 
 
 
 
 
Adverse Events 
SAF 
Descriptive statistics 
No 
Yes for 
selected AE 
summary 
No 
Skin infection TEAE 
 
SAF 
Incidence of skin infection 
TEAE (excluding herpetic 
infections) through week 16 
Descriptive summary 
(incidence) 
 
No 
No 
TE-SAE 
 
SAF 
Incidence of treatment-emergent 
serious adverse events (SAE) 
through week 16 
 
Descriptive summary 
(incidence) 
No 
No 
Laboratory Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 67 of 104 
APPENDIX 3. SCHDULE OF EVENTS FOR THE SCREENING, TREATMENT, AND FOLLOW-UP 
PERIOD (PART B)  
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit 
window 
(days) 
- 
- 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Screening/Baseline: 
 
Inclusion/ 
Exclusion22 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parental 
Informed 
Consent23 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 68 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit 
window 
(days) 
- 
- 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Parental 
Informed 
Consent for 
Optional 
Genomic 
Sub-study2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parental 
Informed 
Consent for 
Optional 
Vaccine 
Sub-study3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 69 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit 
window 
(days) 
- 
- 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Parental 
Informed 
Consent for 
Optional 
Tape 
Stripping 
Sub-study 
(selected 
study sites 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 70 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit 
window 
(days) 
- 
- 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Parental 
Informed 
Consent for 
Optional Use 
of 
Photographs 
(selected 
study sites 
only)30 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
vaccination 
plan4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 71 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit 
window 
(days) 
- 
- 
 
±3 
±3 
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±3 
±3 
±3 
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±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmolo
gy Exam 
(patients with 
history of 
certain eye 
disorders)32 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic
s 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 72 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit 
window 
(days) 
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±3 
±3 
±3 
±4 
±4 
±4 
 
 
Randomizati
on 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent/ 
Caregiver 
e-diary 
training5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
TCS 
application6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 73 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit 
window 
(days) 
- 
- 
 
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±3 
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±3 
±3 
±3 
±3 
±4 
±4 
±4 
 
 
TCS 
dispensation 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
X 
 
TCS 
accountabilit
y7 
 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Administer 
Study Drug8 
 
 
X
9 
 
 
 
X 
9 
 
 
 
X 
9 
 
 
 
X 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 74 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
21 
22 
 
 
Week 
- 
- 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
20 
24 
28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
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±3 
±3 
±3 
±4 
±4 
±4 
 
 
Parent/ 
Caregiver 
Counseling 
for e-diary 
Completion 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
X 
 
Parent / 
Caregiver 
Recording of 
TCS Use via 
e-diary 
(daily) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 75 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
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EOS 
 
 
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Week 
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2 
3 
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6 
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8 
9 
10 
11 
12 
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15 
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24 
28 
 
 
Study 
Day(s) 
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to 
-15 
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to 
-1 
1 
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15 
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(days) 
- 
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Parent / 
Caregiver 
Recording of 
Emollient 
Use via e-
diary (daily) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Meds and 
Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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X 
X 
X 
X 
X 
X 
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X 
Efficacy10: 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 76 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
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Std 
 
 
 
P
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EOS 
 
 
Visit 
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Assessment 
of Pruritus 
(worst 
scratch/itch) 
NRS11,12  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment 
of Skin Pain 
NRS and 
Sleep 
Diary12,26  
 
 
X 
X  
X  
 
X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 77 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
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V1 
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V1 
 
P 
V1 
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V1 
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V1 
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EOS 
 
 
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IGA, EASI, 
SCORAD, 
BSA, GISS 
X 
 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
CDLQI12, 13 
IDQOL12, 13, 
14, DFI12, 13 
POEM12, 14 
Caregiver 
Missed 
Workdays 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 78 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
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P
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V1 
 
P 
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P
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V1 
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T 
 
 
EOS 
 
 
Visit 
1 
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Study 
Day(s) 
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to 
-15 
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1 
8 
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Visit 
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CGID 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
CGIC 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
PASQ12,14,28 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
CNSQ12,14,29 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 79 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
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V1 
 
P 
V1 
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V1 
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V1 
 
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V1 
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T 
 
 
EOS 
 
 
Visit 
1 
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5 
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±3 
±4 
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±4 
 
 
Photograph 
AD Areas 
(Selected 
Study Sites 
only) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 80 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
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V1 
 
P 
V1 
P 
V1 
P 
V1 
 
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V1 
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V1 
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EOS 
 
 
Visit 
1 
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Safety: 
Weight 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
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Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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X 
 
X 
Vital Signs 
X 
 
X
15 
X 
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X 
15 
 
 
 
X 
15 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
ECG27 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 81 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
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Std 
 
 
 
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P
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V1 
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EOS 
 
 
Visit 
1 
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Adverse 
Events33 
X 
X 
X
15 
X 
X 
X 
X 
15 
X 
X 
X 
X 
15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing16: 
Hematology 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Blood 
Chemistry 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 82 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
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V1 
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V1 
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T 
 
 
EOS 
 
 
Visit 
1 
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5 
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±4 
±4 
 
 
HIV, 
HBsAg, 
HBsAb, 
HBcAb, 
Hepatitis C 
Ab, TB17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
sample for 
vaccination 
response18 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Biomarkers19: 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 83 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
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V1 
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V1 
 
P 
V1 
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V1 
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V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
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131 
141 
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16 
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Day(s) 
-56 
to 
-15 
-14 
to 
-1 
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78 
85 
92 
99 
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169 
197 
 
 
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window 
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±3 
±3 
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±3 
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±4 
±4 
 
 
TARC 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Serum 
Immunoglob
ulin 
profiling, 
antigen-
specific IgE 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 84 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
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16 
17 
18 
19 
20 
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Week 
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9 
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11 
12 
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20 
24 
28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
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36 
43 
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85 
92 
99 
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169 
197 
 
 
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window 
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±4 
±4 
 
 
Research 
Testing25: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional 
DNA buccal 
sample2 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional tape 
stripping 
sample31 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
PK/Drug Concentration and ADA Samples25: 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 85 of 104 
Study 
Procedure 
Screening 
Period24 
B
L 
Treatment Period 
Follow-Up 
Un-
schedule
d Visit21 
ET 
Visit 
 
SC
N 
TC
S 
Std 
 
 
 
P
V1 
 
P
V1 
P
V1 
P 
V1 
 
P 
V1 
P 
V1 
P 
V1 
 
P
V1 
P
V1 
P 
V1 
EO
T 
 
 
EOS 
 
 
Visit 
1 
2 
3 
4 
5 
61 
7 
81 
9 
101 
11 
121 
131 
141 
15 
16 
17 
18 
19 
20 
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Week 
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12 
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28 
 
 
Study 
Day(s) 
-56 
to 
-15 
-14 
to 
-1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
141 
169 
197 
 
 
Visit 
window 
(days) 
- 
- 
 
±3 
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±3 
±3 
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±3 
±3 
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±4 
±4 
 
 
PK/Drug 
concentration 
sample19 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X  
ADA 
sample20 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Note: AD = atopic dermatitis; ADA = anti0drug antibody; AESI=adverse event of special interest; BL = Baseline; BSA = body surface area; CDLQI = 
Childrens’ Dermatology Life Quality Index; CGIC = Caregiver Global Impression of Change; CGID = Caregiver Global Impression of Disease; CNSQ = 
Caregiver-Reported Nasal Symptom Questionnaire; DFI = Dermatitis Family Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; e-
diary = electronic diary; EOT = End of treatment; EOS = End of Study; ET = Early Termination; GISS = Global Individual Signs Score; HBcAb = hepatitis B 
core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; ICF = informed consent 
form; IDQOL = Infants’ Dermatology Quality of Life Index; IGA = Investigator Global Assessment; IgE = immunoglobulin E; NRS = numeric rating scale;  
PASQ  = Pediatric Asthma Symptom Questionnaire; PK = pharmacokinetic; POEM = Patient Oriented Eczema Measure; PV = phone visit; Q4W = every 
4 weeks; SCN = screening; SCORAD = SCORing Atopic Dermatitis; TARC = thymus and activation regulated chemokine; TB = tuberculosis; TCS = topical 
corticosteroid; Std = standardization. 
                                        VV-RIM-00152867-1.0 Approved - 07 May 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
R668-AD-1539 Part B 
Statistical Analysis Plan 
April 28, 2021 
 
CONFIDENTIAL 
Page 86 of 104 
1 
The site will contact the parent/caregiver by telephone to conduct these visits. 
2 
For patients whose parents or legal guardians agree to their participation and provide a specific written informed consent for the optional genomics sub-study (DNA sample 
collection), DNA sample should be collected at the day 1 visit but can be collected at any visit during the study.   
3 
Parents/caregivers of patients will be encouraged to provide vaccination plans for any vaccines which are in line with the patient’s age, and local medical practice (live 
attenuated vaccines are excluded) during the study.  Parents or legal guardians of patients planning to receive any vaccines during the study may optionally sign a separate 
informed consent for collection of 2 blood samples (a pre-vaccine and post-vaccine sample) for assay of vaccine IgG in serum for each vaccination. 
4 
The study team on site will collect information from the parents/caregivers regarding the vaccinations planned during the next 6 months from screening.  The study team 
should refer to the patient’s medical records and national vaccination schedule to gather this information.  The study team can also contact the patient’s primary physician 
and/or pediatrician to gather this information. 
5 
Training of parents/caregivers regarding completion of e-diary at visit 1 to record a) completion of assessment of pruritus NRS (worst scratch/itch scale), skin pain NRS, sleep 
diary, and CNSQ and b) TCS and emollient usage.  Provide additional training as necessary based on review of e-diary use.  
6 
As per the standardized regimen outlined in Section 5.2 of the study protocol. 
7 
The type, amount, and potency of topical products used during the study will be recorded.  The amount of TCS used will be determined by weighing the tube at each visit 
through the end of the study. 
8 
The dose regimens, including frequency of administration in part B are placebo Q4W or dupilumab Q4W tiered fixed-dose (200 mg for patients ≥5-<15kg or 300 mg for 
patients ≥15-<30 kg). 
9 
Patients will be monitored at the study site at visits 3, 7 and 11 for a minimum of 2 hours after study drug administration. 
10 Assessments/procedures should be conducted in the following order: patient reported outcomes, investigator assessments, safety and laboratory assessments, administration of 
study drug. 
11 The assessment will be recorded daily.  Parents/caregivers will complete an e-diary daily to record pruritus (worst scratch/itch) NRS in patients. 
12 The questionnaires will be administered only to those patients and/or parents/caregivers who speak fluently the language in which the questionnaire is presented (based on 
availability of validated translations in participating countries).  It is recommended that the same person complete the questionnaire on behalf of the patient throughout the 
study. 
13 Childrens’ Dermatology Life Quality Index (CDLQI) for patients ≥4 years of age, Infants’ Dermatitis Quality of Life Index (IDQOL) for patients <4 years of age, Dermatology 
Family Index (DFI) to be completed by an adult family member of a child affected by dermatitis. 
14 Questionnaire will be completed by the parent/caregiver on behalf of the patient.  It is recommended that the same person complete the questionnaire on behalf of the patient 
throughout the study. 
15 Patients will be monitored at the study site at visits 3, 7, and 11 for a minimum of 2 hours after study drug administration.  Vital signs (sitting systolic and diastolic blood 
pressures, heart rate, respiratory rate, and body temperature) and AE assessments will be done at 30 minutes (±10 minutes) post-injection, and then at 2 hours (±15 minutes) 
post-injection. 
16 Samples will be collected before the injection of study drug.   
17 TB testing will be performed on a country-by-country basis, according to local guidelines, if required by regulatory authorities or ethics boards. 
18 Optional collection of blood for assay of vaccine IgG in serum for each vaccine administered.  The first sample should be drawn within 6 weeks prior to vaccination, and the 
second sample should be drawn 3 to 4 weeks (maximum 6 weeks) after vaccination.  Vaccinations should be performed in compliance with the patient’s recommended 
immunization schedule.  Blood collections should be conducted at regularly scheduled study visits but, if this is not feasible, samples can also be drawn at unscheduled visits.   
19 Samples to measure functional dupilumab concentration and biomarkers will be collected prior to injection of study drug.   
20  Samples to be collected prior to injection of study drug.  Patients who are ADA positive at their last study visit (early termination, or end of study) and who do not participate 
in the OLE may be considered for follow-up based on the overall clinical presentation at that time.  Patients who are considered for follow-up may be asked to return to the 
clinic to have additional samples collected for analysis.  
21  The specific assessments that will be performed at the unscheduled visit will depend upon the reason for the unscheduled visit.  In the event of suspected SAEs, such as 
anaphylaxis or hypersensitivity, additional PK and ADA samples may be collected at or near to the event as practically possible. 
22  Eligibility based on age at time of screening visit. 
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23  Assent collected from patient, if applicable, as per local regulatory (competent authority/ethics) guidelines, based upon the age and level of maturity of the patient. 
24  The length of the screening period is not fixed but must not exceed 56 days (including TCS standardization).  The length of the TCS standardization period is fixed at 14 days. 
25  Any unused serum samples collected for dupilumab concentrations or ADA measurements may be used for exploratory biomarker research related to AD, inhibition of the 
IL-4Rα pathway with an antibody, treatment response (PD and or predictive), or vaccine response, as well as to investigate unexpected AEs or to identify markers associated 
with adverse reactions. 
26  Pain and sleep will be assessed daily for the 14 days leading up to the baseline visit, the 7 days leading up to the week 1 visit, the 7 days leading up to the week 2 visit, the 7 
days leading up to the week 4 visit, the 7 days leading up to the week 16 visit, and 7 days leading up to the week 28 visit.  Parents/caregivers will complete a daily e-diary on 
these days to record skin pain and sleep in patients. 
27  ECGs should be conducted prior to collection of blood samples at visits requiring blood draws. 
28  Completed only for the subset of patients with ongoing asthma. 
29  Completed only for the subset of patients with a medical history of allergic rhinitis.  Caregivers will be instructed on using the e-diary to record the CNSQ for 14 days before 
baseline/day 1 and for the 7 days preceding visits 7, 19, and 22 (weeks 4, 16, and 28). 
30  Optional parental informed consent for use of photographs for educational/marketing purposes (selected study sites only). 
31  An optional tape stripping sub-study may be performed at a subset of study sites.  Parents or legal guardians who agree for their child to participate in the tape stripping 
sub-study will be required to sign a separate sub-study ICF before collection of the samples.  Baseline samples should be collected on day 1/baseline (pre-dose).  A second 
sample will be collected at week 16. 
32  Patients who have history of certain eye disorders (conjunctivitis, blepharitis or keratitis) within 12 months prior to the screening visit will be referred to an ophthalmologist 
(see protocol Section 6.2.3.6).  Any baseline findings will be documented as part of the patient’s medical history and/or physical exam, as appropriate. 
33  Any patient who experiences an AESI related to an eye disorder will be referred to an ophthalmologist (see protocol Section 7.2.3). 
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APPENDIX 4. AESI  AND  OTHER AES CRITERIA 
AESI 
Search Criteria 
Anaphylactic reactions  
 
Narrow SMQ for “anaphylactic reaction”  
Systemic hypersensitivity reactions  
 
Narrow SMQ for “hypersensitivity” 
Note:  manual adjudication of relevant PTs will be required by the study medical monitor, before 
database lock 
Helminthic infections 
Include the following HLTs  
1. HLT = Cestode infections 
2. HLT = Helminthic infections NEC 
3. HLT = Nematode infections 
4. HLT = Trematode infections 
Any severe type of conjunctivitis or 
blepharitis 
Broad CMQ Conjunctivitis PTs 
Conjunctivitis  
Conjunctivitis allergic    
Conjunctivitis bacterial    
Conjunctivitis viral    
Atopic keratoconjunctivitis    
Blepharitis    
Dry eye    
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Eye irritation    
Eye pruritus    
Lacrimation increased    
Eye discharge    
Foreign body sensation in eyes    
Photophobia    
Ocular hyperaemia   
Conjunctival hyperaemia    
Xerophthalmia,  
 
and  
PTs: 
Bacterial blepharitis 
Blepharitis allergic 
AND 
Serious AE= “Yes” OR Severity= “severe” 
 
Keratitis 
Narrow SMQ for “corneal disorders” 
Clinically symptomatic eosinophilia 
HLT = Eosinophilic disorders  
OR 
PT = Eosinophil count increased 
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Note: manual adjudication of relevant PTs will be required by the study medical monitor, 
before database lock. 
Other AEs 
Search Criteria 
Skin Infections 
SOC = ('Infections and infestations', 'Skin and subcutaneous tissue disorders') 
Herpes Infections 
HLT = Herpes viral infections  
Injection Site Reactions 
HLT = Injection Site Reactions  
 
The search criteria are meant to assist the process of identification of TEAE of Special Interest/TEAE Syndrome.  However, since these criteria might not be 
exhaustive in some cases or may not be specific in other cases. Hence an additional blinded review of all PTs in the database may be performed by the Medical 
monitor, based on medical judgement, to identify any TEAE of Special Interest/TEAE Syndrome that might have been missed by the criteria or to identify any 
TEAE may been inaccurately assigned as AESI by the algorithmic search 
 
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APPENDIX 5. PCSV CRITERIA 
Criteria for Treatment-Emergent Potentially Clinical Significant Value for Pediatric Patients (>= 6months to <6 years old) 
Age range 
Parameter 
TE PCSV 
Comments 
  
Vital Signs 
  
Ref. : Kidney Disease Outcomes Quality 
Initiatives (KDOQI) Guideline 13; 1996; 
The fourth report on the diagnosis, 
evaluation, and treatment of high blood 
pressure in children and adolescents, 
Pediatrics 2004; Bowman E & Fraser S 
Neonatal Handbook 2012;  Mulberg AE et 
al. Pediatric Drug Development Concepts 
and applications. John Wiley & sons, Inc. 
2009; Pediatric respiratory rates 
http://www.health.ny.gov/ 
6 months - <1 
year 
HR 
≤72 bpm and decrease from baseline ≥20 
bpm 
≥175 bpm and increase from baseline 
≥20 bpm 
 
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1- <3 years 
HR 
≤63 bpm and decrease from baseline ≥20 
bpm 
≥140 bpm and increase from baseline 
≥20 bpm 
 
3-<6 years 
HR 
≤59 bpm and decrease from baseline ≥20 
bpm 
 
≥140 bpm and increase from baseline 
≥20 bpm 
 
6 months -<1 
year  
SBP  
≤70 mmHg and decrease from baseline 
≥20 mmHg 
≥110 mmHg and increase from baseline 
≥20 mmHg 
  
1 - <3 years 
SBP  
≤70 mmHg and decrease from baseline 
≥20 mmHg 
≥116mHg and increase from baseline 
≥20 mmHg 
  
3-<6 years 
SBP 
≤70 mmHg and decrease from baseline 
≥20 mmHg 
≥121 mHg and increase from baseline 
≥20 mmHg 
 
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6 months -< 1 
year months 
DBP 
≤34 mmHg and decrease from baseline 
≥10 mmHg 
≥72mHg and increase from baseline ≥10 
mmHg 
  
1-<3 years 
DBP 
≤34 mmHg and decrease from baseline 
≥10 mmHg 
≥77mHg and increase from baseline ≥10 
mmHg 
 
3 - <6 years 
DBP 
≤34 mmHg and decrease from baseline 
≥10 mmHg  
≥83mHg and increase from baseline ≥10 
mmHg  
  
6 months - <6 
years 
Temperature 
Rectal, ear or temporal artery: >102.2 
°F/39.0 °C 
Oral or pacifier: >102.2°F/39.0°C 
Axillary or skin infrared: >102.2 °F/39.0 
°C 
 
6 months - <1 
year months 
Respiratory rate 
< 24 per minute and ≥ 24 per minute at 
baseline 
> 40 per minute and ≤ 40 per minute at 
baseline 
  
1 - <6 years 
Respiratory rate 
< 20 per minute and ≥ 20 per minute at 
baseline 
> 34 per minute and ≤ 34 per minute at 
baseline 
  
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6 months - <6 
years 
Weight 
>5 % weight loss from baseline 
Based on identification of trends in the 
child’s growth with a series of visits 
 
WHO Multicentre Reference Study Group, 
2006; Center for Disease Control. Growth 
chart 2007 
  
Clinical Chemistry  
  
Ref Molleston JP et al. JPGN 2011; Moritz 
et al., Pediatrics 1999; Moritz et al., Pediatr 
Nephrol 2005 ; Sedlacek et al., Seminars in 
Dialysis 2006) Gong G et al. Clinical 
Biochemistry 2009; Masilamani et al. Arch 
Dis Children 2012; Mulberg AE et al. 
Pediatric Drug Development Concepts and 
applications. John Wiley & sons, Inc. 2009 
6 months - <6 
years 
ALT 
≥3 ULN and baseline <3 ULN 
 
Based on normal ranges: 
5 to 45 U/L (Females 6 months-<6 years)  
5 to 49 U/L (Males 6 months- <6 years) 
6 months - <6 
years 
AST 
≥3 ULN and baseline <3 ULN 
 
Based on normal ranges:  
9 to 50 U/L (Females 6 months-<6 years)  
9 to 60 U/L (Males 6 months-<6 years) 
6 months - <6 
years 
Alkaline Phosphatase 
(ALP) 
≥1.5 ULN and baseline < 1.5 ULN 
Based on normal ranges:  
70 to 350 U/L (6 months-<1 year) 
125 to 320 U/L (≥1- ≤3 years) 
150 to 370 U/L (≥4- <6 years) 
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6 months - <6 
years 
Total Bilirubin 
≥1.3 ULN and baseline < 1.3 ULN 
CF = mg x 1.7 = µmol 
Based on normal ranges: ≤1 mg/dL  
6 months - <6 
years 
Conjugated Bilirubin 
(Direct Bilirubin >35% Total Bilirubin 
(TBILI) and TBILI ≥1.3 ULN) and 
(Direct Bilirubin ≤35%  TBILI or TBILI 
<1.3 ULN) at baseline 
CF = mg x 1.7 = µmol 
Based on normal range: 0 to 0.4 mg/dL  
6 months- <6 
years  
ALT/AST and Total 
Bilirubin 
((ALT >3 ULN or AST>3 ULN) and 
TBILI>2 ULN) and ((ALT ≤3 ULN and 
AST ≤3 ULN) or TBILI ≤2 ULN)) at 
baseline 
  
6 months - <6 
years 
CPK 
≥3 ULN and < 3 ULN at baseline 
  
6 months - < 
1 year  
Creatinine 
>53 µmol/L or 0.6 mg/dL and ≤ 53 
µmol/L or 0.6 mg/dL at baseline 
(Females 6 months- <1 year) 
>62 µmol/L or 0.7 mg/dL and ≤ 62 
µmol/L or 0.7 mg/dL at baseline (Males 
6 months- <1 year) 
 
CF = mg x 8.8 = µmol 
 
1- ≤3 years 
Creatinine 
>62 µmol/L or 0.7 mg/dL and ≤ 62 
µmol/L or 0.7 mg/dL at baseline  
 
 
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4- <6 years 
Creatinine 
>71 µmol/L or 0.8 mg/dL and ≤ 71 
µmol/L or 0.8 mg/dL at baseline  
 
 
6 months - <6 
years 
Uric Acid  
≥8.0 mg/dL or 476 µmol/L and <8.0 
mg/dL or 476 µmol/L at baseline 
CF = mg x 5.95 = µmol 
 
6 months - <6 
years  
Blood Urea Nitrogen 
(BUN) 
≥6.4 mmol/L or 18 mg/dl and <6.4 
mmol/L or 18 mg/dl at baseline 
  
6 months - <6 
years 
Chloride 
≤80 mmol/L or 80 mEq/L and >80 
mmol/L or 80 mEq/L at baseline 
≥115 mmol/L or 115 mEq/L and <115 
mmol/L or 115 mEq/L at baseline 
CF = 1 
 
6 months - <6 
years 
Sodium 
≤129 mmol/L or 129 mEq/L and >129 
mmol/L or 129 mEq/L at baseline 
≥150 mmol/L or 150 mEq/L and <150 
mmol/L or 150 mEq/L at baseline 
CF = 1 
6months - ≤1 
year 
Potassium 
≤3.5 mmol/L or 3.5 mEq/L and >3.5 
mmol/L or 3.5 mEq/L at baseline 
≥6.1 mmol/L or 6.1 mEq/L and <6.0 
mmol/L or 6.0 mEq/L at baseline 
  
>1 - <6 years  
Potassium 
≤3.5 mmol/L or 3.5 mEq/L and >3.5 
mmol/L or 3.5 mEq/L at baseline 
≥5.5 mmol/L or 5.5 mEq/L and <5.5 
mmol/L or 5.5 mEq/L at baseline 
  
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6 months - <6 
years 
Calcium total 
≤2.0 mmol/L or 8.0 mg/dL and >2.0 
mmol/L or 8.0 mg/dL at baseline 
≥2.9 mmol/L or 11.6 mg/dL and <2.9 
mmol/L or 11.6 mg/dL at baseline 
CF = mg x 0.025 = mmol 
 
6 months - <6 
years 
Total Cholesterol 
>6.20 mmol/L or 240 mg/dL and ≤6.20 
mmol/L or 240 mg/dL at baseline 
CF = g x 2.58 = mmol 
 
6 months - <6 
years 
Triglycerides 
>4.0 mmol/L or 350 mg/dL and ≤4.0 
mmol/L or 350 mg/dL at baseline 
After >12 hours of fast) 
CF = g x 1.14 = mmol 
 
6 months - <6 
years 
Glucose 
Hypoglycaemia: <2.7 mmol/L and ≥2.7 
mmol/L at baseline (or < 50 mg/dL and 
≥ 50 mg/dL at baseline)  
Hyperglycaemia: ≥10 mmol/L (unfasted) 
and < 10 mmol/L (unfasted) at baseline 
(or ≥180 mg/dl and <180 mg/dl at 
baseline); ≥7 mmol/L (fasted) and <7 
mmol/L (fasted) at baseline (or ≥120 
mg/dL and <120 mg/dL at baseline) 
CF = g x 5.55 = mmol 
 
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Hematology 
  
Common Terminology Criteria for Adverse 
Events v3.0 (CTCAE), 2006 ; Division of 
Microbiology and Infections Diseases 
Pediatric Toxicity Tables, 2007 ; Division 
of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, 2004; 
Mulberg AE et al. Pediatric Drug 
Development Concepts and applications. 
John Wiley & sons, Inc. 2009; Family 
Practice Notebook, LLC, 2012; Tietz NW et 
al. Clinical Guide to Laboratory Testing, 3rd 
edition 1995 
6 - 23 months 
WBC 
<4.0 GIGA/L or 4,000 /mm3 and ≥ 4.0 
GIGA/L or 4,000 /mm3 at baseline 
>20.0 GIGA/L or 20,000 /mm3 and 
≤20.0 GIGA/L or 20,000 /mm3 at 
baseline 
  
2 - <6 years 
WBC 
<3.0 GIGA/L or 3,000 /mm3 and ≥ 3.0 
GIGA/L or 3,000 /mm3 at baseline 
>16.0 GIGA/L or 16,000 /mm3 and ≤ 
16.0 GIGA/L or 16,000 /mm3 at baseline 
  
6 months- <1 
year 
Lymphocytes (ALC) 
<2.0 GIGA/L or 2,000 /mm3 and ≥ 2.0 
GIGA/L or 2,000 /mm3 at baseline 
>17.0 GIGA/L or 17,000/mm3 and 
≤17.0 GIGA/L or 17,000 /mm3 at 
baseline 
  
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≥1 - <6 years 
Lymphocytes (ALC) 
<1.0 GIGA/L or 1,000 /mm3 and ≥ 1.0 
GIGA/L or 1,000 /mm3 at baseline 
>10.5 GIGA/L or 10,500/mm3 and 
≤10.5 GIGA/L or 10,500 /mm3 at 
baseline 
6 months - <6 
years 
Absolute Neutrophil 
Count (ANC) 
<1.2 GIGA/L or 1,200 /mm3 and ≥ 1.2 
GIGA/L or 1,200 /mm3 at baseline (3-24 
months) 
 
  
6 months - <6 
years 
Eosinophils 
(>0.5 Giga/L and >ULN) and (≤0.5 
Giga/L or ≤ ULN at baseline) 
6 - 23 months 
Hemoglobin 
< 1.40 mmol/L or 9.0 g/dL and ≥ 1.40 
mmol/L or 9.0 g/dL at baseline or any 
decrease > 0.31 mmol/L or 2 g/dL 
  
2 - <6 years 
Hemoglobin 
< 1.55 mmol/L or10.0 g/dL and ≥ 1.55 
mmol/L or10.0 g/dL at baseline or any 
decrease > 0.31 mmol/L or 2 g/dL 
6 - 23 months 
Hematocrit 
< 0.29 l/l or 29 % and ≥ 0.29 l/l or 29 % 
at baseline 
> 0.42 l/l or 42 % and ≤0.42 l/l or 42 % 
at baseline 
  
2 - <6 years 
Hematocrit 
< 0.32 l/l or 32 % and ≥ 0.32 l/l or 32 % 
at baseline 
> 0.47 l/l or 47 % and ≤ 0.47 l/l or 47 % 
at baseline 
   
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6 months - <6 
years 
Platelets 
<100 GIGA/L or 100,000 /mm3 and ≥ 
100 GIGA/L or 100,000 /mm3 at 
baseline 
> 700 GIGA/L or 700,000 /mm3 and 
≤700 GIGA/L or 700,000 /mm3 at 
baseline 
  
ECG parameters 
  
Ref. : Rijnbeek P.R. et al., Eur Heart J 
2001; Davignon A. et al., Ped Cardiol 
1979/1980; Semizel E.et al., Cardiol Young 
2008; Mulberg AE et al. Pediatric Drug 
Development Concepts and applications. 
John Wiley & sons, Inc. 2009 
6 - 23 months 
PR 
≥140 ms and <140 ms at baseline  
  
2 - <6 years 
PR 
≥160 ms and <160 ms at baseline  
  
6 - 23 months 
QRS 
≥85 ms and <85 ms at baseline  
  
2 - <6 years 
QRS 
≥95 ms and <95 ms at baseline  
  
6 months - <6 
years 
QTc  
Absolute values (ms)  
Borderline: 431-450 ms and <431 ms at 
baseline  
Prolonged*: >450 to <500 ms and ≤450 
ms at baseline  
Additional: ≥500 ms and <500 ms at 
baseline  
 
Increase from baseline 
To be applied to QTcF 
*QTc prolonged and DQTc>60 ms are the 
PCSA to be identified in individual 
subjects/patients listings. 
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Borderline: Increase from baseline 30-60 
ms 
Prolonged*: Increase from baseline >60 
ms 
 
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APPENDIX 6. RESCUE TREATMENTS  
Algorithm for RESCUE TREATMENTS  
1. Not required to adjudicate rescue treatment:  
a. Always considered rescue: 
Following post-baseline medications (WHODD-coded) given for indications consistent with AD  
• ATC2 = CORTICOSTEROIDS FOR SYSTEMIC USE unless used before day 15 
• ATC2 = IMMUNOSUPPRESSANTS unless used before day 15 
• Preferred Drug Name = Ciclosporin 
• Preferred Drug Name = Methotrexate 
• Preferred Drug Name = Mycophenolate sodium 
• Preferred Drug Name = Mycophenolic acid 
• Preferred Drug Name = Mycophenolate mofetil 
• Preferred Drug Name = Azathioprine 
b. Never considered rescue 
• ATC2 = EMOLLIENTS AND PROTECTIVES 
• ATC2 = VASOPROTECTIVES 
• ATC2 = ANALGESICS 
• ATC2 = ANTI-ACNE PREPARATIONS 
• ATC2 = TOPICAL PRODUCTS FOR JOINT AND MUSCULAR PAIN 
• ATC2 = ANTIBIOTICS AND CHEMOTHERAPEUTICS FOR DERMATOLOGICAL USE 
• ATC2 = ANTIVIRALS FOR SYSTEMIC USE 
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• ATC2 = ANTIFUNGALS FOR DERMATOLOGICAL USE 
• ATC2 = ANTISEPTICS AND DISINFECTANTS 
• ATC2 = ANTIHISTAMINES FOR SYSTEMIC USE 
• ATC2 = ANTIPRURITICS, INCL. ANTIHISTAMINES, ANESTHETICS, ETC. 
• ATC2 = GENERAL NUTRIENTS 
• ATC2 = VITAMINS 
• ATC2 = DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES 
• ATC2 = OPHTHALMOLOGICALS 
• ATC2 = ANTIINFLAMMATORY AND ANTIRHERUMATIC PRODUCTS 
• ATC2 = PSYCHOLEPTICS 
• ATC4 = CORTICOSTEROIDS, WEAK (GROUP I) 
• ATC1 = ANTIINFECTIVES FOR SYSTEMIC USE 
• ATC1 = BLOOD AND BLOOD FORMING ORGANS 
• ATC1 = ALIMENTARY TRACT AND METABOLISM 
• ATC1 = MUSCULO-SKELETAL SYSTEM 
• ATC2 = COUGH AND COLD PREPARATIONS 
• ATC2 = CORTICOSTEROIDS, DERMATOLOGICAL PREPARATIONS, if  
used before Day 15 
• Preferred Drug Name = Tacrolimus, if used before Day 15 
• Preferred Drug Name = Pimecrolimus, if used before Day 15 
• Preferred Drug Name= Crisaborole, if used before Day 15 
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A blinded review of all post-baseline medications to adjudicate rescue treatment, based on medical judgement, may be performed in 
addition. A listing of treatments classified as rescue/non-rescue in a manner inconsistent with the classification under #1 will be 
provided, along with supporting rationale.  
2. Required to adjudicate rescue treatment: 
• All other medications (not noted in 1 above) given for indications consistent with AD2 
• Medications noted in 1a above, when given for indications not consistent with AD  
2 Below is a list of indications consistent with AD based on PT level from concomitant medication/procedure data using MedDRA 
dictionary 
System Organ Class 
High Level Term 
Preferred Term 
Preferred 
Term Code 
Infections and infestations 
Bacterial infections NEC 
Eczema impetiginous 
10051890 
Infections and infestations 
Skin structures and soft tissue infections 
Dermatitis infected 
10012470 
Infections and infestations 
Skin structures and soft tissue infections 
Eczema infected 
10014199 
Skin and subcutaneous tissue disorders 
Dermatitis and eczema 
Dermatitis 
10012431 
Skin and subcutaneous tissue disorders 
Dermatitis and eczema 
Dermatitis atopic 
10012438 
Skin and subcutaneous tissue disorders 
Dermatitis and eczema 
Eczema 
10014184 
Skin and subcutaneous tissue disorders 
Dermatitis and eczema 
Neurodermatitis 
10029263 
 
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