Conditions: Dermatitis, Atopic
Keywords: Eczema
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 367
Healthy volunteers: no

Brief summary:
The main objective of the trial is to demonstrate the efficacy of dupilumab administered concomitantly with topical corticosteroids (TCS) in participants ≥6 years to \<12 years of age with severe atopic dermatitis (AD).

The secondary objective is to assess the safety of dupilumab administered concomitantly with TCS in patients ≥6 years to \<12 years of age with severe AD.

Detailed description:

Arms:
arm 1: Participants will receive dupilumab, dosing regimen 1 arm 2: Participants will receive dupilumab, dosing regimen 2 arm 3: Participants will receive matching placebo

Interventions: intervention 1: Dupilumab intervention 2: Matching Placebo intervention 3: Background Treatment: Topical Corticosteroids intervention 4: Background Treatment: Moisturizers
Intervention descriptions: intervention 1: Pharmaceutical form: Solution for injection in pre-filled syringe;

Route of administration: Subcutaneous (SC) intervention 2: Pharmaceutical form: Solution for injection;

Route of administration: Subcutaneous (SC) intervention 3: All participants are required to initiate treatment with a medium potency TCS using a standardized regimen. It is recommended that participants use triamcinolone acetonide 0.1% cream, fluocinolone acetonide 0.025% cream, or clobetasone butyrate 0.05%. intervention 4: All participants should apply moisturizers throughout the study. All types of moisturizers are permitted, but participants may not initiate treatment with prescription moisturizers. Participants may continue using stable doses of such moisturizers if initiated before the screening visit.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
R668-AD-1652 Amendment 3 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 109 
CONFIDENTIAL 
IND Number: 107969 
EudraCT Number: 2016-004997-16 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO INVESTIGATE THE EFFICACY AND SAFETY OF DUPILUMAB 
ADMINISTERED CONCOMITANTLY WITH TOPICAL 
CORTICOSTEROIDS IN PATIENTS, ≥6 YEARS TO <12 YEARS OF AGE, 
WITH SEVERE ATOPIC DERMATITIS 
Compound: 
Dupilumab 
Clinical Phase: 
3 
Protocol Number: 
R668-AD-1652 
Protocol Version 
R668-AD-1652/Amendment 3 
Amendment 3 Date of Issue: 
See appended electronic signature page 
Amendment 3 CZ Date of Issue: 
18 Jan 2018 (Issued to CZ sites only) 
Amendment 2 Date of Issue: 
14 Sep 2017 
Amendment 1 Date of Issue 
01 Sep 2017 
Scientific/Medical Monitor: 
 
Director Clinical Sciences, Immunology and Inflammation 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
. 
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NCT03345914


Clinical Study Protocol  
 
R668-AD-1652 Amendment 3 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 109 
 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 3 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Due to an inadvertent operational error, 68 patients were 
potentially unblinded. 
In order to properly power for a sensitivity analysis for 
the subset of patients who were not potentially 
unblinded, additional patients will be enrolled and 
randomized. 
Included introduction of the modified full analysis set 
(mFAS), which excludes potentially unblinded patients, 
and will be used for sensitivity analysis. 
Stated that potentially unblinded patients will be 
excluded from the per protocol set (PPS). 
Added power calculation for the full analysis set (FAS) 
with the additional patients. 
Clinical Study Protocol Synopsis:  Study Design 
Clinical Study Protocol Synopsis:  Population 
Clinical Study Protocol Synopsis:  Statistical Plan – 
Sample Size Consideration, Efficacy Analysis Sets 
Section 5.1 Study Description and Duration 
Figure 1 Study Design 
Section 6.1 Number of Patients Planned 
Section 7.6 Method of Treatment Assignment 
Section 10.2 Justification of Sample Size 
Section 10.3.1 Efficacy Analysis Sets 
Section 10.4 Patient Disposition 
Section 10.5.2 Efficacy Analyses 
Extended the duration of the visit window between 
Visit 1 and Visit 2 from 21 days to 63 days (ie, changed 
start of Visit 1 from -35 days to -77 days) and removed 
the limit of rescreen once to allow for the seamless 
screening/enrolment of all new patients into the study.  
This was considered  necessary to remain compliant with 
Good Clinical Practice (GCP) regulations regarding 
enrolment practices until approval of this protocol 
amendment. 
Clinical Study Protocol Synopsis:  Study Design 
Section 5.1 Study Description and Duration, Figure 2 
Section 6.2.1 Inclusion Criteria, #7 
Section 8.1 - Table 1 Schedule of Events (Screening, 
TCS Standardization, Baseline, and Treatment Period) 
Revised Inclusion Criterion #9: 
At least 11 (of a total of 14) applications of a stable dose 
of topical emollient (moisturizer) during the 
7 consecutive days immediately before the baseline visit. 
The criterion prior to this amendment requiring 100% 
compliance with application of a stable dose of topical 
emollient twice daily for the entire 7 consecutive days 
immediately before the baseline visit is overly restrictive 
for this patient population.  This change would ensure 
that pediatric patients do not unnecessarily screen fail 
entry into this study. 
Clinical Study Protocol Synopsis: Background 
Treatment 
Section 5.1 Study Description and Duration  
Section 6.2.1 Inclusion Criteria, #9 
Section 7.2 Background Treatment 
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CONFIDENTIAL 
Change 
Section Changed 
Added rationale for the inclusion of a placebo treatment 
group in the study design and a description of the risks 
and benefits to patients assigned to the placebo treatment 
group.  This change had previously been requested by 
the Czech Republic (Czechia) regulatory agency and had 
been included in a country-specific amendment, but it is 
now being incorporated into the global protocol. 
Section 3.2.1 Rationale for Study Design 
Added a benefit-risk section for treatment of atopic 
dermatitis with dupilumab.  This change had previously 
been requested by the Czechia regulatory agency and 
had been included in a country-specific amendment, and 
is now being incorporated into the global protocol.  The 
section summarizes relevant previous Regeneron studies. 
It notes that the safety profile was consistent between 
pediatric and adult populations, and that dupilumab was 
efficacacious in all previous Regeneron trials. 
New Section 3.2.4, Section 3.2.4.1, Section 3.2.4.2, and 
Section 3.2.4.3 
Revised Figure 1 and its title to clarify that patients 
randomized to dupilumab Q4W receive 300 mg 
dupilumab regardless of body weight (Arm B). 
Section 5.1 - Figure 1 Study Design 
Corrected the description of age limit of the study 
population from “aged ≥6 to <12 years at the time of 
baseline” to “aged ≥6 to <12 years at the time of 
screening” to be consistent with the wording in the 
Inclusion Criteria and other sections of the protocol. 
Section 6.2 Study Population 
Revised language for accelerated reporting of pregnancy 
to sponsor and the duration patients who are female of 
childbearing potential and sexually active are required to 
use highly effective methods of contraception after the 
last dose of study drug, to align with the current 
dupilumab label. 
Section 6.2.2 Exclusion Criteria, #31 
Section 9.4.3 Other Events that Require Accelerated 
Reporting 
Added body temperature to the list of post-dose vital 
signs to be assessed. 
Section 7.1 Investigational and Reference Treatments 
Table 1 Schedule of Events (Screening, TCS 
Standardization, Baseline, and Treatment Period) 
(Added footnote “5” to the row “Study drug 
administration (patients receiving Q4W treatment)” for 
visits 3, 7, and 11 
Section 8.1.1.1 Footnotes for Schedule of Events Table 1 
(footnote 5) 
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CONFIDENTIAL 
Change 
Section Changed 
Revised text to emphasize that the use of very-high-
potency topical corticosteroids (TCS) is prohibited 
during the study, as their use is not recommended in 
patients under 12 years of age.  Also included examples 
of very-high-potency TCS. 
Section 7.2 Background Treatment (6th bullet) 
Section 7.3 Rescue Treatment 
Section 7.4.2.1 Reason for Permanent Discontinuation of 
Study Drug 
Section 7.8.1 Prohibited Medications and Procedures 
(8th bullet) 
Included “injection observation” for the every 4 week 
regimen in the Schedule of Events table, to identify the 
visits at which the observation occurs. 
Section 8.1 - Table 1 Schedule of Events (Screening, 
TCS Standardization, Baseline, and Treatment Period) 
Removed Footnote #18 (shown below) in the row for 
Ophthalmology Exam in the Schedule of Events table. 
“In the event the ophthalmology examination cannot be 
performed within the 35-day screening visit window 1 
the screening period can be extended by 4 weeks; 
however, the 14-day interval between visits 2 and visits 
3 may not be extended.” 
The rationale for removing this footnote is that all 
patients will now have an additional 4 weeks of 
screening. 
Section 8.1 - Table 1 Schedule of Events (Screening, 
TCS Standardization, Baseline, and Treatment Period) 
Section 8.1.1.1 Footnotes for Schedule of Events 
Table 1, original #18 (removed) 
Revised the adverse events of special interest definition 
for conjunctivitis, keratitis, and blepharitis.  It originally  
read: Conjunctivitis (any type or etiology), keratitis, or 
blepharitis (only events that are either severe or serious 
or lasting ≥4 weeks will be reported as AESIs).  The 
criteria “or lasting ≥4 weeks” was removed.  In previous 
dupilumab trials for the treatment of atopic dermatitis, 
including one in adolescent patients, events of mild to 
moderate severity were not found to be clinically 
meaningful, even when lasting >28 days during the 
study, as they did not result in sequelae or treatment 
discontinuation. 
Section 9.4.3 Other Events that Require Accelerated 
Reporting 
Specified the list of potential major protocol violation 
types for the PPS, per request from the United States 
Food and Drug Administration. 
Clinical Study Protocol Synopsis:  Statistical Plan – 
Efficacy Analysis Sets 
Section 10.3.1 Efficacy Analysis Sets 
Appendix 3 Potential Major Protocol Violations (added) 
Revision was made to clarify that the hierarchical testing 
order for the primary endpoint and key secondary 
endpoints is shown in Table 3 is an abbreviated, 
preliminary plan as it is stated that the complete 
hierarchy including all the secondary endpoints will be 
provided in the statistical analysis plan (SAP). 
Section 10.5.2.1 Multiplicity Considerations, Table 3  
 
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CONFIDENTIAL 
Amendment 2 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Corrected the header to read R668-AD-1652 versus 
R668-AD-1526. 
Section 8.1 Schedule of Events (Screening, TCS 
Standardization, 
Baseline, 
and Treatment 
Period) 
Table 1 
 
Amendment 1 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Modified the other secondary endpoint of “Mean weekly 
dose of TCS in grams potency TCS from baseline to 
week 16” to include low-potency TCS 
Section 4.2.2 Secondary Endpoints 
Synopsis 
As per regulatory agency request, added inclusion 
criteria #7 for Baseline worst itch score  
Section 6.2.1 Inclusion Criteria 
Revised exclusion criteria #21: 
Children who are engaging in heavy exercise can have 
transient increases in CPK that are not clinically 
relevant. 
Section 6.2.2 Exclusion criteria 
Section 7.4.2.2 Reasons for Temporary Discontinuation 
of Study Drug 
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 7.2 Background Treatment 
Modified the reporting schedule for patient assessment 
of pruritus.  Patients will answer both questions in the 
evening. 
Section 8.2.2.1 Patient Assessment of Pruritus Using 
Worst Itch Scale 
Deleted “alcohol and drug drug screen test” under 
“Other Laboratory Tests” and throughout the protocol. 
Section 8.2.3.5 Laboratory Testing 
Section 8.2.1 Procedures Performed only at the 
Screening/Baseline Visit 
Updated this section to delete the reference to region-
specific, allergen- specific IgE as this is not being 
collected. 
Section 8.2.5 Biomarker Procedures 
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CONFIDENTIAL 
Change 
Section Changed 
As per regulatory agency request, added an 
Ophthalmological Examination section for patients who 
have history of certain eye disorders (conjunctivitis, 
blepharitis or keratitis) within the last 12 months and 
patients who experience adverse events of special 
interest related to eye disorders. 
Certain types of eye disorders (conjunctivitis, 
blepharitis, keratitis) are  adverse events 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 8.2.3.6 Ophthalmological Examination 
 
Added the Mantel-Fleiss (MF) criterion.  If it is not 
met, sensitivity analyses including each factor 
separately in CMH test will be conducted.  
Section 10.5.2.1 Primary Efficacy Analysis 
Synopsis 
Added other secondary endpoints: 
 
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 at week 16 
 
Time to onset of effect on pruritus during the 
16-week treatment period ( ≥4 reduction of 
weekly average of daily worst itch score from 
baseline) 
 
Time to onset of effect on pruritus during the 
16-week treatment period ( ≥3 point reduction 
of weekly average of daily worst itch score 
from baseline) 
As per regulatory agency request, added additional 
details regarding the multiple imputation procedure.   
Section 6.2.1 Inclusion criteria 
Section 4.2.2 Secondary Endpoints 
Section 10.5.2.2.Secondary Efficacy Analysis 
Synopsis 
 
As per regulatory agency request, added the 
hierarchical testing order for the primary endpoint and 
key secondary endpoints 
Section 10.5.2.3 Multiplicity Considerations 
 
Added the Investigator’s Global Assessment (IGA) 
scale to the protocol.  The scale was already included in 
the efficacy procedures and in the Study Manual and 
was added to Appendix 2 for further clarification. 
Appendix 2 IGA Scale 
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CONFIDENTIAL 
Change 
Section Changed 
Minor editorial changes 
Cover page:  Updated the name of the Scientific/Medical 
Monitor: 
Section 8.1 Schedule of Events (Screening, TCS 
Standardization, 
Baseline, 
and Treatment 
Period) 
Table 1  
Section 8.1.1.1 Footnotes for Schedule of Events Table 1 
Section 8.1 Schedule of Events (Follow-Up Period, 
Unscheduled Visits, and Early Termination) 
Section 8.1.1.2 Footnotes for Schedule of Events Table 2 
Section 8.2.2.9 Investigator’s Global Assessment 
Section 8.2.5 Biomarker Procedures 
 
 
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Page 8 of 109 
 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the 
Efficacy and Safety of Dupilumab Administered Concomitantly with Topical 
Corticosteroids in Patients, ≥6 Years to <12 Years Of Age, with Severe Atopic 
Dermatitis 
Site Locations 
 
Principal Investigator 
Multiple sites in North America and the European Union (EU). 
To be determined 
Objectives 
The primary objective of the study is to demonstrate the efficacy of dupilumab 
administered concomitantly with topical corticosteroids (TCS) in patients 
≥6 years to <12 years of age with severe atopic dermatitis (AD). 
The secondary objective of the study is to assess the safety of dupilumab 
administered concomitantly with TCS in patients ≥6 years to <12 years of age 
with severe AD. 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group study to 
investigate the efficacy and safety of dupilumab administered concomitantly with 
TCS in pediatric patients with severe AD. The study population will include 
patients ≥6 years to <12 years of age with severe AD whose disease cannot be 
adequately controlled with topical medications. Approximately 330 study 
patients are planned to be randomized to 1 of the following treatment groups: 
 
dupilumab every 2 weeks (Q2W) treatment group: 100 mg for patients 
<30 kg or 200 mg for patients ≥30 kg 
 
dupilumab every 4-weeks (Q4W) treatment group: 300 mg 
 
placebo group 
The study will consist of the following periods: screening of up to 9 weeks, a 
TCS standardization period of 2 weeks, treatment period of 16 weeks, and a 
follow-up period of 12 weeks. 
After the parents or legal guardians provide an informed assent (as appropriate), 
the patients will be assessed for study eligibility at the screening visit. 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 at the discretion of the investigator. Starting on 
day -14, all patients will initiate a standardized TCS treatment regimen and will 
continue this regimen through the end of the study. Patients may be rescreened, 
unless the reason for the screen failure is related to failing the disease severity 
inclusion criteria. Patients should apply moisturizers twice daily for at least 
7 days before 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 1:1:1 ratio stratified by 
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CONFIDENTIAL 
baseline weight group (<30 kg and ≥30kg) and region (North America/Europe) 
as follows: 
 
dupilumab Q2W treatment group:  Patients with baseline weight <30 kg 
will receive Q2W subcutaneous (SC) injections of 100 mg dupilumab 
following a loading dose of 200 mg on day 1.  Patients with baseline 
weight ≥30 kg will receive Q2W SC injections of 200 mg dupilumab 
following a loading dose of 400 mg on day 1 
 
dupilumab Q4W treatment group:  Patients regardless of weight will 
receive Q4W SC injections of 300 mg dupilumab following a loading 
dose of 600 mg on day 1.  
 
placebo treatment group: Patients will receive matching placebo 
(including doubling the amount of placebo on day 1 to match the 
loading dose). In order to maintain blinding, the patients in the <30 kg 
weight stratum will be randomly assigned to receive, in a 1:1 ratio, 
either Q2W SC injections of placebo (0.7 mL) matching the 100 mg 
dupilumab (including doubling the amount of placebo on day 1 to match 
the loading dose) or Q4W SC injections of placebo (2 mL) matching the 
300 mg dupilumab (including doubling the amount of placebo on day 1 
to match the loading dose). In the ≥30 kg weight stratum, the patients 
randomized to the placebo group will receive, in a 1:1 ratio, either Q2W 
SC injections of placebo (1.14 mL) matching the 200 mg dupilumab 
(including doubling the amount of placebo on day 1 to match the 
loading dose) or Q4W SC injections of placebo (2 mL) matching the 
300 mg dupilumab (including doubling the amount of placebo on day 1 
to match the loading dose). 
During the treatment period, patients will have weekly in-clinic visits through 
week 4, then every 4 weeks in-clinic visits through week 16, with weekly 
telephone visits in between in-clinic visits. Parents/caregivers will be trained on 
injecting study drug during in-clinic visit 3 (day 1) to visit 7 (week 4). During 
weeks in which no in-clinic visit is scheduled, the parent/caregiver will 
administer study drug to the patient. In case the parent/caregiver does not want to 
administer study drug to patient, they may have the clinic staff administer all the 
study drug injections in the clinic. Safety, laboratory, and clinical assessments 
will be performed at specified clinic visits. The end of treatment period visit will 
occur at week 16. The co-primary endpoints will be assessed at this visit.  
Patients who participate in the study may subsequently be eligible to participate 
in an open-label extension (OLE) study. 
Study Duration 
The duration of the study for each patient is approximately 16 weeks, excluding 
the screening period, for patients entering the OLE and 28 weeks, excluding the 
screening period for patients who decline to enter the OLE. 
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CONFIDENTIAL 
Population 
 
 
Sample Size: 
Approximately 330 patients are planned to be enrolled into 3 groups:  dupilumab 
Q2W treatment group (100 mg Q2W or 200 mg Q2W), dupilumab Q4W 
treatment group (300 mg Q4W), or placebo group. 
 
Target Population: 
The study population includes pediatric patients (aged ≥6 to <12 years at the time 
of screening) who have severe AD that cannot be adequately controlled with 
topical AD medications. 
Treatments  
 
 
Study Drug 
 
Dose/Route/Schedule: 
Dupilumab will be given Q2W or Q4W: 
 
dupilumab Q2W treatment: 
o 
SC injections of dupilumab, 200 mg loading dose on day 1, then 
100 mg Q2W from week 2 to week 14, or 
o 
SC injections of dupilumab, 400 mg loading dose on day 1, then 
200 mg Q2W from week 2 to week 14 
 
dupilumab Q4W treatment:  SC injections of dupilumab, 600 mg loading 
dose on day 1, then 300 mg Q4W from week 4 to week 12. 
 
Placebo 
 
Route/Schedule: 
3 matching placebo formulations (without addition of active substance) will be 
used during the study: 
1. 2 mL placebo matching 300 mg dupilumab 
2. 1.14 mL placebo matching 200 mg dupilumab formulation 
3. 0.7 mL placebo matching 100 mg dupilumab 
SC injections of placebo matching dupilumab Q2W (100 and 200 mg) or Q4W 
(300 mg) (including doubling the amount of placebo on day 1 to match the 
loading dose). 
 
Background Treatment 
 
Dose/Route/Schedule: 
All patients should apply moisturizers (emollients) at least twice daily for at least 
the 7 consecutive days immediately before randomization and are to continue to 
apply moisturizers throughout the study (all 28 weeks where applicable). 
However, to allow adequate assessment of skin dryness, moisturizers should not 
be applied on the area(s) of nonlesional skin designated for such assessments for 
at least 8 hours before each clinic visit. All types of moisturizers are permitted, 
but patients may not initiate treatment with prescription moisturizers (eg, 
ceramide containing products like epiceram®) or moisturizers containing 
additives (ceramide, hyaluronic acid, urea, filaggrin degradation products) 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 will initiate a standardized TCS treatment 
regimen and will continue this regimen through the end of the study. 
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CONFIDENTIAL 
Endpoints 
 
 
Primary : 
 Proportion of patients with Investigator’s Global Assessment (IGA) 0 or 1 (on 
a 5-point scale) at week 16 
 
Co-primary (for 
European Medicines 
Agency (EMA) and EMA 
Reference Market 
Countries Submissions): 
 Proportion of patients with Eczema Area and Severity (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 
 
Secondary: 
Key Secondary Endpoints: 
 
Proportion of patients with EASI-75 (≥75% improvement from 
baseline) at week 16 (this is not a secondary endpoint for ex-US 
countries as it is already a co-primary endpoint) 
 
Percent change in EASI score from baseline to week 16 
 
Percent change from baseline to week 16 in weekly average of daily 
worst itch score 
Other Secondary Endpoints: 
 
Change from baseline to week 16 in weekly average of daily worst itch 
score 
 
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 Body Surface Area (BSA) 
affected by AD 
 
Percent change from baseline to week 16 in SCORing AD (SCORAD) 
 
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 at week 16 
 
Time to onset of effect on pruritus during the 16-week treatment period 
(≥4 point reduction of weekly average of daily worst itch score from 
baseline) 
 
Time to onset of effect on pruritus during the 16-week treatment period 
(≥3 point reduction of weekly average of daily worst itch score from 
baseline) 
 
Change from baseline to week 16 in Children’s Dermatology Life 
Quality Index (CDLQI) 
 
Change from baseline to week 16 in Patient Oriented Eczema Measure 
(POEM) 
 
Change from baseline to week 16 in Dermatitis Family Index (DFI) 
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CONFIDENTIAL 
 
Change from baseline to week 16 in Patient-Reported Outcomes 
Measurement Information System (PROMIS) pediatric anxiety short 
form scale score 
 
Change from baseline to week 16 in PROMIS pediatric depressive 
symptoms short form scale score 
 
Topical treatment for AD – proportion of TCS medication-free days 
from baseline to week 16 
 
Mean weekly dose of TCS in grams for low- and medium-potency TCS 
from baseline to week 16 
 
Mean weekly dose of TCS in grams for high-potency TCS from 
baseline to week 16 
 
Incidence of skin-infection treatment-emergent adverse events (TEAEs) 
(excluding herpetic infections) through week 16 
 
Incidence of serious TEAEs through week 16 
Procedures and Assessments 
Efficacy will be assessed during the study at specified clinic visits using 
patient-reported assessments (including worst itch score, patient global 
impression of disease, patient global impression of change, CDLQI, POEM, DFI, 
Patient Reported Outcomes Measurements Information Systems (PROMIS) 
anxiety and depression scores, Faces pain scale, and investigator-reported 
assessments (including BSA affected by AD, SCORAD, Global Individual Signs 
Score [GISS], and EASI that measure the extent and severity of AD, and the IGA 
that rates the overall severity of AD). 
Safety will be assessed by vital signs, physical examinations, clinical laboratory 
tests, 12-lead electrocardiograms (ECGs), and clinical evaluations. Patients will 
be asked to monitor all adverse events (AEs) experienced from the time of 
informed consent/assent until their last study visit. 
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Statistical Plan 
Sample Size Consideration: 
Based on the initial sample size of 240 patients (prior to this amendment), it is 
estimated that with 80 patients per group, at the 2-sided 5% significance level, 
the study will have: 
 97% power to detect a difference of 23% between dupilumab Q2W treatment 
and placebo treatment (both in combination with TCS) in the percentage of 
patients who achieve an IGA score 0 or 1 at week 16, assuming that the 
percentages are 28% and 5% for dupilumab Q2W and placebo, respectively 
 87% power to detect a difference of 17% between dupilumab Q4W treatment 
and placebo treatment (both in combination with TCS) in the percentage of 
patients who achieve an IGA score 0 or 1 at week 16, assuming that the 
percentages are 22% and 5% for dupilumab Q4W and placebo, respectively 
 99% power to detect a difference of 51% in the percentages of patients 
achieving EASI-75 response at week 16, assuming that the percentages are 
68% and 17% for dupilumab Q2W and placebo, respectively, (both in 
combination with TCS) 
 99% power to detect a difference of 45% in percentages of patients achieving 
EASI-75 response at week 16, assuming that the percentages are 62% and 
17% for dupilumab Q4W and placebo, respectively, (both in combination with 
TCS) 
Due to an inadvertent operational error, 68 patients were potentially unblinded. 
Details about the error and why it may have been unblinding are not included in 
the protocol but will be described in the clinical study report. An additional 
approximately 90 patients will be added to the study to ensure that the original 
number of blinded patients for all treatment groups is available for sensitivity 
analyses that exclude the potentially unblinded patients.  This will maintain study 
balance and power. 
The total sample size of the study will be up to approximately 330 patients 
(110 patients per group), and approximately 262 patients (80, 91 and 91 in Q2W, 
Q4W and placebo group respectively) if excluding the potentially unblinded 
patients. With the sample size of 330 patients or 262 patients, the power for the 
co-primary endpoints will be greater than 90%. 
Efficacy Analysis Sets: 
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 considered to be 
the primary analysis set. 
The modified full analysis set (mFAS) includes all randomized patients but 
excludes potentially unblinded patients.  The primary endpoint, co-primary 
endpoint, and selected secondary endpoints will be evaluated in the mFAS as 
sensitivity analyses. 
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The per protocol set (PPS) includes all patients in the FAS except for those who 
are excluded because of major protocol violations. A preliminary list of potential 
major protocol violations is provided in Appendix 3 and a final list will be 
generated prior to database lock.  The PPS will also exclude potentially 
unblinded patients. 
The primary and co-primary endpoints will also be evaluated in the PPS. 
Analysis Methods: 
Primary Efficacy Analyses 
The Cochran-Mantel-Haenszel test adjusted by randomization strata (baseline 
weight group and region) will be used for analyzing the percentage of patients 
with IGA 0 or 1 at week 16 or percentage of patients with EASI-75 at week 16.  
The Mantel-Fleiss (MF) criterion will be checked, and if it is not met, sensitivity 
analyses including each stratification factor separately in CMH test will be 
conducted. 
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, the patient will be classified as a nonresponder from the time 
the rescue is used.  
If a patient withdraws from study, this patient will be counted as a nonresponder 
for endpoints after withdrawal.  
Sensitivity analysis using the last observation carried forward (LOCF) approach 
to determine patient’s status at week 16 will be conducted to assess the 
robustness of the primary efficacy analysis with regards to handling of missing 
data. The efficacy data will be set to missing after rescue treatment is used, then 
the LOCF method will be used to determine patients’ status at week 16.  
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. A patient with missing data will be counted as a non-responder. Other 
sensitivity analyses may be conducted. 
Secondary Efficacy Analyses 
For binary endpoints, the secondary efficacy analysis will use the same approach 
as that used for the primary analysis. 
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For continuous endpoints: 
 The multiple imputation (MI) with analysis of covariance (ANCOVA) model 
will be used for analysis. Missing data from the FAS will be imputed 40 times 
to generate a complete dataset at each imputation by using the MI Statistical 
Analysis System (SAS) procedure. These complete datasets will be analyzed 
using an ANCOVA model with treatment, randomization strata (region and 
weight group) and relevant baseline included in the model, and the SAS 
MIANALYZE procedure will be used to generate valid statistical inferences 
by combining results from these multiple analyses using Rubin’s formula. 
 To account for the impact of rescue treatment on the efficacy effect: If a 
patient receives rescue treatment, the efficacy data collected after rescue 
treatment is initiated will be treated as missing.  
 In addition to the MI method described previously, sensitivity analyses such 
as ANCOVA model with LOCF and MI method with ANCOVA model on all 
observed data regardless of rescue use will be conducted. Additional details 
on these sensitivity analyses will be provided in the statistical analysis plan 
(SAP).  
Multiplicity Consideration 
A hierarchical procedure for multiplicity adjustment will be used to control the 
overall Type-1 error rate at 0.05 for the primary endpoint and the secondary 
endpoints across the 2 dupilumab dose regimens. The hierarchical testing 
procedure at the 2-sided 0.05 significance level will be used for all comparisons 
with the placebo.  
Safety Analyses 
Safety analysis will be based on the SAF. This includes reported TEAEs and 
other safety information (eg, clinical laboratory evaluations, vital signs, and 
12-lead ECG results). 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................8 
1. 
INTRODUCTION ......................................................................................................24 
2. 
STUDY OBJECTIVES ..............................................................................................27 
2.1. 
Primary Objective .......................................................................................................27 
2.2. 
Secondary Objectives .................................................................................................27 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................28 
3.1. 
Hypothesis ..................................................................................................................28 
3.2. 
Rationale .....................................................................................................................28 
3.2.1. 
Rationale for Study Design .........................................................................................28 
3.2.2. 
Rationale for Dose Selection ......................................................................................29 
3.2.3. 
Safety Considerations .................................................................................................32 
3.2.4. 
Risk/Benefits of Participating in the Study ................................................................33 
3.2.4.1. 
Benefits .......................................................................................................................33 
3.2.4.2. 
Risks ...........................................................................................................................33 
3.2.4.3. 
Risk/Benefit Conclusion .............................................................................................33 
4. 
STUDY VARIABLES................................................................................................34 
4.1. 
Demographic and Baseline Characteristics ................................................................34 
4.2. 
Primary and Secondary Endpoints..............................................................................34 
4.2.1. 
Primary Endpoint ........................................................................................................34 
4.2.2. 
Secondary Endpoints ..................................................................................................34 
4.2.3. 
Other Endpoints and Assessments ..............................................................................35 
4.3. 
Pharmacokinetic Variables .........................................................................................35 
4.4. 
Anti-Drug Antibody Variables ...................................................................................35 
5. 
STUDY DESIGN .......................................................................................................36 
5.1. 
Study Description and Duration .................................................................................36 
5.1.1. 
End of Study Definition ..............................................................................................39 
5.2. 
Planned Interim Analysis ............................................................................................39 
5.3. 
Study Committees .......................................................................................................39 
5.3.1. 
Independent Data Monitoring Committee ..................................................................39 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............40 
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6.1. 
Number of Patients Planned .......................................................................................40 
6.2. 
Study Population .........................................................................................................40 
6.2.1. 
Inclusion Criteria ........................................................................................................40 
6.2.2. 
Exclusion Criteria .......................................................................................................41 
6.3. 
Premature Withdrawal from the Study .......................................................................45 
6.4. 
Replacement of Patients .............................................................................................45 
7. 
STUDY TREATMENTS............................................................................................46 
7.1. 
Investigational and Reference Treatments ..................................................................46 
7.2. 
Background Treatment ...............................................................................................47 
7.3. 
Rescue Treatment .......................................................................................................48 
7.4. 
Dose Modification and Study Drug Discontinuation Rules .......................................48 
7.4.1. 
Dose Modification ......................................................................................................48 
7.4.2. 
Study Drug Discontinuation .......................................................................................49 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................49 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................49 
7.5. 
Management of Acute Reactions ................................................................................50 
7.6. 
Method of Treatment Assignment ..............................................................................50 
7.6.1. 
Blinding ......................................................................................................................50 
7.6.2. 
Emergency Unblinding ...............................................................................................51 
7.7. 
Treatment Logistics and Accountability .....................................................................51 
7.7.1. 
Packaging, Labeling, and Storage ..............................................................................51 
7.7.2. 
Supply and Disposition of Treatments .......................................................................51 
7.7.3. 
Treatment Accountability ...........................................................................................51 
7.7.4. 
Treatment Compliance ................................................................................................52 
7.8. 
Concomitant Medications and Procedures .................................................................52 
7.8.1. 
Prohibited Medications and Procedures .....................................................................52 
7.8.2. 
Permitted Medications and Procedures ......................................................................53 
7.9. 
Continuation of Dupilumab Treatment in an Open-Label Extension Study ..............53 
8. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS.........................53 
8.1. 
Schedule of Events .....................................................................................................53 
8.1.1. 
Footnotes for Schedule of Events Table .....................................................................61 
8.1.1.1. 
Footnotes for Schedule of Events Table 1 ..................................................................61 
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8.1.1.2. 
Footnotes for Schedule of Events Table 2 ..................................................................62 
8.1.2. 
Early Termination Visit ..............................................................................................63 
8.1.3. 
Unscheduled Visits .....................................................................................................63 
8.2. 
Study Procedures ........................................................................................................63 
8.2.1. 
Procedures Performed only at the Screening/Baseline Visit ......................................63 
8.2.2. 
Efficacy Procedures ....................................................................................................63 
8.2.2.1. 
Patient Assessment of Pruritus Using Worst Itch Scale .............................................64 
8.2.2.2. 
Patient Global Impression of Disease .........................................................................64 
8.2.2.3. 
Patient Global Impression of Change .........................................................................65 
8.2.2.4. 
Children's Dermatology Life Quality Index ...............................................................65 
8.2.2.5. 
Patient Oriented Eczema Measure ..............................................................................66 
8.2.2.6. 
Dermatitis Family Index .............................................................................................66 
8.2.2.7. 
Faces Pain Scale – Revised .........................................................................................67 
8.2.2.8. 
PROMIS Anxiety and Depression Scale ....................................................................67 
8.2.2.9. 
Investigator’s Global Assessment ...............................................................................68 
8.2.2.10. 
Eczema Area and Severity Index ................................................................................68 
8.2.2.11. 
Global Individual Signs Score ....................................................................................68 
8.2.2.12. 
SCORing Atopic Dermatitis .......................................................................................69 
8.2.2.13. 
Body Surface Area Involvement of Atopic Dermatitis ..............................................69 
8.2.2.14. 
Assessment of Missed School Days ...........................................................................69 
8.2.2.15. 
Caregiver Assessment of Missed Workdays ..............................................................70 
8.2.2.16. 
Atopic Dermatitis Area Photographs ..........................................................................70 
8.2.2.17. 
Topical Corticosteroids Accountability ......................................................................70 
8.2.3. 
Safety Procedures .......................................................................................................70 
8.2.3.1. 
Vital Signs ..................................................................................................................70 
8.2.3.2. 
Body Weight and Height ............................................................................................70 
8.2.3.3. 
Physical Examination .................................................................................................71 
8.2.3.4. 
Electrocardiogram .......................................................................................................71 
8.2.3.5. 
Laboratory Testing ......................................................................................................71 
8.2.3.6. 
Ophthalmological Examinations ................................................................................72 
8.2.4. 
Pharmacokinetic and Antibody Procedures ................................................................73 
8.2.4.1. 
Drug Concentration Measurements and Samples .......................................................73 
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8.2.4.2. 
Anti-Drug Antibody Measurements and Samples ......................................................73 
8.2.5. 
Biomarker Procedures ................................................................................................73 
 
 
 
 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................74 
9.1. 
Obligations of Investigator .........................................................................................74 
9.2. 
Obligations of Sponsor ...............................................................................................74 
9.3. 
Definitions ..................................................................................................................75 
9.3.1. 
Adverse Event .............................................................................................................75 
9.3.2. 
Serious Adverse Event ................................................................................................75 
9.3.3. 
Adverse Events of Special Interest .............................................................................76 
9.4. 
Recording and Reporting Adverse Events ..................................................................76 
9.4.1. 
Adverse Events ...........................................................................................................76 
9.4.2. 
Serious Adverse Events ..............................................................................................76 
9.4.3. 
Other Events that Require Accelerated Reporting ......................................................77 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................77 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................78 
9.4.6. 
Follow-up ....................................................................................................................78 
9.5. 
Evaluation of Severity and Causality .........................................................................78 
9.5.1. 
Evaluation of Severity ................................................................................................78 
9.5.2. 
Evaluation of Causality ...............................................................................................79 
9.6. 
Safety Monitoring .......................................................................................................79 
9.7. 
Investigator Alert Notification ....................................................................................80 
10. 
STATISTICAL PLAN................................................................................................80 
10.1. 
Statistical Hypothesis ..................................................................................................80 
10.2. 
Justification of Sample Size........................................................................................80 
10.3. 
Analysis Sets ...............................................................................................................81 
10.3.1. 
Efficacy Analysis Sets ................................................................................................81 
10.3.2. 
Safety Analysis Set .....................................................................................................82 
10.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................82 
10.3.4. 
Analysis Set for Anti-Drug Antibody Data ................................................................82 
10.4. 
Patient Disposition ......................................................................................................82 
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10.5. 
Statistical Methods ......................................................................................................82 
10.5.1. 
Demography and Baseline Characteristics .................................................................83 
10.5.2. 
Efficacy Analyses .......................................................................................................83 
10.5.2.1. 
Primary Efficacy Analysis ..........................................................................................83 
10.5.2.2. 
Secondary Efficacy Analysis ......................................................................................84 
10.5.2.3. 
Multiplicity Considerations ........................................................................................84 
10.5.2.4. 
First-Step Analysis......................................................................................................85 
10.5.3. 
Safety Analysis ...........................................................................................................85 
10.5.3.1. 
Adverse Events ...........................................................................................................86 
10.5.3.2. 
Other Safety ................................................................................................................86 
10.5.3.3. 
Treatment Exposure ....................................................................................................87 
10.5.3.4. 
Treatment Compliance ................................................................................................87 
10.5.4. 
Analysis of Drug Concentration Data .........................................................................87 
10.5.5. 
Analysis of Anti-Drug Antibody Data ........................................................................88 
10.5.6. 
Analysis of Biomarker Data .......................................................................................88 
10.6. 
Additional Statistical Data Handling Conventions .....................................................88 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........88 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................89 
11.1. 
Data Management .......................................................................................................89 
11.2. 
Electronic Systems ......................................................................................................89 
12. 
STUDY MONITORING ............................................................................................89 
12.1. 
Monitoring of Study Sites ...........................................................................................89 
12.2. 
Source Document Requirements ................................................................................89 
12.3. 
Case Report Form Requirements ................................................................................90 
13. 
AUDITS AND INSPECTIONS .................................................................................90 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................90 
14.1. 
Good Clinical Practice Statement ...............................................................................90 
14.2. 
Informed Consent .......................................................................................................91 
14.3. 
Patient Confidentiality and Data Protection ...............................................................91 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................92 
15. 
PROTOCOL AMENDMENTS ..................................................................................92 
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16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................92 
16.1. 
Premature Termination of the Study ...........................................................................92 
16.2. 
Close-out of a Site ......................................................................................................93 
17. 
STUDY DOCUMENTATION ...................................................................................93 
17.1. 
Certification of Accuracy of Data ...............................................................................93 
17.2. 
Retention of Records ..................................................................................................93 
18. 
CONFIDENTIALITY ................................................................................................94 
19. 
FINANCING AND INSURANCE .............................................................................94 
20. 
PUBLICATION POLICY ..........................................................................................94 
21. 
REFERENCES ...........................................................................................................95 
22. 
INVESTIGATOR’S AGREEMENT ..........................................................................98 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................109 
 
LIST OF TABLES 
Table 1: 
Schedule of Events (Screening, TCS Standardization, Baseline, and 
Treatment Period) .......................................................................................................54 
Table 2: 
Schedule of Events (Follow-Up Period, Unscheduled Visits, and Early 
Termination) ...............................................................................................................60 
Table 3: 
Preliminary Statistical Hierarchy for Multiplicity Control .........................................85 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................38 
Figure 2: 
Study Flow Diagram ...................................................................................................39 
 
LIST OF APPENDICES 
Appendix 1. 
Factors to Consider in Assessing the Relationship of Adverse Events to 
Study Drug ..........................................................................................................99 
Appendix 2. 
IGA Scale ..........................................................................................................100 
Appendix 3. 
Potential Major Protocol Violations .................................................................102 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS 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 
ARISg 
Pharmacovigilance and clinical safety software system 
AST 
Aspartate Aminotransferase 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CDLQI 
Children’s Dermatology Life Quality Index 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
DFI 
Dermatitis Family Index 
EASI 
Eczema Area and Severity Index 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
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 
HIV 
Human immunodeficiency virus 
IAF 
Informed assent form 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IGA 
Investigator’s Global Assessment 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IL-4Rα 
IL-4 receptor alpha subunit 
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IRB 
Institutional Review Board 
IVRS 
Interactive voice response system  
IWRS 
Interactive web responses system 
LDH 
Lactate dehydrogenase 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
Modified full analysis set 
MI 
Multiple imputation 
NAb 
Neutralizing antibody 
NRS 
Numerical Rating Scale 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
POEM 
Patient Oriented Eczema Measure 
PPS 
Per protocol set 
PROMIS 
Patient Reported Outcomes Measurements Information Systems 
PT 
Preferred term 
QOL 
Quality of life 
QW 
Once a week 
Q2W 
Once every 2 weeks 
Q4W 
Once every 4 weeks 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCORAD 
SCORing Atopic Dermatitis 
SOC 
System organ class 
TARC 
Thymus and activation-regulated chemokine 
TCI 
Topical calcineurin inhibitors 
TCS 
Topical corticosteroids 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
ULN 
Upper limit of normal 
WBC 
White blood cell 
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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 disease affects over 20% of children in many industrialized countries (Deckers 2012).  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 (Kay 1994).  Phase 3 of the International Study of 
Asthma and Allergies in Childhood (ISAAC) showed a 1-year period prevalence rate for AD in 
the 6 to 7 year age group to be 15% or more in Australia, England, and Scandinavia 
(Asher 2006).  A study conducted in the United States (US) in school-going children aged 5 to 
9 years old showed similar prevalence rate of around 17% (Laughter 2000). 
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 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).  The prevalence of 
asthma in children 6 years and older who had developed eczema during the first 4 years of their 
life has been estimated to be around 35% (Van der Hulst 2007).  In a prospective study on 
‘Atopic March’ in which children with eczema during infancy were followed, 47% of patients 
had allergic rhino-conjunctivitis and 29% had asthma (Ekback 2014) by the age of 10 years.  
More severe skin disease is directly correlated with a higher risk of developing comorbidities 
(asthma, allergic rhinitis, food allergy, and mental health disorders) and is associated with more 
severe comorbidities (Silverberg 2013).  The incidence of mental health disorders like anxiety, 
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depression, and Attention Deficit Hyperactivity Disorder (ADHD) is also higher in children with 
AD (Yaghmaie 2013).  The course of the disease in school-going children can be complicated by 
potentially life-threatening complications like eczema herpeticum (Luca 2012). 
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 proinflammation 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. 
There is currently a high unmet medical need for a safe and effective therapy for AD in young 
children.  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.  The more effective TCI products (tacrolimus 0.1%) 
are not approved for use in children aged 6 to 11 years old.  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 (refer to products’ US prescribing 
information). 
Systemic agents are used off-label in children aged 6 to 11 years old (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, cutaneous atrophy, hypertension, osteoporosis, and rebound 
exacerbation after discontinuation (corticosteroids), myelosuppression and hepatotoxicity 
(methotrexate), nephrotoxicity and hypertension (cyclosporine), increased risk of malignancies 
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(cyclosporine, azathioprine), 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 
moderate-to-severe AD in patients intolerant of, or whose disease is not adequately controlled 
with, topical treatments. 
Overall, 7408 subjects have been enrolled into the dupilumab development program (completed 
and ongoing studies) as of 30 September 2016: 222 healthy volunteers, 4182 patients with AD, 
2909 patients with asthma, 60 patients with nasal polyposis, and 35 patients with eosinophilic 
esophagitis. In completed or unblinded studies, 3927 subjects have received dupilumab: 
202 healthy volunteers, 2853 patients with AD, 842 patients with asthma and 30 patients with 
nasal polyposis. Taking into account patients exposed to dupilumab in blinded studies, the total 
number of patients exposed to dupilumab is over 5,000.  
Further, 1 clinical study with dupilumab in the pediatric population has been completed at the 
time of this protocol development; a phase 2 study (R668-AD-1412) investigating the safety, 
pharmacokinetics (PK), immunogenicity, and exploratory efficacy of dupilumab in patients aged 
≥6 to <18 years with AD, and an open-label extension (OLE) study to assess the long-term safety 
and efficacy of dupilumab in patients aged ≥6 to <18 years with AD (R668-AD-1434) is 
ongoing.  A total of 78 pediatric patients were exposed to dupilumab at doses of either 2 mg/kg 
or 4 mg/kg (single dose, weight dependent) followed by 4 weekly doses of 2 mg/kg or 4 mg/kg 
(weight-dependent, once a week [QW] regimen). The safety data gathered from these pediatric 
studies are summarized in Section 3.2.3. 
A total of 1,379 adult patients with moderate-to-severe AD were enrolled in the identically 
designed SOLO 1 and SOLO 2 phase 3 adult studies.  Patients were enrolled if they were not 
adequately controlled with topical medications, or if topical treatment was not medically 
advisable.  Patients were randomized into 1 of 3 treatment groups: dupilumab 300 mg SC QW, 
dupilumab 300 mg SC every 2 weeks (Q2W), or placebo for 16 weeks following an initial 
dupilumab loading dose of 600 mg SC, or placebo.  Results at 16 weeks included the following:   
For SOLO 1 and SOLO 2, respectively, 37% and 36% of patients who received 
dupilumab 300 mg QW, and 38% and 36% of patients who received dupilumab 300 mg 
Q2W, achieved clearing or near-clearing of skin lesions (IGA 0 or 1), compared to 10% 
and 8.5% with placebo (p<0.0001).  This was the primary endpoint of the study in the US 
and one of the primary endpoints in the European Union (EU). 
For SOLO 1 and SOLO 2, respectively, 52.5% and 48% of patients who received 
dupilumab 300 mg QW, and 51% and 44% of patients who received dupilumab 300 mg 
Q2W, achieved EASI-75 compared to 15% and 12% with placebo (p<0.0001).  This was 
the key secondary endpoint in the US and one of the primary endpoints in the EU. 
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For SOLO 1 and SOLO 2, respectively, the percent improvement in Eczema Area and 
Severity Index (EASI) from baseline was 72% and 69% in patients who received the 
300 mg QW dose, and 72% and 67% for patients who received dupilumab 300 mg Q2W, 
compared to 38% and 31% for placebo patients (p<0.0001). 
Nonclinical repeat-dose toxicity studies and reproductive and developmental toxicity studies 
have shown a lack of any general or reproductive toxicology and postnatal effects observed with 
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. 
Dupilumab was shown to be generally well tolerated with a favorable safety profile in concluded 
phase 3 studies in adult patients with moderate-to-severe AD (SOLO 1, SOLO 2).  The overall 
incidence of treatment-emergent adverse events (TEAEs) was similar across all treatment groups 
(300 mg QW, 300 mg Q2W, placebo).  The incidence of any treatment-emergent serious adverse 
event (SAEs) was higher in the placebo groups than in the dupilumab groups.  The incidence of 
any TEAEs leading to permanent treatment discontinuation was similar across all groups.  There 
is no indication that dupilumab treatment increased the incidence of acute allergic reactions 
overall.  The incidence of treatment-emergent adverse events of special interest (AESI) of acute 
allergic reactions requiring treatment was <1% in dupilumab-treated patients and lower than in 
placebo-treated patients.  In the SOLO studies, there was no report of anaphylaxis or serum 
sickness in dupilumab-treated patients.  There was no increase in infections in general, serious 
infections, or any of the infection AESIs with dupilumab compared to placebo.  Further, the 
incidence of severe infection and opportunistic infection AESI was higher in placebo-treated 
patients than in dupilumab-treated patients. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to demonstrate the efficacy of dupilumab administered 
concomitantly with TCS in patients, ≥6 years to <12 years of age, with severe AD. 
2.2. 
Secondary Objectives 
The secondary objective of the study is to assess the safety of dupilumab administered 
concomitantly with TCS in patients ≥6 years to <12 years of age with severe AD. 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
In pediatric patients ≥6 years to <12 years old who are suffering from severe AD that is 
inadequately responsive to topical therapies (TCS with/without TCIs), treatment with dupilumab, 
in addition to TCS, will result in clinically relevant and statistically significant incremental 
benefit versus treatment with TCS alone, as measured by proportion of patients who achieve 
Investigator’s Global Assessment (IGA) score of 0 or 1 (clear or almost clear disease) and 
Eczema Area and Severity Index (EASI)-75 (at least 75% reduction in EASI score from 
baseline). 
3.2. 
Rationale 
3.2.1. 
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 on the use of dupilumab concomitantly with TCS to 
support regulatory approval in patients, ≥6 years to <12 years of age, with severe AD. 
Since TCS represent the mainstay of pharmacological treatment of AD, many patients may use 
dupilumab in combination with TCS.  Hence, the use of topical therapy as background 
medication will allow the study design to reflect more closely the anticipated real-life use of 
dupilumab.  This design seeks to maximize clinical benefit for patients enrolled in the study. 
Although the target population consists of patients who are inadequately responsive to TCS, 
these patients are still expected to receive some benefit from the use of TCS.  Data from phase 3 
studies in adults (R668-AD-1334, R668-AD-1416, and R668-AD-1224) in which dupilumab was 
evaluated both as monotherapy (R668-AD-1334 and R668-AD-1416) and concomitantly with 
TCS (R668-AD-1224) showed that for certain clinical endpoints, the combination regimen was 
more efficacious than monotherapy.  Moreover, this design will also generate data on the 
potential steroid-sparing effect of dupilumab.  
The 16-week treatment duration is the same as in 2 of the adult pivotal trials (R668-AD-1416 
and R668-AD-1334).  This duration has been chosen because it is expected that the vast majority 
of patients will achieve maximum therapeutic effect for dupilumab by this time.  Moreover, in 
previous studies, the selected dupilumab dose regimens have been shown to achieve steady state 
concentration before the end of this period.  The 12-week follow-up period is based on the 
expected PK of dupilumab after the last dose, ie, the time for serum concentrations to decline to 
nondetectable levels (below the lower limit of quantification) in most patients. 
The co-primary endpoints chosen in the study (proportion of patients achieving IGA 0 or 1 and 
proportion of patients with ≥75% reduction in EASI from baseline [EASI-75] at week 16) are the 
same as those used in the adult pivotal studies (R668-AD-1334 and R668-AD-1416).  These 
endpoints are both investigator-assessed outcome measures of objective AD signs, which are 
broadly validated in drug development for this indication.  Based on prior discussions with 
health authorities for the pivotal adult AD studies (R668-AD-1334 and R668-AD-1416), it is 
expected that different health authorities will request different primary endpoints for this study 
(for example, the US Food and Drug Administration (FDA) requested IGA 0/1 as the primary 
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endpoint in the adult AD program while European Medicines Agency (EMA) requested both 
EASI-75 and IGA 0/1 as co-primary endpoints).  Eczema Area and Severity Index has been 
validated in the pediatric population including in patients aged 6 to 11 years old in a prior study 
(Barbier 2004).  These endpoints were included in the Pediatric Investigation Plan and Pediatric 
Study Plan and agreed to by Paediatric Committee and FDA, respectively. 
As the efficacy and safety of dupilumab for the treatment of AD has not yet been established in 
this age group, 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 adverse 
effects in patients randomized to the placebo group: 
 Mandatory requirement for use of concomitant topical corticosteroids 
 Starting on day -14, all patients will initiate a standardized TCS treatment 
regimen with a medium-potency TCS that may be adjusted based on clinical 
response.  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 
(except for very-high-potency TCS, as their use is not recommended in patients 
<12 years of age):  high-potency TCS, systemic corticosteroids, and nonsteroidal 
immunosuppressive drugs 
 Open-Label Extension Study (OLE) 
 Patients who participate in the study may subsequently be eligible to participate in 
an OLE study.  All patients will be offered the opportunity to screen for entry into 
the OLE study at the end of the treatment period (week 16).  Additional details 
concerning eligibility for the OLE can be found in Section 7.9. 
As described in Section 5.3.1, an Independent Data Monitoring Committee (IDMC), will monitor 
patient safety by conducting formal reviews of accumulated safety data on a program-wide level. 
3.2.2. 
Rationale for Dose Selection 
The dose justification for pediatric patients aged ≥6 years to <12 years is based on the observed 
efficacy and safety in the dose ranging study in adult AD patients (R668-AD-1021), the observed 
efficacy and safety in the phase 3 monotherapy studies in adult AD patients (R668-AD-1334 and 
R668-AD-1416), the observed PK data, efficacy and safety results in a pediatric AD study of 
patients ≥6 to <18 years old (R668-AD-1412).  The selection of these dosing regimens is further 
supported by population PK modeling. 
The adult dose-ranging study evaluated dupilumab dose regimens of 300 mg QW, 300 mg Q2W, 
300 mg once every 4 weeks (Q4W), 200 mg Q2W, and 100 mg Q4W versus placebo, 
administered for 16 weeks.  All 5 dose regimens were efficacious.  The mean pharmacodynamic 
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(PD) effect/efficacy of dupilumab (represented by change in EASI, IGA, and Pruritus Numerical 
Rating Scale [NRS] scores) at week 16 generally aligned in the same rank order as the total 
monthly dose and the mean concentrations of functional dupilumab at week 16.  Thus, the 
300 mg QW regimen was consistently the most efficacious dose regimen in this study across 
multiple endpoints, followed closely by the 300 mg Q2W dose regimen.  Differences in the 
efficacy and safety outcomes between the 300 mg QW and 300 mg Q2W were relatively small.  
The 200 mg Q2W and 300 mg Q4W doses also showed good efficacy responses but were 
numerically inferior to the 300 mg Q2W and 300 mg QW regimens for the majority of efficacy 
endpoints. The efficacy of the 100 mg Q4W regimen (100 mg total monthly dose) appeared to be 
sub-optimal 
Study R668-AD-1412 was a phase 2a, multicenter, open-label, ascending-dose, sequential-cohort 
study investigating the safety, tolerability, PK, immunogenicity, and efficacy of single-dose and 
repeat-doses of dupilumab administered SC in pediatric patients with moderate to severe AD (for 
adolescents ≥12 to <18 years old) or severe AD (for school-going children ≥6 to <12 years old) 
that was not adequately controlled with topical treatments.  The 2 assessed dose regimens at 
2 mg/kg and 4 mg/kg correspond to the weight normalized dose in adults at 150 mg and 300 mg, 
respectively.  Dupilumab administered as single and repeated weekly doses of 2 mg/kg and 
4 mg/kg for 4 weeks was generally well tolerated with an acceptable safety profile in both 
pediatric age groups included in that study.  There was a higher incidence of TEAEs following 
single and repeated weekly administration of 4 mg/kg compared to 2 mg/kg in both age-groups. 
This was driven by a higher incidence of nasopharyngitis and skin infections in the 4 mg/kg dose 
arm versus the 2 mg/kg dose arm.  However, most of the adverse events (AEs) were mild in 
intensity, transient in nature, and not related to study drug.  The most common AE reported after 
both single doses and repeated weekly doses was nasopharyngitis. 
In children aged ≥6 to <12 years, dupilumab administered as a single dose of either 2 mg/kg or 
4 mg/kg, in the study R668-AD-1412, induced a significant and rapid reduction of disease 
activity in patients at week 2 (37% and 33% reduction in EASI score from baseline for 2 mg/kg 
and 4 mg/kg doses, respectively).  Repeated weekly doses of dupilumab led to a further 
improvement in disease severity in patients in both dose groups (76% and 63% reduction in 
EASI score from baseline for 2 mg/kg and 4 mg/kg doses, respectively, at week 12).  There did 
not appear to be a clear dose response, as the 2 dose groups showed similar efficacy on the 
various endpoints evaluated during the study.  The small sample size may have limited the 
precision of this study, but these data are consistent with saturation of the IL-4 receptor after 
4 weekly doses of either 2 mg/kg or 4 mg/kg. 
The collective clinical data on the exposure versus efficacy and safety in the adults and pediatric 
population as observed to date supports a similar exposure-response relationship for efficacy and 
safety between the adult and pediatric populations down to 6 years of age and justify the 
approach of selecting dose regimens for this study based on the criteria of matching adult 
exposure. 
To account for body size difference in the pediatric population and taking into account the 
observed large therapeutic indices of dupilumab, a tiered fixed dosing regimen was chosen over 
weight based (mg/kg) dosing for ongoing development.  This approach reduces the risk of dosing 
errors that can occur with weight-based dosing, as well as allowing for dosing convenience by 
simplifying administration using a prefilled syringe/device. 
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A population PK model was used to describe the exposure of dupilumab in the population 
identified in this protocol.  This model, initially based on drug concentration data from studies 
conducted in adults, was further informed by the exposure data of the study(s) conducted in 
pediatric patients (R668-AD-1412).  The PK modeling for dupilumab has shown weight to be the 
most important covariate influencing exposure, with exposure being inversely correlated with 
body weight.  Outside of the effect of body weight on PK, the existing data do not suggest an 
age-related effect on exposure. 
Data gathered from NHANES (n=1269) show that median weight in the children aged 6 
to11 years old is = 32 kg (Q1=25, Q3=42).  Simulations from the PK model suggest that the 
adult dose regimens (300 mg QW and 300 mg Q2W) may lead to systemic exposure in these 
children that is greater than the maximum exposure observed in adults.  Hence, these doses are 
not supported by the safety data obtained in adults and will not be studied in children. 
For the 200 mg Q2W regimen in children aged ≥6 to <12 years old who weigh >30 kg, the 
simulated exposure substantially overlaps with the efficacious exposure in adults from studies 
R668-AD-1021, R668-AD-1334, R668-AD-1416 and R668-AD-1224 (300 mg Q2W and QW). 
In addition, in study DRI12544 (a phase 2b study in patients with moderate to severe 
uncontrolled asthma) (300 mg Q2W) a strongly positive benefit-risk was identified.  Hence, the 
proposed 200 mg Q2W dosing regimen for children aged ≥6 to <12 years old weighing >30 kg is 
expected to have a significant clinical benefit with an appropriate safety profile, under the 
assumption that PK/PD relationship is similar in pediatrics and adult patients. 
A dose regimen of 100 mg Q2W SC has not been evaluated to date in the dupilumab program. 
However, based on simulations from the PK model, the use of 100 mg Q2W is expected to 
provide mean exposure in children ≥6 to <12 years old who weigh <30 kg that is similar to that 
for 200 mg Q2W in children >30 kg, thereby supporting the use of this regimen in the lower 
weight group.  Moreover, the 100 mg dose can be delivered using a lower volume of injection. 
Since volume of injection has been shown to be an important factor impacting the tolerability of 
SC injections (Heise 2014), the smaller injection volume associated with the100 mg injection 
may offer some advantage in this population.  
The 300 mg Q4W regimen was chosen to be included as a dosing option with less frequent 
injections.  With this regimen, in children ≥6 to <12 years old and weight >30 kg, simulated 
dupilumab exposure at steady-state, specifically Cmax, Ctrough, and weekly area under the curve 
(AUC) were lower than for the 200 mg Q2W.  Study R668-AD-1021 demonstrated that efficacy 
for the 300 mg Q4W regimen was statistically superior to placebo in adults.  Pharmacokinetic 
simulations have shown that in children with weight >30 kg, the steady-state exposure was 
higher for the 300 mg Q4W regimen than in adults with the same regimen, but is not expected to 
exceed that for adults receiving 300 mg Q2W.  
In children with weight <30 kg, simulated mean weekly AUC at steady-state for the 300 mg 
Q4W regimen was similar to that in adults receiving 300 mg Q2W, while Cmax was higher and 
Ctrough was lower.  Data gathered from this dose regimen will enable PK/PD modeling to better 
characterize the exposure-response relationship in pediatric patients.  A less frequent dosing 
regimen is expected to enhance compliance, especially in a pediatric population. 
The administration of the loading dose of dupilumab will allow systemic concentrations to reach 
effective concentrations faster, and potentially reduce the time to onset of clinical effect. 
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3.2.3. 
Safety Considerations 
R668-AD-1412 was a phase 2 study to evaluate the PK and safety of dupilumab in patients aged 
≥6 years to <18 years, with moderate-to-severe AD.  Dupilumab administered as single and 
repeated weekly doses of 2 mg/kg and 4 mg/kg for 4 weeks was generally well tolerated with an 
acceptable safety profile in both pediatric age groups (12 to 17 years old and 6 to 11 years old) 
included in this study.  There was a higher incidence of TEAEs after administration of a single 
dose of 4 mg/kg as compared to 2mg/kg dose in both age-groups.  Similarly, there was a higher 
incidence of TEAEs after administration of repeated weekly doses of 4 mg/kg as compared to 
repeated weekly doses of 2 mg/kg in both age-groups.  This was driven by a higher incidence of 
nasopharyngitis and skin infections in the 4 mg/kg as compared to 2 mg/kg dose arm.  The most 
common AE reported after both single doses and repeated weekly doses was nasopharyngitis. 
In children 12 to <18 years old, there were 2 SAEs reported in each dose group (in the 2 mg/kg 
group, the SAEs reported were palpitations and infected AD; in the 4 mg/kg group, the SAEs 
reported were staphylococcal skin infection and infected AD).  In children 6 to 11 years old, 
2 patients in the 4 mg/kg dose group had serious TEAEs (2 events of exacerbation of AD, septic 
arthritis of the hip joint, and infected AD).  None of these serious TEAEs was assessed by the 
investigators as drug-related.  The events of infected AD and staphylococcal skin infections 
occurred in patients who were not being treated with dupilumab at time of onset of the SAE 
(patients were either in follow-up period of part A or in follow-up period of part B).  It is well 
known that a very high proportion of patients with AD have skin colonization (Ong 2010) and 
patients with AD are prone to developing skin infections.  Dupilumab, by treating AD, should 
lead to a reduction in skin infections.  This is supported by data from phase 3 trials in adults with 
AD in which the incidence of serious and severe infections was numerically higher in the 
placebo group as compared to dupilumab (0.5% to 1% dupilumab and 2% to 3% placebo). 
Positive anti-drug antibody (ADA) was observed in 50 patients (64.9 %) at any time, 31 of which 
(40.3% out of total) were categorized as persistent treatment-emergent ADA.  The rate of 
occurrence of persistent ADA were similar across cohorts with a trend of higher rates in the 
adolescents compared with school-going children.  Six patients (12.0%) had high titers 
(>10,000), 4 from the 2 mg/kg groups and 2 from 4 mg/kg groups.  Within each age group, there 
also seemed to be a trend for higher incidence of persistent ADA in lower dose cohorts as 
compared to higher dose cohorts.  Dupilumab concentrations in patients with high titers were 
markedly reduced compared to those with a negative response, or low or moderate titers.  These 
patients had an inferior clinical response to the study drug as compared to the overall study 
population.  The high titer ADAs were not associated with any systemic symptoms of 
hypersensitivity in these patients, although one of these patients did experience an injection site 
reaction, which was mild in intensity. 
Standard safety monitoring used in previous trials with dupilumab is planned to be conducted 
during this study.  An internal safety monitoring team will be reviewing blinded data at regular 
intervals during the study to monitor the safety of patients.  An Independent Data Monitoring 
Committee (IDMC) overseeing the entire dupilumab clinical development 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 the safety of the patients. 
Additional information can be found in the Investigator’s Brochure. 
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3.2.4. 
Risk/Benefits of Participating in the Study 
3.2.4.1. 
Benefits 
The efficacy and safety of dupilumab in adults was evaluated in 4 randomized, double-blind, 
placebo-controlled studies and 1 dose-ranging study in patients with moderate-to-severe atopic 
dermatitis.  In all studies, dupilumab treatment consistently reduced both the extent and severity 
of lesions as well as the severity of pruritus. 
The first clinical study of dupilumab in pediatric patients aged 6 years to <18 years old has been 
completed (R668-AD-1412).  Dupilumab administered as single and repeated weekly doses 
provided significant clinical benefit to pediatric patients in both age groups (6 years to 11 years 
and 12 to <18 years) consistent with that observed in adults. 
3.2.4.2. 
Risks 
Of the adverse drug reactions identified in the dupilumab adult AD clinical program, injection 
site reactions were very common (≥10%).  Common adverse reactions (≥1% and <10%) included 
conjunctivitis, allergic conjunctivitis, eye pruritus, blepharitis, oral herpes, eosinophilia, and 
headache. 
Serum sickness and serum sickness-like reactions occurred very rarely (<0.01%) (Dupixent 
[SmPC], 2017). 
In the pediatric trial, the safety profile was consistent with that reported in adults.  There were no 
new safety signals detected with dupilumab in the pediatric population. 
One serious case each of serum sickness and serum sickness-like reaction (both associated with 
high ADA titers) were reported in adult AD studies.  Additionally, there has been 1 report of 
anaphylaxis considered related to study drug by the investigator in an asthma study (Dupilumab 
[Investigator Brochure, 2017].  No AEs of systemic hypersensitivity were reported in the 
pediatric study.  In study R668-AD-1652, patients will be monitored at the trial site 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. 
A higher incidence of conjunctivitis-related events has been observed in dupilumab-treated 
subjects as compared to placebo in the AD studies.  A predominant number of these cases were 
non-serious, mild to moderate in severity, reported recovered/recovering during the active study 
periods, and infrequently led to study drug discontinuation.  Neither a consistent dose response 
nor a consistent time to onset of these events have been observed. 
Similarly, a higher incidence of injection site reactions has been observed in the dupilumab 
treated subjects, consistent with the subcutaneous injection of a protein biologic.  There have 
been no serious events of ISR, and these events have infrequently led to study drug 
discontinuation (Dupilumab [Investigator Brochure, 2017]). 
3.2.4.3. 
Risk/Benefit Conclusion 
The safety data available to date, in conjunction with the risk monitoring and mitigation 
strategies in the study protocol, and the clinical benefit of dupilumab demonstrated in multiple 
AD studies, support a favorable benefit-risk profile for dupilumab. 
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4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc.), 
disease characteristics including medical history (including asthma), and medication history for 
each patient. 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
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 EMA and EMA 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 
4.2.2. 
Secondary Endpoints 
The key secondary endpoints are: 
 Proportion of patients with EASI-75 (≥75% improvement from baseline) at week 16 
(this is not a secondary endpoint for ex-US countries as it is already a co-primary 
endpoint) 
 Percent change in EASI score from baseline to week 16 
 Percent change from baseline to week 16 in weekly average of daily worst itch score 
Other secondary endpoints are: 
 Change from baseline to week 16 in weekly average of daily worst itch score 
 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 Body Surface Area (BSA) affected by 
AD 
 Percent change from baseline to week 16 in Scoring Atopic Dermatitis (SCORAD) 
 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 at week 16 
 Time to onset of effect on pruritus during the 16-week treatment period (≥4 point 
reduction of weekly average of daily worst itch score from baseline) 
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 Time to onset of effect on pruritus during the 16-week treatment period (≥3 point 
reduction of weekly average of daily worst itch score from baseline) 
 Change from baseline to week 16 in Children’s Dermatology Life Quality Index 
(CDLQI) 
 Change from baseline to week 16 in Patient Oriented Eczema Measure (POEM) 
 Change from baseline to week 16 in Dermatitis Family Index (DFI) 
 Change from baseline to week 16 in Patient Reported Outcomes Measurements 
Information Systems (PROMIS) pediatric anxiety short form scale score 
 Change from baseline to week 16 in PROMIS pediatric depressive symptoms short 
form scale score 
 Topical treatment for AD – proportion of TCS medication-free days from baseline to 
week 16 
 Mean weekly dose of TCS in grams for low- and medium-potency TCS from baseline 
to week 16 
 Mean weekly dose of TCS in grams for high-potency TCS from baseline to week 16 
 Incidence of skin-infection TEAEs (excluding herpetic infections) through week 16 
 Incidence of serious TEAEs through week 16  
4.2.3. 
Other Endpoints and Assessments 
Other endpoints and assessments, as applicable, will be specified in the statistical analysis plan 
(SAP). 
4.3. 
Pharmacokinetic Variables 
Concentration of functional dupilumab in serum at each time point will be considered to be 
trough values (Ctrough.timepoint). 
4.4. 
Anti-Drug Antibody Variables 
Anti-drug (dupilumab) antibody variables include status (positive or negative) and titer as 
follows:  
 Total number of patients negative in ADA assay at all time 
 Total number of patients positive in ADA assay at any time 
 Total number of patients with preexisting immunoreactivity – defined as either an ADA 
positive response in the assay at baseline with all post-baseline ADA results negative, or 
a positive response at baseline with all post-baseline ADA titer <4-fold over baseline titer 
level 
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 Total number of patients with treatment-emergent ADA response in ADA assay – defined 
as a positive response in the ADA assay post-first dose, when baseline results are 
negative, or missing. The treatment-emergent responses will be further characterized into 
the following categories: 
 Persistent ADA response – a treatment-emergent ADA positive response with 
2 or more consecutive positives in the ADA assay separated by greater than a 
12-week period, with no ADA negative samples in between 
 Transient ADA response – a treatment-emergent ADA positive response that is 
not considered persistent or indeterminate 
 Indeterminate ADA response – a treatment-emergent ADA positive response with 
only the last collected sample positive in the ADA assay 
 Total number of patients with a treatment-boosted response – defined as a positive 
response in the ADA assay post first dose that is ≥4-fold over baseline titer levels when 
baseline results are positive 
 Titer value category 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
Anti-drug antibody positive samples will be further characterized for the presence of neutralizing 
antibody (NAb) response: 
 Total number of patients positive in the NAb assay at the time points analyzed. 
5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This is a randomized, double-blind, placebo-controlled, parallel-group study in which study 
treatments 
(dupilumab/placebo) 
will 
be 
administered 
concomitantly 
with 
TCS.  
Approximately330 study patients are planned to be enrolled in the study. 
The study will consist of the following periods (Figure 2):  
1. Screening of up to 9 weeks, 
2. TCS standardization period of 2 weeks,  
3. Treatment period of 16 weeks, and  
4. Follow-up of 12 weeks (for patients who do not enter the OLE) 
After the parents or legal guardians provide informed consent and patients provide assent, the 
patients will be assessed for study eligibility at the screening visit.  During the screening period, 
systemic treatments for AD will be washed out, as applicable, according to the eligibility 
requirements (provided in Section 6.2.1 and Section 6.2.2).  The use of TCS (±TCI) will be 
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permitted at the discretion of the investigator during the screening period until day -14. Starting 
on day -14, all patients will initiate a standardized TCS treatment regimen according to the 
guidelines in Section 7.2.  Patients may be rescreened, unless the reason for the screen failure is 
related to failing the disease severity inclusion criteria. Patients should apply moisturizers twice 
daily for at least 7 days before randomization. 
Patients  who continue to meet eligibility criteria at baseline will undergo day 1/baseline 
assessments and will be randomized in a 1:1:1 ratio stratified by baseline body weight (<30 kg 
and ≥30 kg) (Figure 1) and region (North America, Europe) as follows:   
 dupilumab Q2W treatment group:   
 Patients with baseline weight <30 kg will receive Q2W SC injections of 100 mg 
dupilumab (0.7 mL of a 150 mg/mL solution) from week 2 to week 14, following 
a loading dose of 200 mg on day 1.  
 Patients with baseline weight ≥30 kg will receive Q2W SC injections of 200 mg 
dupilumab (1.14 mL of a 175 mg/mL solution) from week 2 to week 14, 
following a loading dose of 400 mg on day 1  
 dupilumab Q4W treatment group:  all patients regardless of weight will receive Q4W 
SC injections of 300 mg dupilumab (2 mL of a 150 mg/mL solution) from week 4 to 
week 12, following a loading dose of 600 mg on day 1.  
 placebo treatment group: Patients will receive matching placebo (including doubling 
the amount of placebo on day 1 to match the loading dose).  In order to maintain 
blinding, the patients in the <30 kg weight stratum will be randomly assigned to 
receive, in a 1:1 ratio, either Q2W SC injections of placebo (0.7 mL) matching the 
100 mg dupilumab (including doubling the amount of placebo on day 1 to match the 
loading dose) or Q4W SC injections of placebo (2 mL) matching the 300 mg 
dupilumab (including doubling the amount of placebo on day 1 to match the loading 
dose).  In the ≥30 kg weight stratum, the patients randomized to the placebo group 
will receive, in a 1:1 ratio, either Q2W SC injections of placebo (1.14 mL) matching 
the 200 mg dupilumab (including doubling the amount of placebo on day 1 to match 
the loading dose) or Q4W SC injections of placebo (2 mL) matching the 300 mg 
dupilumab (including doubling the amount of placebo on day 1 to match the loading 
dose).   
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Figure 1: 
Study Design 
 
Arm A consists of patients receiving Q2W treatment, either 100 mg for patients weighing <30 kg or 200 mg for 
patients weighing ≥30 kg. Arm B consists of patients receiving Q4W treatment , 300 mg regardless of weight. 
Arm C consists of patients receiving placebo treatment Q2W and Q4W and matching the dupilumab Q2W and Q4W 
dose regimens. 
During the treatment period, patients will have weekly in-clinic visits through week 4, and then 
in-clinic visits Q4W through week 16 with weekly telephone visits in between the in-clinic 
visits.  Parents/caregivers will be trained on injecting study drug during in-clinic visit 3 (day 1), 
visit 5 (week 2), and visit 7 (week 4) (this only applies to patients who will receive Q2W 
treatment during the study).  During weeks in which no in-clinic visit is scheduled, the 
parent/caregiver will administer study drug to the patient. In case the parent/caregiver does not 
want to administer study drug to patient, they may have the clinic staff administer all the study 
drug injections in the clinic.  Safety, laboratory, and clinical assessments will be performed at 
specified clinic visits, as noted in Table 1.  The end of treatment period visit will occur at 
week 16, two weeks after the last dose of study drug for patients randomized to the Q2W 
treatment group or placebo Q2W group, and 4 weeks after the last dose of study drug for patients 
randomized to the Q4W treatment or placebo Q4W group.  The co-primary endpoints will be 
assessed at this visit.  If patients prematurely discontinue study treatment, the patients will be 
encouraged to stay in the study to have data collected at all remaining scheduled visits until 
completion of the planned end of study visit.  Patients who participate in the study may 
subsequently be eligible to participate in an OLE study.  All patients will be offered the 
opportunity to screen for entry into the OLE study at the end of the treatment period (week 16).  
Patients who decline to enroll in the OLE study or those who fail eligibility criteria for the OLE 
study will have a 12-week follow-up period.  For these patients, after week 16, follow-up visits 
will occur every 4 weeks from week 20 to week 28.  During the follow-up period, patients will 
be monitored for safety and tolerability and have laboratory and clinical assessments as noted in 
Table 2. 
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Figure 2: 
Study Flow Diagram 
 
D = study day; W = study week 
Note:  The length of the screening period is not fixed, but the screening period and TCS standardization must not 
exceed 77 days.  The length of the TCS standardization period is fixed at 14 days. 
1 For patients who enter the OLE, week 16 is the end of study. 
5.1.1. 
End of Study Definition 
The end of study definition is defined as the last visit for the last patient. 
5.2. 
Planned Interim Analysis 
No interim analysis with alpha spending is planned for this study.  An unblinded first-step 
analysis may be performed once all patients in the study 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 first-step analysis will be considered the final 
analysis for the primary and secondary efficacy endpoints.  A description of the statistical 
methods to be employed and blinding implications are in Section 10.5.2.4.  
5.3. 
Study Committees  
5.3.1. 
Independent Data Monitoring Committee 
An IDMC, composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety by conducting formal reviews of accumulated safety 
data that will be blinded by treatment group; if requested, the IDMC may have access to the 
treatment allocation code or 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 also institute any measures that may be required for ensuring the integrity of the study 
results during the study execution. 
All activities and responsibilities of the IDMC are described in the IDMC charter. 
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6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 330 patients are planned to be enrolled at multiple sites in the US and EU into 
3 groups (at 1:1:1 ratio):  dupilumab Q2W treatment group (100 mg Q2W or 200 mg Q2W), 
dupilumab Q4W treatment group (300 mg Q4W), or placebo group (Q2W or Q4W). 
6.2. 
Study Population 
The study population includes pediatric patients (aged ≥6 to <12 years at the time of screening) 
who have severe AD that cannot be adequately controlled with topical AD medications.  
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female ≥6 to <12 years of age at time of screening visit 
2. Diagnosis of AD according to the American Academy of Dermatology consensus criteria 
(Eichenfield 2003) at screening visit 
3. Chronic AD diagnosed at least 1 year prior to the screening visit 
4. IGA = 4 at screening and baseline visits 
5. EASI ≥21 at the screening and baseline visits 
6. BSA ≥15% at screening and baseline visits 
7. Baseline worst itch score weekly average score for maximum itch intensity ≥4 
NOTE: Baseline worst itch average score for maximum itch intensity will be determined 
based on the average of daily worst itch scores for maximum itch intensity (the daily 
score ranges from 0 to 10) during the 7 days immediately preceding randomization. A 
minimum of 4 daily scores out of the 7 days is required to calculate the baseline average 
score.  A complete daily score consists of answers to both questions.   
 “What was the worst itch you had today?” 
 “What was the worst itch you had last night?” 
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 
postponed until this requirement is met, but without exceeding the 77-day maximum 
duration for screening plus TCS standardization. 
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8. With documented recent history (within 6 months before the baseline visit) of inadequate 
response to topical AD medication(s).  For more information, see the note below. 
NOTE: 
 Inadequate response is defined as failure to achieve and maintain remission or a low 
disease activity state (comparable to IGA 0=clear to 2=mild) despite treatment with a 
daily regimen of TCS of medium to high potency (±TCI as appropriate), applied for 
at least 28 days  
 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, applied for at least 28 days during the screening 
period (including the 2 weeks TCS standardization period). Patients who demonstrate 
inadequate response during this period, as defined above, will be eligible for inclusion 
in the study, as long as they meet other eligibility criteria. 
9. At least 11 (of a total of 14) applications of a stable dose of topical emollient 
(moisturizer) twice daily during the 7 consecutive days immediately before the baseline 
visit  
10. Willing and able to comply with all clinic visits and study-related procedures 
11. Patient, either alone or with help of parents/legal guardians, as appropriate, must be able 
to understand and complete study-related questionnaires 
12. Parent or legal guardian must provide signed informed consent. Patients must also 
provide separate informed assent to enroll in the study, and sign and date either a separate 
informed assent form (IAF) or the informed consent form (ICF) signed by the 
parent/legal guardian (as appropriate based on local regulations and requirements) 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Participation in a prior dupilumab clinical study 
2. Treatment with a systemic investigational drug before 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 
3. Treatment with a topical investigational drug within 2 weeks prior to the baseline visit 
4. Treatment with crisabarole within 2 weeks prior to the baseline visit 
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5. History of important side effects of medium-potency topical corticosteroids 
(eg, intolerance to treatment, hypersensitivity reactions*, significant skin atrophy, 
systemic effects), as assessed by the investigator or patient’s treating physician  
* If a patient has a history of hypersensitivity reaction to any particular TCS, 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 
TCS drug product that does not have cross-reactivity to the drug product that caused the 
hypersensitivity. 
6. Treatment with a TCI within 2 weeks prior to the baseline visit 
7. Having used any of the following treatments within 4 weeks before the baseline visit, or 
any condition that, in the opinion of the investigator, is likely to require such treatment(s) 
during the first 4 weeks of study treatment: 
a. Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, 
cyclosporine, mycophenolate-mofetil, interferon gamma, Janus kinase inhibitors, 
azathioprine, methotrexate, etc) 
b. Phototherapy for AD 
8. 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 before the baseline visit, 
whichever is longer 
9. 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 
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: 
 Patients for whom administration of live (attenuated) vaccine can be safely postponed 
would be eligible to enroll into the study. 
 Patients who have their vaccination preponed can enroll in the study only after a gap 
of 4 weeks following administration of the vaccine. 
10. Planned or anticipated use of any prohibited medications and procedures during study 
treatment 
11. Body weight <15 kg at baseline 
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12. 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) 
13. Regular use (more than 2 visits per week) of a tanning booth/parlor within 8 weeks of the 
baseline visit 
14. 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 
15. 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, other 
mycobacterial infections, 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 
16. 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. 
17. Known history of human immunodeficiency virus (HIV) infection or HIV seropositivity 
at the screening visit 
18. With an established diagnosis of hepatitis B viral infection at the time of screening or is 
positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) at 
the time of screening 
NOTE: Patients who have gained immunity for hepatitis B virus infection after 
vaccination (patients who are HBsAg negative, hepatitis B surface antibody [HBsAb] 
positive, and HBcAb negative) are eligible for the study.  
19. With an established diagnosis of hepatitis C viral infection at the time of screening or is 
positive for hepatitis C antibody at the screening visit 
20. 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  
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21. Presence of any 1 or more of the following abnormalities in laboratory test results at 
screening: 
 Platelets ≤100 × 103/μL 
 Neutrophils <1.5 × 103/μL 
 Creatine phosphokinase (CPK) >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. Only if the repeat test confirms the abnormality, the patient 
would be categorized as a screen failure. 
22. 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. 
23. History of malignancy before the baseline visit 
24. 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 
25. Severe concomitant illness(es) that, in the investigator’s judgment, would adversely 
affect the patient’s participation in the study. Examples include, but are not limited to 
patients with short life expectancy, patients with uncontrolled diabetes (hemoglobin A1c 
≥9%), patients with cardiovascular conditions (eg, Class III or IV cardiac failure 
according to the New York Heart Association classification), severe renal conditions (eg, 
patients on dialysis), hepato-biliary conditions (eg, Child-Pugh class B or C), 
neurological conditions (eg, demyelinating diseases), active major autoimmune diseases 
(eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe 
endocrinological, gastrointestinal, metabolic, pulmonary, 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). 
26. 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.). 
27. Planned major surgical procedure during the patient’s participation in this study 
28. Patient or his/her immediate family is a member of the dupilumab investigational team 
29. Patient is female who is pregnant, breastfeeding, or planning to become pregnant or 
breastfeed during the study 
30. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities 
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31. Patient is female of childbearing potential* and sexually active, who is unwilling to use 
highly effective methods of contraception prior to the initial dose, during the study and 
for at least 12 weeks after the last dose of study drug. Highly effective contraceptive 
measures include stable use of combined (estrogen and progestogen containing) 
hormonal contraception (oral, vaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening; intrauterine device (IUD); 
intrauterine hormone-releasing system (IUS); bilateral tubal ligation; vasectomized 
partner; and or sexual abstinence**. 
* 
For the purpose of this study, any female who has had her first menstrual period 
(menarche) and is sexually active will be considered to be of childbearing potential. 
Female patients who are not of childbearing potential at the start of the study but have 
the onset of menarche during the course of the study and are sexually active will also 
have to follow adequate birth control methods to continue participation in the study.  
** 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject. 
NOTE:  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a study, and 
withdrawal are not acceptable methods of contraception. 
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion.  The parent/caregiver has the right to withdraw permission to have the patient 
participate in 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 8.1. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study or study treatment will not be replaced. 
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7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
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) 
Dupilumab 150 mg/ml: Each 0.7 mL single-use, prefilled glass syringe with snap-off cap 
delivers 100 mg study drug (0.7 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 monoclonal antibody).  Three matching placebo formulations 
will be used:   
1. 2 mL placebo matching 300 mg dupilumab formulation 
2. 1.14 mL placebo matching 200 mg dupilumab formulation 
3. 0.7 mL placebo matching 100 mg dupilumab formulation 
Patients will be randomized to receive 1 of the treatment regimens described in Section 5.1. 
Study drug will be administered per the schedule described in Section 8.1.  
Subcutaneous 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 administrations.  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 study reference manual. 
Parents/caregivers will have the option to administer study drug outside the study site during 
weeks in which no in-clinic visit is scheduled (for patients receiving Q2W treatment).  The study 
staff will train the parent/caregiver on preparation and administration of study drug on day 1 and 
will administer the first of the 2 injections required for the loading dose.  The parent/caregiver 
will administer the second injection required for the loading dose under the supervision of the 
clinic staff.  The parent/caregiver will administer study drug under the supervision of the clinic 
staff at visits 5 and 7 (weeks 2 and 4, respectively) and at other in-clinic visits.  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], 5 [week 2], and 7 [week 4] for patients receiving Q2W treatment and visits 3 [day 1], 
7 [week 4], and 11 [week 8] for patients receiving Q4W treatment); vital signs (sitting blood 
pressure, 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).  The parent/caregiver will 
administer study drug outside of the clinic during weeks in which no clinic visit is scheduled. 
Parents (or caregivers) who prefer to have the clinic staff administer study drug may choose to 
have injections administered in the clinic. 
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7.2. 
Background Treatment 
All patients should apply moisturizers (emollients) at least twice daily for at least the 
7 consecutive days immediately before randomization.  After randomization, patients are 
required to continue to apply moisturizers throughout 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 (eg, ceramide containing products like 
epiceram®) or moisturizers containing additives (ceramide, hyaluronic acid, urea, filaggrin 
degradation products) 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 are required to initiate treatment with TCS using a standardized 
regimen according to the following guidelines: 
 Apply medium-potency TCS once daily to areas with active lesions.  Based on 
investigator discretion, low-potency TCS may be used once daily on areas of thin skin 
(face, neck, intertriginous, and genital areas, areas of skin atrophy, etc.) or for areas 
where continued treatment with medium-potency TCS is considered unsafe.   
 Once the patient achieves an IGA score of 2 or less, decrease the frequency of use of 
medium-potency TCS to 3 times per week, and then stop once lesions are clear 
(IGA 0). Patients should be instructed to use TCS only on active lesions, and to stop 
use of TCS if lesions clear completely in between clinic visits. 
 If lesions return, reinstitute treatment with medium-potency TCS, with the same 
step-down approach described above upon lesion resolution. 
 In case there are signs of local (eg, impending skin atrophy), or systemic TCS toxicity 
with medium-potency steroids, patients should be switched to low-potency steroids. 
 For lesions persisting or worsening under daily treatment with medium-potency TCS, 
patients may be treated (rescued) with high-potency TCS (super-potent/ very-high-
potency steroids are not allowed even for rescue), unless higher potency TCS are 
considered unsafe (a potent 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.   
 A list of steroids that can be used during the study will be provided to the 
investigators as part of the study manual.  The use of very-high potency or 
superpotent 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, they may substitute with products of the same 
potency from the list provided in the study manual. It is recommended that patients 
use triamcinolone acetonide 0.1% cream, fluocinolone acetonide 0.025% cream, or 
clobetasone butyrate 0.05% for medium potency, and hydrocortisone acetate 1% 
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cream for low potency.  If rescue with TCS is needed, it is recommended that patients 
use mometasone furoate 0.1% ointment as high-potency steroid.  If patients have 
tolerance issues with any of these steroids or if they are not commercially available, 
they may substitute with products of the same potency from the list provided in the 
study reference manual. 
 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. 
7.3. 
Rescue Treatment 
Rescue treatment for AD may be provided to patients during 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 = 4, or have intolerable symptoms.  If 
possible, investigators are encouraged to consider rescue initially with topical treatment (eg, 
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.  The use of very-high-potency or superpotent TCS is 
prohibited in this study, even as rescue treatment, as their use is not recommended in patients 
under 12 years of age.  Very-high-potency topical corticosteroids include: 
 Betamethasone dipropionate augmented 0.05% ointment 
 Clobetasol propionate 0.05% solution, foam, cream or ointment 
 Diflorasone diacetate 0.05% ointment 
 Halobetasol propionate 0.05% cream or ointment 
Patients who receive systemic corticosteroids or systemic non-steroidal immunosuppressive 
drugs (eg, 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 (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 efficacy 
analysis, patients who receive rescue treatment during the study will be considered treatment 
failures. 
7.4. 
Dose Modification and Study Drug Discontinuation Rules 
7.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
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7.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
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 will be asked to complete study assessments, per 
Section 8.1. 
7.4.2.1. 
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 dupilumab 
 Diagnosis of a malignancy during study 
 Evidence of pregnancy 
 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 that are deemed to be related to dupilumab: 
 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) 
 Treatment with any prohibited concomitant medication or procedure (Section 7.8.1). 
NOTE: The use of TCI is prohibited during the 2-week TCS standardization period 
leading up the baseline visit, and the treatment and follow-up periods. The use of 
very-high-potency or superpotent TCS is not allowed throughout the study (as their 
use is not recommended in patients under 12 years of age). However, high-potency 
TCS can be used as rescue. In this situation, the study drug will be continued. 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing may be temporarily discontinued in the event of: 
 Clinically important laboratory abnormalities, such as: 
 ALT or AST 3 × ULN but ≤5 × ULN 
 Neutrophil count <1.5 × 103/µL but >0.5 × 103/µL 
 Platelet count ≤100 × 103/µL but >50 × 103/µL 
 CPK >5 × ULN 
 Serum creatinine >1.5 × ULN  
 Eosinophils >5000/μL 
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 Severe laboratory abnormalities (as noted in Section 7.4.2.1) where a causal 
relationship to dupilumab can be reasonably excluded (ie, an alternative cause is 
evident). In these cases, study treatment will be discontinued while the clinical 
circumstances are being assessed but it may be resumed when the laboratory 
parameters normalize sufficiently. A decision to resume treatment will be made 
jointly by the investigator and medical monitor. 
 Other intercurrent illnesses or major surgery 
 An infection that requires parenteral treatment with antibiotic, antifungal, antiviral, 
antiparasitic, or antiprotozoal agents, or requires oral treatment with such agents for 
longer than 2 weeks 
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. Note that dosing may NOT be resumed if patient met conditions for 
permanently discontinuing study drug described in Section 7.3. 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. 
7.5. 
Management of Acute Reactions 
Acute systemic reactions following injection of study drug (SC) should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice. 
7.6. 
Method of Treatment Assignment 
Approximately 330 patients will be randomized, stratified by weight group (<30 kg or ≥30 kg) 
and region (North America, Europe), to 1 of the treatment groups described in Section 5.1 
according to a central randomization scheme provided by an interactive voice response system 
(IVRS)/interactive web response system (IWRS) to the designated study pharmacist (or qualified 
designee). 
7.6.1. 
Blinding 
With the exception of the IDMC members and the provisions in Section 7.6.2, this study will 
remain blinded to all individuals until the prespecified unblinding to conduct the primary 
analyses.  
Blinded study drug kits coded with a medication numbering system will be used. 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. 
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7.6.2. 
Emergency Unblinding 
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 any other significant medical event (eg, pregnancy). 
 If unblinding is required: 
 Only the investigator will make the decision to unblind the treatment assignment. 
 Only the affected patient will be unblinded. 
 The IVRS/IWRS will provide the treatment assignment to the investigator. 
 The investigator will notify Regeneron and/or designee immediately that the 
patient has been unblinded. 
7.7. 
Treatment Logistics and Accountability 
7.7.1. 
Packaging, Labeling, and Storage 
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 
; storage instructions will be 
provided in the pharmacy manual. 
7.7.2. 
Supply and Disposition of Treatments 
Study drug will be shipped 
 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 destroyed or 
returned to the sponsor or designee. 
7.7.3. 
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. 
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7.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and must be made available for inspection by 
the sponsor and regulatory agency inspectors. 
7.8. 
Concomitant Medications and Procedures 
Any treatment administered from the time of the first dose of study drug to the final study visit 
will be considered concomitant medication. This includes medications that were started before 
the first dose of study drug and are ongoing during the study. 
7.8.1. 
Prohibited Medications and Procedures 
Treatment with the following concomitant medications is prohibited during the study: 
 Treatment with a live (attenuated) vaccine; below is a list of examples of such 
vaccines; refer to study manual for a current, comprehensive list of prohibited 
vaccines 
Chickenpox (Varicella) 
FluMist-Influenza 
Intranasal influenza 
Measles (Rubeola) 
Measles-mumps-rubella combination 
Measles-mumps-rubella-varicella 
combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rubella 
Smallpox (Vaccinia) 
Yellow fever 
Bacillus Calmette-Guerin 
Rotavirus 
Varicella Zoster (shingles) 
 Treatment with an investigational drug (other than dupilumab) 
 Treatment with immunomodulating biologics 
 Treatment with systemic nonsteroid immunosuppressant (may be used as rescue, see 
Section 7.3 for details) 
 Treatment with systemic corticosteroids (may be used as rescue, see Section 7.3 for 
details) 
 Treatment with crisabarole 
 Treatment with TCI 
Note: The use of TCI is prohibited during the 2-week standardization period leading up to 
the baseline visit, and the treatment and follow-up periods 
 Treatment with high-potency TCS, (high-potency TCS may be used as rescue, see 
Section 7.3 for details).  The use of very-high-potency or superpotent TCS (a 
fluticasone or hydrocortisone comparator strength) is prohibited during the study (as 
their use is not recommended in patients < 12 years of age). 
 Initiation of treatment of AD with prescription moisturizers 
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The following concomitant procedures are prohibited during study participation: 
 Major elective surgical procedures 
 Tanning in a bed/booth 
 Phototherapy (UVA, UVB, nbUVB, high dose UVA and PUVA) 
7.8.2. 
Permitted Medications and Procedures 
Other than the prohibited medications listed in Section 7.8.1, treatment with concomitant 
medications is permitted during the study. This includes basic skin care (cleansing and bathing, 
including bleach baths), emollients (required as background treatment), topical anesthetics, 
antihistamines, and topical and systemic anti-infective medications for any duration. 
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. 
7.9. 
Continuation of Dupilumab Treatment in an Open-Label Extension 
Study 
All patients will be offered the opportunity to screen for entry into OLE at end of treatment 
period (week 16). Patients who decline to enroll in the OLE study, or those who fail eligibility 
criteria for OLE, will have a 12-week follow-up period. 
8. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1 (screening, 
baseline, and treatment period) and in Table 2 (follow-up period, unscheduled visits, and early 
termination). 
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Table 1: 
Schedule of Events (Screening, TCS Standardization, Baseline, and Treatment Period)  
 
SCN 
TCS 
standard
ization 
Treatment Period 
 
 
 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W
2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient and/or 
parents/caregiver diary 
training3 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection 
training/observation 
(patients receiving Q2W 
treatment)4 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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SCN 
TCS 
standard
ization 
Treatment Period 
 
 
 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W
2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Study drug 
administration (patients 
receiving Q2W 
treatment) 
 
 
X5 
 
X5 
 
X5 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Injection observation 
(patients receiving Q4W 
treatment)5 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Study drug 
administration (patients 
receiving Q4W 
treatment) 
 
 
X5 
 
 
 
X5 
 
 
 
X5 
 
 
 
X 
 
 
 
 
Patient and/or 
parents/caregiver diary 
completion to record 
self-admin of study 
drug (patients receiving 
Q2W treatment) 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Study drug dispensing 
(patients receiving Q2W 
treatment) 6 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Study drug 
accountability (patients 
receiving Q2W 
treatment) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
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SCN 
TCS 
standard
ization 
Treatment Period 
 
 
 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W
2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Review home diary 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
TCS application7  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TCS dispensing  
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
TCS accountability8  
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Patient and 
parents/caregiver 
counseling for diary 
completion 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Patient recording of 
TCS use via diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient recording of 
emollient use via diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient assessment of 
pruritus intensity using 
worst itch score via 
diary (daily)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient global 
impression of 
disease,10,11  
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
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SCN 
TCS 
standard
ization 
Treatment Period 
 
 
 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W
2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Patient global 
impression of 
change10,11 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CDLQI10,11 POEM,10,11 
DFI12, PROMIS 
anxiety and 
depression scale10,11 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
IGA, EASI, GISS, 
SCORAD, BSA 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Faces pain scale for 
injection pain  
 
 
X 
 
X1
3 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Assess missed school 
days 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Assess caregiver missed 
workdays 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Photograph AD areas 
(select sites) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs5 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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SCN 
TCS 
standard
ization 
Treatment Period 
 
 
 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W
2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Chemistry 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test, 
WOCBP only 
Ser 
 
Ur 
 
Ur
16 
 
Ur 
 
 
 
Ur 
 
 
 
Ur 
 
 
 
 
HIV, HBsAg, HBsAb, 
HBcAb, Hep C Ab, 
TB15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TARC 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Immunoglobulin 
profiling 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SCN 
TCS 
standard
ization 
Treatment Period 
 
 
 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W
2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Drug Concentration 
and ADA:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional dupilumab 
concentration sample 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ADA sample 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
SCN = screening; BL = baseline; Ser = serum; Ur = urine; WOCBP = women of childbearing potential; TB = tuberculosis 
Note: The length of the screening period is not fixed, but the duration for screening and TCS standardization must not exceed 77 days.  The length of the TCS 
standardization period is fixed at 14 days. 
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Table 2: 
Schedule of Events (Follow-Up Period, Unscheduled Visits, and Early 
Termination) 
Study Procedure 
Follow-Up Period7 
Unscheduled 
Visit8 
Early 
Termination 
Visit 
 
 
 
EOS 
In-clinic Visit (V) 
V20 
V21 
V22 
 
 
Week (W) 
W20 
W24 
W28 
 
 
Study Day (D) 
D141 
D169 
D197 
 
 
Window in days 
±4 
±4 
±4 
 
 
Treatment: 
 
 
 
 
 
Study drug accountability 1 
 
 
 
X 
X 
TCS application  
X 
X 
X 
 
 
TCS dispensing 
X 
X 
 
X 
 
TCS accountability  
X 
X 
X 
X 
X 
Patient recording of TCS use via diary 
X 
X 
X 
X 
X 
Patient recording of emollient use via diary 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
Efficacy:2  
 
 
 
 
 
Patient assessment of pruritus intensity using 
worst itch score via diary (daily)  
X 
X 
X 
X 
X 
Patient global impression of disease  
X 
X 
X 
X 
X 
Patient global impression of change  
X 
X 
X 
X 
X 
Patient-reported CDLQI3,4, POEM3,4, DFI5, 
PROMIS anxiety and depression scale3,4 
X 
X 
X 
X 
X 
IGA, EASI, GISS, SCORAD, BSA 
X 
X 
X 
X 
X 
Assess missed school days 
X 
X 
X 
X 
X 
Assess caregiver missed work days 
X 
X 
X 
X 
X 
Photograph AD areas (select sites) 
 
 
X 
 
X 
Safety 
 
 
 
 
 
Weight 
 
 
X 
 
X 
Height 
 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
Physical examination 
 
 
X 
X 
X 
ECG 
 
 
X 
X 
X 
Adverse events9 
X 
X 
X 
X 
X 
Laboratory Testing:6 
 
 
 
 
 
Hematology 
 
 
X 
X 
X 
Chemistry 
 
 
X 
X 
X 
Urinalysis 
 
 
X 
X 
X 
Pregnancy test, WOCBP only 
 
 
Urine 
Urine 
Urine 
Biomarker:  
 
 
 
 
 
TARC 
 
 
X 
X 
X 
Immunoglobulin profiling 
 
 
X 
X 
X 
Drug Concentration and ADA Samples:  
 
 
 
 
 
Functional dupilumab concentration sample 
 
X 
X 
X 
X 
ADA sample 
 
 
X 
X 
X 
EOS = End of Study 
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8.1.1. 
Footnotes for Schedule of Events Table 
8.1.1.1. 
Footnotes for Schedule of Events Table 1 
1. The site will contact the patient or parents/caregiver by telephone to conduct these visits. 
The parents/caregiver may administer study drug during phone visits. Patients who 
receive study drug outside the study center will complete a dosing diary to document 
compliance with study drug administration and to document any related issues. 
 
 
 
. 
3. Training of patients and parents/caregiver regarding completion of diary to record (a) 
administration of each dose of drug outside the clinic by parent/caregiver; (b) completion 
of the assessment of pruritus using worst itch scale; (c) emollient use; (d) TCS use 
4. Parents/caregivers will be trained on how to administer study drug. This will enable 
administration at home in between clinic visits.  
5. Patients will be monitored at the study site at visits 3, 5, and 7 (for patients receiving 
Q2W treatment) and at visits 3, 7, and 11 (for patients receiving Q4W treatment) for a 
minimum of 2 hours after study drug administration. Vital signs (sitting blood pressure, 
heart rate, respiratory rate, and body temperature) and AEs will be assessed at 30 minutes 
(±10 minutes) post-injection and then at 2 hours (±15 minutes). 
6. Starting at visit 7, study drug will be dispensed to the parents (or caregivers) for the dose 
that will be administered before the next clinic visit. Parents (or caregivers) will return 
the study kit box (for prefilled syringes) at each subsequent in-clinic visit.  At these 
in-clinic visits, sites will perform accountability assessment for the study drug that the 
parents (or caregivers) have returned to the site. 
7. As per standardized regimen outlined in Section 7.2 
8. 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. 
9. Assessments/procedures should be conducted in the following order: patient reported 
outcomes (other than patient assessment of injection pain), investigator assessments, 
safety and laboratory assessments (including sample collection for ADA, PK, biomarker, 
), administration of study drug, and assessment of injection pain.  
10. The questionnaires will be administered only to the subset of patients or 
parents/caregivers who speak fluently the language in which the questionnaire is 
presented (based on availability of validated translations in participating countries). 
11. Refer to Section 8.2.2 for details on who (parent or caregiver) is required to complete the 
specific questionnaires. 
12. DFI is to be completed by parent/caregiver.  
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13. Injection pain assessment at week 2 will only be performed for patients on Q2W 
treatment 
14. Samples will be collected before the injection of study drug 
15. TB testing will be performed on a country-by-country basis, according to local guidelines 
if required by regulatory authorities or ethics boards. 
16. Urine pregnancy testing at week 2 will only be performed for patients who receive Q2W 
treatment. 
17. EOT is end of study for patients who enter the OLE. 
18. Patients who experience adverse events of special interest related to eye disorders (refer 
to Section 9.4.3) 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. 
8.1.1.2. 
Footnotes for Schedule of Events Table 2 
1. Starting at visit 4, study drug will be dispensed to the parents (or caregivers) for the dose 
that will be administered before the next clinic visit. Parents (or caregivers) will return 
the study kit box (for prefilled syringes) at each subsequent in-clinic visit.  At these 
in-clinic visits, sites will perform accountability assessment for the study drug that the 
parents (or caregivers) have returned to the site. 
2. Assessments/procedures should be conducted in the following order: patient reported 
outcomes (other than patient assessment of injection pain), investigator assessments, 
safety and laboratory assessments (including sample collection for ADA, PK, biomarker, 
), administration of study drug, and assessment of injection pain.  
3. The questionnaires will be administered only to the subset of patients or 
parents/caregivers who speak fluently the language in which the questionnaire is 
presented (based on availability of validated translations in participating countries). 
4. Refer to Section 8.2.2 for details on who (parent or caregiver) is required to complete the 
specific questionnaires. 
5. DFI is to be completed by parent/caregiver.  
6. Samples will be collected before the injection of study drug 
7. Only for patients who do not enter the OLE. 
8. Specific assessments to be performed at the unscheduled visit will depend upon the 
reason for the unscheduled visit. 
9. Patients who experience adverse events of special interest related to eye disorders (refer 
to Section 9.4.3) 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. 
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8.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study will be asked to return to the clinic for early 
termination assessments as per Table 2. 
8.1.3. 
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 on the reason for the unscheduled visit. 
8.2. 
Study Procedures 
Assessments/procedures at the clinic visit should be performed in the following order: 
1. Patient Reported Outcomes (completed by patients with help of parents/caregiver if 
required).  Patient assessment of injection pain will be performed after administration of 
study drug. 
2. Investigator assessments (performed only by adequately trained and qualified 
investigators or sub-investigators; it is recommended that the same investigator or 
sub-investigator perform all the evaluations for a given patient throughout the entire 
study period) 
3. Safety and laboratory assessments 
4. Administration of study drug 
8.2.1. 
Procedures Performed only at the Screening/Baseline Visit 
These procedures will be performed for the sole purpose of determining study eligibility or 
characterizing the baseline population:  medical history and demographics.  The following tests 
will be performed at screening:  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). 
8.2.2. 
Efficacy Procedures 
A variety of parameters will be collected during the study to assess efficacy/effectiveness of 
dupilumab, including measures of AD severity, use of concomitant treatment for AD, and 
patient-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 study manual for instructions on the administration and use of all patient-reported 
instruments (including worst itch score, patient global impression of disease, patient global 
impression of change, CDLQI, POEM, PROMIS anxiety and depression score, Faces pain scale, 
and DFI). 
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8.2.2.1. 
Patient Assessment of Pruritus Using Worst Itch Scale 
The worst itch scale is a simple assessment tool that patients will use to report the intensity of 
their pruritus (itch). This is an 11-point scale (0 to 10) in which 0 indicates no itching while 10 
indicates worst itching possible. Patients will be asked the following 2 questions: 
“What was the worst itch you had today?” 
“What was the worst itch you had last night?” 
Patients will be asked to provide answers to these 2 questions daily throughout the entire study 
(screening period, treatment period, and follow-up period; see time point in Section 8.1).  Both 
questions will be answered in the evening (it is recommended that the questions be answered and 
the responses provided in the diary in the 6:00 PM to 11:00 PM local time window).  The daily 
worst itch score will be calculated as the worse of the scores for the 2 questions. 
Patients will be instructed on using the patient diary to record their worst itch score at the 
screening and baseline visits. Clinical sites will check and remind patients to complete the diary 
at each visit. 
This questionnaire measures concept(s), which are known only/best to the patient suffering from 
AD.  As such the questionnaire is designed for self-report.  Where possible the patient should 
read and complete the questionnaire alone. Where required, a caregiver (parent or other) can read 
the questions and response options aloud to the person with AD.  However, it is important that 
the patient’s selected responses to the questions are entered directly into the questionnaire.  The 
caregiver must not influence or question the response given by the person with AD. This should 
be communicated to caregivers during the first visit.  A field to indicate whether the question and 
response options were read out to the patient by caregiver has been added to the first page of the 
diary/questionnaire.   
8.2.2.2. 
Patient Global Impression of Disease 
Patients will rate their disease based on the 5-level scale as follows: 
In general, how itchy have you been during the last 7 days? 
 Not itchy at all 
 A little itchy 
 Medium itchy 
 Pretty itchy 
 Very itchy 
Patients will undergo this assessment at time points according to Section 8.1.  This questionnaire 
measures concept(s), which are known only/best to the patient suffering from AD.  As such the 
questionnaire is designed for self-report. Where possible the patient should read and complete 
the questionnaire alone.  Where required, a caregiver (parent or other) can read the questions and 
response options aloud to the person with AD.  However, it is important that the patient’s 
selected response to the questions are entered directly into the questionnaire.  The caregiver must 
not influence or question the response given by the person with AD.  This should be 
communicated to caregivers during the first visit.  A field to indicate whether the question and 
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response options were read out to the patient by caregiver has been added to the first page of the 
diary/questionnaire.  This information will be transferred to the eCRF. 
The assessment tool is provided in the study reference manual. 
8.2.2.3. 
Patient Global Impression of Change 
Patients will respond to the following question based on the 5-level scale as follows:  
Since you started your study medication, how has your itching changed?  
 Much better 
 A little better 
 The same 
 A little worse 
 Much worse  
Patients will undergo this assessment at time points according to Section 8.1.  This questionnaire 
measures concept(s), which are known only/best to the patient suffering from AD.  As such the 
questionnaire is designed for self-report.  Where possible the patient should read and complete 
the questionnaire alone.  Where required, a caregiver (parent or other) can read the questions and 
response options aloud to the person with AD.  However, it is important that the patient’s 
selected response to the questions are entered directly into the questionnaire.  The caregiver must 
not influence or question the response given by the person with AD.  This should be 
communicated to caregivers during the first visit.  A field to indicate whether the question and 
response options were read out to the patient by caregiver has been added to the first page of the 
diary/questionnaire.  This information will be transferred to the eCRF. 
The assessment tool is provided in the study reference manual. 
8.2.2.4. 
Children's Dermatology Life Quality Index 
The CDLQI is a validated questionnaire designed to measure the impact of skin disease on the 
QOL in children (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.  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. 
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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. 
Patients will undergo this assessment at time points according to Section 8.1.  This questionnaire 
measures concept(s), which are known only/best to the patient suffering from AD.  As such the 
questionnaire is designed for self-report.  Where possible the patient should read and complete 
the questionnaire alone.  Where required, a caregiver (parent or other) can read the questions and 
response options aloud to the person with AD.  However, it is important that the patient’s 
selected response to the questions are entered directly into the questionnaire.  The caregiver must 
not influence or question the response given by the person with AD.  This should be 
communicated to caregivers during the first visit.  A field to indicate whether the question and 
response options were read out to the patient by caregiver has been added to the first page of the 
diary/questionnaire.  This information will be transferred to the eCRF. 
The CDLQI is provided in the study reference manual. 
8.2.2.5. 
Patient Oriented Eczema Measure 
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 be administered at time points according to Section 8.1.  This 
questionnaire asks the caregiver to report their perception of patient’s AD symptoms.  It is 
therefore completed by the caregiver.  To ensure consistency in perception over longitudinal 
administration and to minimize respondent variability, it is important that the same caregiver 
complete the questionnaire at each time point.  This should be communicated to caregivers 
during consent and prior to the first completion of the questionnaire.  A field has been added to 
the first page of the diary/questionnaire to indicate who completed the questionnaire 
(mother/female guardian, father/male guardian, other caregiver).  This information will be 
transcribed into the eCRF along with the questionnaire. 
8.2.2.6. 
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.  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 
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reference is the past week.  A higher DFI score indicates greater impairment in family QOL as 
affected by AD.  
The assessment will be performed a time points according to Section 8.1.  This questionnaire 
asks the caregiver to report the impact of having a child with AD on the QOL of the family.  It is 
therefore completed by the caregiver.  To ensure consistency in perception over longitudinal 
administration and to minimize respondent variability, it is important that the same caregiver 
complete the questionnaire at each time point.  This should be communicated to caregivers 
during consent and prior to the first completion of the questionnaire.  A field has been added to 
the first page of the diary/questionnaire to indicate who completed the questionnaire 
(mother/female guardian, father/male guardian, other caregiver). This information will be 
transcribed into the eCRF along with the questionnaire. 
The DFI questionnaire is provided in study reference manual. 
8.2.2.7. 
Faces Pain Scale – Revised 
The Faces Pain Scale – Revised (FPS-R) is a self-report measure of pain intensity developed for 
children (Hicks 2001). It was adapted from the Faces Pain Scale to make it possible to score the 
sensation of pain on the widely accepted 0 to 10 metric. The scale shows a close linear 
relationship with visual analog pain scales across the age range of 4 to 16 years. It is easy to 
administer and requires no equipment except for the photocopied faces. The instrument has well 
established psychometric properties and has been validated in school-going children.  
The instrument will be used to assess injection site pain at the time points specified in 
Section 8.1.  This instrument measures concept(s), which are known only/best to the person who 
is administered the injection.  As such the instrument is designed for self-report.  Where possible 
the patient should read the instructions and complete the instrument alone.  Where required a 
caregiver (parent or other) can read the instructions aloud to the person with AD.  However, it is 
important that the person with AD’s selected response is entered directly into the instrument.  
The caregiver must not influence or question the response given by the person with AD.  This 
should be communicated to caregivers during the first visit.  A field to indicate whether the 
instructions were read out to the patient by caregiver has been added to the first page of the 
diary/questionnaire.  This information will be transferred to the eCRF. 
The assessment tools are provided in the study reference manual. 
8.2.2.8. 
PROMIS Anxiety and Depression Scale 
The PROMIS Anxiety instrument measures self-reported fear (fearfulness, panic), anxious 
misery (worry, dread), hyperarousal (tension, nervousness, restlessness), and somatic symptoms 
related to arousal (racing heart, dizziness). The PROMIS Depression instrument assesses 
self-reported negative mood (sadness, guilt), views of self (self-criticism, worthlessness), and 
social cognition (loneliness, interpersonal alienation), as well as decreased positive affect and 
engagement (loss of interest, meaning, and purpose). 
Both of these assessments need to be completed at the time points specified in Section 8.1.  This 
questionnaire asks the caregiver to report their perception of the patient’s anxiety and depressive 
symptoms.  It is therefore completed by the caregiver.  To ensure consistency in perception over 
longitudinal administration and to minimize respondent variability, it is important that the same 
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caregiver complete the questionnaire at each time point.  This should be communicated to 
caregivers during consent and prior to the first completion of the questionnaire.  A field has been 
added to the first page of the diary/questionnaire to indicate who completed the questionnaire 
(mother/female guardian, father/male guardian, other caregiver).  This information will be 
transcribed into the eCRF along with the questionnaire. 
The PROMIS anxiety and depression instruments are provided in the study reference manual. 
8.2.2.9. 
Investigator’s 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 8.1. 
The IGA is provided in the study reference manual and in Appendix 2.   
8.2.2.10. 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 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 8.1. 
NOTE:  Each of the body regions (head and neck, trunk, upper limbs, lower limbs) is assigned a 
proportion of the total body surface area.  These proportions vary with age and are different in 
young children as compared to older children. 
The EASI assessment tool is provided in the study reference manual. 
8.2.2.11. 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) using the EASI severity grading criteria 
(Section 8.2.2.10).  The Global Individual Signs Score (GISS) will be assessed at time points 
according to Section 8.1. 
The GISS assessment tool is provided in the study reference manual. 
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8.2.2.12. SCORing Atopic Dermatitis 
The SCORing Atopic Dermatitis (SCORAD) is a validated tool used in clinical research and 
clinical practice that was developed to standardize the evaluation of the extent and severity of 
AD (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 8.2.2.13) 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 patient or relative on a Visual Analogue Scale, 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 where the maximum is 103.  Patients will undergo 
this assessment at time points according to Section 8.1. 
The SCORAD assessment tool is provided in the study reference manual. 
8.2.2.13. 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 (the possible highest score for each region is: head and neck [9%], anterior trunk [18%], 
back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]) and will be reported as a 
percentage of all major body sections combined. Patients will undergo this assessment at time 
points according to Section 8.1. 
NOTE:  The proportion assigned to different body regions is different in younger children as 
compared to older children (head and neck area is assigned a higher proportion in younger 
children as compared to older children). 
The BSA assessment tool is provided in the study reference manual. 
8.2.2.14. Assessment of Missed School Days 
Patients who are enrolled in school will be asked to report the number of missed school days 
since the last study assessment. Patients will undergo this assessment at time points according to 
Section 8.1. 
The assessment tool is provided in the study reference manual. 
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8.2.2.15. 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 the time points according to 
Section 8.1.  This questionnaire asks the caregiver to report the impact of having a child with AD 
on their workdays.  It is therefore completed by the caregiver.  To ensure consistency in 
perception over longitudinal administration and to minimize respondent variability, it is 
important that the same caregiver complete the questionnaire at each time point.  This should be 
communicated to caregivers during consent and prior to the first completion of the questionnaire.  
A field has been added to the first page of the diary/questionnaire to indicate who completed the 
questionnaire (mother/female guardian, father/male guardian, other caregiver).  This information 
will be transcribed into the eCRF along with the questionnaire. 
8.2.2.16. Atopic Dermatitis Area Photographs 
At select study sites, photographs will be taken of a representative area of AD involvement 
(eg, the lesional area used for SCORAD assessments on day 1/baseline [predose]).  Subsequent 
photographs of the same area will be taken at time points according to Section 8.1. 
Instructions for taking the photographs are provided in the photography reference manual. 
8.2.2.17. Topical Corticosteroids Accountability 
At every in-clinic visit following the TCS standardization visit, the type, amount, frequency, 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, patients will be asked to record TCS use daily, from day -14 until the end of the 
study, by providing the following information on a diary: 
 Use of TCS (Yes/No) 
8.2.3. 
Safety Procedures 
8.2.3.1. 
Vital Signs 
Vital signs (including sitting blood pressure, heart rate, respiration, and temperature) will be 
collected at predose at every in-clinic visit.  At the first 3 administrations of study drug (day 1, 
week 2, and week 4 for patients receiving Q2W treatment and day 1, week 4, and week 8 for 
patients receiving Q4W treatment), sitting blood pressure, heart rate, and respiratory rate will 
also be assessed at 30 (±10) minutes postdose and then at 2 hours (±15 minutes).  See Section 8.1 
for assessment time points. 
8.2.3.2. 
Body Weight and Height 
Body weight and height will be measured at time points according to Section 8.1. 
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8.2.3.3. 
Physical Examination 
A thorough and complete physical examination will be performed at visits according to 
Section 8.1. Care should be taken to examine and assess any abnormalities that may be present, 
as indicated by the patient’s medical history. 
8.2.3.4. 
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 8.1.  
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. 
8.2.3.5. 
Laboratory Testing 
Hematology, serum chemistry, urinalysis, and pregnancy 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 8.1.  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× ULN 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
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Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
Serum and urine pregnancy testing will be performed for all female patients of childbearing 
potential at time points according to Section 8.1.  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). 
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 9.4.5.  
8.2.3.6. 
Ophthalmological Examinations 
Patients who have a history of certain eye disorders (conjunctivitis, blepharitis or keratitis) 
within the last 12 months 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 9.4.3 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. 
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8.2.4. 
Pharmacokinetic and Antibody Procedures 
8.2.4.1. 
Drug Concentration Measurements and Samples 
Serum samples for measuring functional dupilumab concentrations will be collected at time 
points listed in Section 8.1. 
8.2.4.2. 
Anti-Drug Antibody Measurements and Samples 
Serum samples for ADA assessment will be collected at time points listed in Section 8.1. 
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 open-label extension study may be considered 
based on the overall clinical presentation at that time. 
8.2.5. 
Biomarker Procedures 
Thymus and activation-regulated chemokine and total serum IgE are markers of type 2/Th2 
activity as downstream mediators in the IL-4/IL-13 signaling pathway (Wirnsberger 2006, 
Takeda 1997). These analytes may be assessed as measures of type 2/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 levels have also been shown to correlate with disease severity and 
activity in patients with AD (Mukai 1990). 
Serum samples for measurements of biomarkers (including TARC, total IgE, immunoglobulin 
profiling, 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 8.1. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patient. 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. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, IECs/IRBs as appropriate, and to the 
investigators. 
Any AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be 
considered as unexpected. Any worsening of or new onset of symptoms related to AD, which 
occur during the screening/washout period prior to study drug administration will be considered 
expected. 
In addition, the sponsor will report in an expedited manner all SAEs that are expected and at 
least reasonably related to the study drug to the health authorities, according to local regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and IECs/IRB as appropriate. 
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9.3. 
Definitions 
9.3.1. 
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 preexisting condition that is temporally associated with the use of the study drug. 
9.3.2. 
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 admission to a hospital or an emergency room 
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 9.3.3 for more 
information on recording and reporting SAEs. 
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9.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and 
medical concern specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it. Depending on the nature 
of the event, rapid communication by the trial sponsor to other parties (eg, regulators) might also 
be warranted (Section 9.4.3). 
9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
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 study reference manual for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 9.4.6. Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
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 study reference manual 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 (IRB)/Ethics Committee 
(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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9.4.3. 
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. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), by telephone within 24 hours of 
identification, any pregnancy occurring in a female patient during the study or 
within 12 weeks of the last dose of study drug. Any complication of pregnancy 
affecting a female study patient and/or fetus and/or newborn that meets the SAE 
criteria must be reported as an SAE.  Outcome for all pregnancies should be 
reported to the sponsor. 
Adverse Events of Special Interest: Adverse events of special interest (AESI) must be reported 
within 24 hours of identification. Adverse events of special interest for this study 
include:  
 Systemic or extensive hypersensitivity reactions, including anaphylactic 
reactions 
 Malignancy 
 Helminthic infections 
 Suicide-related events 
 Conjunctivitis (any type or etiology), keratitis, or blepharitis (only events 
that are either severe or serious will be reported as AESIs) 
Any patient who experiences an adverse event of special interest related to an eye disorder will 
be referred to an ophthalmologist.  Futher evaluation of these AESIs will be performed including 
any additional tests, as per the discretion of the ophthalmologist.   
Refer to the study reference manual for the procedures to be followed. 
9.4.4. 
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 study reference manual for the procedures to be followed. 
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9.4.5. 
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. 
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 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
 Mild: Does not interfere in a significant manner with the patient’s normal functioning 
level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief 
of symptoms, but may be given because of personality of the patient. 
 Moderate: Produces some impairment of functioning but is not hazardous to health. 
It is uncomfortable or an embarrassment. Treatment for symptom may be needed. 
 Severe: Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health. Treatment for symptom may be given and/or 
patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
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Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-
colon indicates “or” within description of grade: 
 Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of 
erythema or induration that does not interfere with activity 
 Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or 
interferes with activity; discomfort with movement; 5.1 cm to 10 cm erythema or 
induration or induration that interferes with activity 
 Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily 
activity; significant discomfort at rest; >10 cm erythema or induration; prevents daily 
activity; requires ER visit or hospitalization; necrosis or exfoliative dermatitis 
9.5.2. 
Evaluation of Causality 
Relationship of AEs to Study Drug: 
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 AE 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 sponsor will request information to justify the causality assessment of SAEs, as needed. 
9.6. 
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 study 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. 
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9.7. 
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). 
10. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (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 4. 
10.1. 
Statistical Hypothesis 
The following null hypothesis and alternative will be tested for each dupilumab treatment group: 
H0: No treatment difference between dupilumab and placebo 
H1: There is a treatment difference between dupilumab and placebo 
Baseline weight group (<30 kg and ≥30 kg) and region (North America/Europe) will be the 
2 stratification factors for patient randomization and will be accounted for in the statistical 
modeling for efficacy. 
10.2. 
Justification of Sample Size 
Based on the initial sample size of 240 patients (prior to this amendment), it is estimated that 
with 80 patients per group, at the 2-sided 5% significance level, the study will have: 
 97% power to detect a difference of 23% between dupilumab Q2W treatment and 
placebo treatment (both in combination with TCS) in the percentage of patients who 
achieve an IGA score 0 or 1 at week 16, assuming that the percentages are 28% and 
5% for dupilumab Q2W and placebo, respectively 
 87% power to detect a difference of 17% between dupilumab Q4W treatment and 
placebo treatment (both in combination with TCS) in the percentage of patients who 
achieve an IGA score 0 or 1 at week 16, assuming that the percentages are 22% and 
5% for dupilumab 300 mg Q4W and placebo, respectively 
 99% power to detect a difference of 51% in the percentages of patients achieving 
EASI-75 response at week 16, assuming that the percentages are 68% and 17% for 
dupilumab Q2W and placebo, respectively, (both in combination with TCS) 
 99% power to detect a difference of 45% in percentages of patients achieving 
EASI-75 response at week 16, assuming that the percentages are 62% and 17% for 
dupilumab Q4W and placebo, respectively, (both in combination with TCS) 
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The significance level is set to 2-sided, 0.05 level. The assumptions used for the power 
calculations were estimated based on results from the R668-AD-1224 study (phase 3 
combination study for adult AD patients) and R668-AD-1021 study (a phase 2b dose-ranging 
study in adults with AD) for patients with IGA=4 at baseline. Based on the result from the 
R668-AD-1021 study, the efficacy profile for dupilumab 200 mg Q2W is similar to dupilumab 
300 mg Q2W. In the absence of data of dupilumab in pediatric patients with AD, the data 
observed in the adult studies R668-AD-1224 and R668-AD-1021 are used for these sample size 
calculations. This is a conservative assumption as it is expected that the effect of dupilumab in 
children will be greater than that seen in adults. Children have disease for a shorter duration than 
adults and the disease is more Th2 driven in acute phase while it becomes more type 1 helper 
T cell in chronic phase (Thepen 1996, Gittler 2012). In addition, children with AD in general 
respond better to systemic therapies than adults (Schmitt 2007). A recent study compared the 
differences between activated and polarized T-cell subsets in blood of adult and pediatric 
patients with AD. The study found that AD is Th2 dominated in children while it extends to 
additional helper T cell subsets, particularly Th22, in adults (Czarnowicki 2015). The sample 
size calculations were done using nQuery (7.0). 
Due to an inadvertent operational error, 68 patients were potentially unblinded. Details about the 
error and why it may have been unblinding are not included in the protocol but will be described 
in the clinical study report. An additional approximately 90 patients will be added to the study to 
ensure that the original number of blinded patients for all treatment groups is available for 
sensitivity analyses that exclude the potentially unblinded patients. This will maintain study 
balance and power.  
The total sample size of the study will be up to approximately 330 patients (110 patients per 
group), and approximately 262 patients (80, 91 and 91 in Q2W, Q4W, and placebo group, 
respectively) if excluding the potentially unblinded patients.  With the sample size of 
330 patients or 262 patients, the power for the co-primary endpoints will be greater than 90%. 
10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Sets 
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 considered to be the primary analysis set. 
The modified full analysis set (mFAS) includes all randomized patients but excludes potentially 
unblinded patients. The primary endpoint, co-primary endpoint, and selected secondary 
endpoints will be evaluated in the mFAS as sensitivity analyses. 
The per protocol set (PPS) includes all patients in the FAS except for those who are excluded 
because of major protocol violations. A preliminary list of potential major protocol violations is 
provided in Appendix 3 and a final list will be generated prior to database lock. The PPS will 
also exclude potentially unblinded patients. 
The primary and co-primary endpoints will also be evaluated in the PPS. 
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10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF. 
10.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis set includes all randomized patients who received any study drug and who had 
at least 1 non-missing drug concentration result following the first dose of study drug.  
10.3.4. 
Analysis Set for Anti-Drug Antibody Data 
The ADA analysis set includes all treated patients who received any study drug and who had at 
least 1 non-missing ADA result (either “ADA negative” or “ADA positive”) after the first dose 
of study drug. 
10.4. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients: met the inclusion criteria regarding the target 
indication and signed the ICF 
 The total number of randomized patients: received a randomization number 
 The total number of patients in each analysis set 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 The total number of patients potentially unblinded 
 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 
 A listing of potentially unblinded patients 
10.5. 
Statistical Methods 
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. 
All data will be summarized by 3 treatment groups (ie, dupilumab Q2W dose, dupilumab Q4W 
dose, and placebo). All placebo patients will be pooled for analysis regardless of whether it is 
100 mg placebo, 200 mg placebo, or 300 mg placebo. 
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10.5.1. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group. 
10.5.2. 
Efficacy Analyses 
For each dose regimen and all efficacy variables, the analysis will be comparisons of each of the 
dupilumab treatment groups with the placebo group (Q2W and Q4W combined). 
A sensitivity analysis for the primary endpoint and selected secondary endpoints will be 
performed in the mFAS. 
10.5.2.1. Primary Efficacy Analysis 
The Cochran-Mantel-Haenszel test adjusted by randomization strata (baseline weight group and 
region) will be used for analyzing the percentage of patients with IGA 0 or 1 at week 16 or 
percentage of patients with EASI-75 at week 16.  The Mantel-Fleiss (MF) criterion will be 
checked, and if it is not met, sensitivity analyses including each stratification factor separately in 
CMH test will be conducted. 
All efficacy data regardless if the patient is on the study treatment or discontinues the study 
treatment but remains in the study will be used for analysis. Specifically, if a patient stays in the 
study until the end of the planned placebo-controlled treatment period, all efficacy data collected 
up to the planned end of treatment visit will be included in the primary analysis regardless if the 
patient is on treatment or not. 
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 7.3), the 
patient will be specified as a nonresponder from the time the rescue is used.  
If a patient withdraws from study, this patient will be counted as a nonresponder for endpoints 
after withdrawal. 
Sensitivity analysis using the last observation carried forward (LOCF) approach to determine 
patient’s status at week 16 will be conducted to assess the robustness of the primary efficacy 
analysis with regards to handling of missing data. The efficacy data will be set to missing after 
rescue treatment is used, then the LOCF method will be used to determine patients’ status at 
week 16.  
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. A patient with missing data 
will be counted as a non-responder. Other sensitivity analyses may be conducted. 
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10.5.2.2. Secondary Efficacy Analysis 
For binary endpoints, the secondary efficacy analysis will use the same approach as that used for 
the primary analysis. 
For continuous endpoints: 
 The multiple imputation (MI) with analysis of covariance (ANCOVA) model will be 
used as the primary analysis method.  Patients’ efficacy data through week 16 after 
the rescue treatment use will be set to missing first, and then be imputed by the 
multiple imputation method.  Missing data from the FAS will be imputed 40 times to 
generate 40 complete datasets 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.  
 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 and region), and relevant baseline.  
 The week 16 data of each of the 40 complete datasets will be analyzed using an 
analysis of covariance (ANCOVA) model with treatment, randomization strata 
(baseline weight group 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.  
 If a patient receives rescue treatment, the efficacy data collected after rescue 
treatment is initiated will be treated as missing. 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 to the MI method described above, sensitivity analyses such as ANCOVA 
model with LOCF, MI method with ANCOVA model on all observed data regardless 
of rescue use will be conducted. Additional details on sensitivity analyses will be 
provided in the SAP. 
Time to event endpoint will be analyzed using the Cox proportional hazards model. Kaplan-
Meier curves will also be provided. 
10.5.2.3. Multiplicity Considerations 
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 across the 2 dupilumab dose regimens vs 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.   
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Table 3: 
Preliminary Statistical Hierarchy for Multiplicity Control 
 
Endpoints 
Dupilumab 
 
q4w group 
q2w group 
Primary endpoint  Proportion of patients with IGA 0 to 1 (on a 5-point 
scale) at week 16 
5 
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 
 
6 
 
2 
Key Secondary 
endpoints 
Percent change in EASI score from baseline to week 16 
7 
3 
Percent change from baseline to week 16 in weekly 
average of daily worst itch score 
8 
4 
10.5.2.4. First-Step Analysis 
A first-step 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 first-step analysis. The assessment of primary and 
secondary endpoints specified in Section 4.2.1 and Section 4.2.2 performed during the analysis 
will be the final analysis of the primary endpoint and secondary endpoints. Hence there will be 
no need for alpha adjustment due to the first-step analysis. 
If a decision is made to perform the first-step 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 team (including the statistician) that will 
perform the first-step 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.  
10.5.3. 
Safety Analysis 
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.  In addition, safety data for 
the placebo Q2W group and placebo Q4W group will be summarized separately. 
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10.5.3.1. Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined: 
 The pretreatment 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 first dose of study drug to 
end of study. 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) to end of study. 
Treatment-emergent adverse events are defined as those that are not present at baseline or 
represent the exacerbation of a preexisting condition during the on-treatment period. 
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 for overall during the treatment-emergent period, 
during the 16-week treatment period, and during the follow-up period will include: 
 The number (n) and percentage (%) of patient with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
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. 
10.5.3.2. Other Safety 
Vital Signs 
Vital signs (sitting blood pressure, heart rate, respiration, and temperature) 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. 
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Laboratory Tests 
Laboratory test results 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 PCSV will be summarized for 
each clinical laboratory test. The criteria for treatment-emergent PCSVs 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 laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
10.5.3.3. Treatment Exposure 
The duration of exposure during the study will be presented by treatment group and calculated 
as: 
Q2W dosing:  (Date of last study drug injection – date of first study drug injection) + 14 days  
Q4W dosing:  (Date of last study drug injection – date of first study drug injection) + 28 days 
The number (%) of patients randomized and exposed to double-blind study drug will be 
presented by specific time periods for each treatment 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 treatment group 
using number of patients, means, standard deviation, minimums, Q1, medians, Q3, and 
maximums. 
A summary of the number of doses by treatment group will be provided. 
10.5.3.4. Treatment Compliance 
The compliance with study treatment will be calculated as follows: 
Treatment Compliance = (Number of study drug injections during exposure 
period)/(Number of planned study drug injections during exposure period) × 100% 
The treatment compliance will be presented by specific ranges for each treatment group. The 
ranges of interest will be specified in the SAP. 
10.5.4. 
Analysis of Drug Concentration Data 
No formal statistical analysis will be performed. Trough functional dupilumab concentration in 
serum (Ctrough.timepoint) will be summarized at each time point using descriptive statistics. The data 
may be combined with data from other pediatric studies as well as adult studies, as applicable, 
for analysis using population methods. Any population PK analysis will be reported separately. 
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10.5.5. 
Analysis of Anti-Drug Antibody Data 
The ADA variables described in Section 4.4 will be summarized using descriptive statistics by 
treatment group. Drug concentration data will be examined and the influence of ADAs on 
individual concentration-time profiles will be evaluated. Assessment of the potential impact of 
ADA on safety and efficacy may be provided. 
10.5.6. 
Analysis of Biomarker Data 
All exploratory biomarker data analyses will be performed on the FAS and no multiplicity 
adjustment is planned. Analyses of exploratory measures will be provided in the SAP. 
10.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
 The baseline assessment will be the latest, valid pre-first-dose assessment available 
General rules for handling missing data: 
 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. 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with nonprotocol 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. 
10.7. 
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 16.1. 
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11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
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. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IVRS/IWRS system – randomization for sample collection schedules for dupilumab 
concentration and ADA, study drug supply 
 EDC system – data capture 
 SAS – statistical review, analysis, and reporting  
 ARISg – a pharmacovigilance and clinical safety software system (Regeneron) 
 AWARE, Business Objects XI – pharmacovigilance activities (Sanofi) 
12. 
STUDY MONITORING 
12.1. 
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 ICH guidelines, the monitor will compare the CRF entries with the appropriate source 
documents. Additional review may include, but is not limited 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. 
12.2. 
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. 
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12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel. All required electronic CRFs 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 electronic CRF will be entered in the electronic 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. 
13. 
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/IAFs, 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 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. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
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 and applicable 
regulatory requirements. 
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14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF/IAF 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/IAF 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 assent from each patient and 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 fullest possible 
extent in language that the patient (if applicable) and 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 the same investigator or designee who explained the ICF, and the IAF be signed and dated 
by the patient (if applicable) and the same investigator or designee who explained the IAF. 
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. The patient may also be required to sign and date the 
ICF or a separate IAF, as determined by the IRB/EC and in accordance with the local regulations 
and requirements. 
 Patients/parents or legal guardians who can write but cannot read will have the 
assent/consent form read to them before writing their name on the form. 
 Patients/parents or legal guardians 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 IAF/ICF to confirm that informed consent was given. 
The original IAF/ICF must be retained by the investigator as part of the patient's study record, 
and a copy of the signed IAF/ICF must be given to the patient/patient’s parent(s) or legal 
guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, the 
ICF/IAF must be reviewed and updated appropriately. All study patients and their parent(s) or 
legal guardian(s) must be informed of the new information and provide their written assent (if 
applicable) or consent if they wish the patient to continue in the study. The original signed 
revised ICF/IAF must be maintained in the patient’s study record and a copy must be given to 
the patient/patient’s parent(s) or legal guardian(s). 
14.3. 
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 initials and a 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/IAF) must be kept in strict confidence. 
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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. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF/IAF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF/IAF 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. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design or operation of the protocol or ICF/IAF 
without an IRB/EC-approved amendment. Regulatory approvals will also be obtained where 
required by local legislation. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
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. 
The end of the study will be when the last patient completes the last visit as per schedule of 
events. 
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16.2. 
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. 
17. 
STUDY DOCUMENTATION 
17.1. 
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. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs/IAFs, 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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18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
19. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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21. 
REFERENCES 
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of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three 
repeat multicountry cross-sectional surveys. Lancet. 2006 Aug 26;368(9537):733-43. Erratum in: 
Lancet. 2007 Sep 29;370(9593):1128. 
Barbier N1, Paul C, Luger T, Allen R, De Prost Y, Papp K, Eichenfield LF, Cherill R, Hanifin J. 
Validation of the Eczema Area and Severity Index for atopic dermatitis in a cohort of 1550 
patients from the pimecrolimus cream 1% randomized controlled clinical trials programme. Br J 
Dermatol. 2004 Jan;150(1):96-102.\ 
Beattie PE1, Lewis-Jones MS. A comparative study of impairment of quality of life in children 
with skin disease and children with other chronic childhood diseases. Br J Dermatol. 2006 
Jul;155(1):145-51. 
Beck LA, Thaci D, Hamilton JD, Graham NM, Bieber T et al. Dupilumab treatment in adults 
with Moderate-to-Severe Atopic Dermatitis. N Engl J Med 2014;371:130-9. 
Bieber T. Atopic dermatitis. The New England journal of medicine. 2008 Apr 
3;358(14):1483-94. PubMed PMID: 18385500. 
Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development and 
initial validation of a new tool for measuring atopic eczema severity from the patients' 
perspective. Archives of dermatology. 2004 Dec;140(12):1513-9. PubMed PMID: 15611432. 
Czarnowicki T, Esaki H, Gonzalez J, 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 Oct;136(4):941-951.e3. doi: 
10.1016/j.jaci.2015.05.049. 
Deckers IA, McLean S, Linssen S, et al. Investigating international time trends in the incidence 
and prevalence of atopic eczema 1990-2010: a systematic review of epidemiological studies. 
PLoS One 2012 Jul 11;7(7):e39803. doi: 10.1371/journal.pone.0039803. Epub 2012.  
Ekbäck M1, Tedner M2, Devenney I1, at al. Severe eczema in infancy can predict asthma 
development. A prospective study to the age of 10 years. PLoS One. 2014 Jun 10;9(6):e99609. 
doi: 10.1371/journal.pone.0099609. eCollection 2014. 
Eichenfield LF, Hanifin JM, Luger TA, et al. Consensus conference on pediatric Atopic 
Dermatitis. J Am Acad Dermatol 2003; 49: 1088-95. 
European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD 
index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 
1993;186(1):23-31. PubMed PMID: 8435513. 
Gittler JK, Shemer A, Suarez-Farinas M et al. Progressive activation of TH2/TH22 cytokines and 
selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin 
Immunol 2012;130:1344-54. 
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Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and 
psoriasis--part I: clinical and pathologic concepts. The Journal of allergy and clinical 
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Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and 
psoriasis--part II: immune cell subsets and therapeutic concepts. The Journal of allergy and 
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reliability in atopic dermatitis. Exp Dermatol 2001; 10: 11-18. 
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during subcutaneous injections into the abdomen and thigh: a single-centre, randomized 
controlled trial. Diabetes Obes Metab. 2014 Oct;16(10):971-6.  
Hicks CL, von Baeyer CL, Spafford PA, et al. The Faces Pain Scale-Revised: toward a common 
metric in pediatric pain measurement. Pain. 2001 Aug;93(2):173-83 
Howell MD. The role of human beta defensins and cathelicidins in atopic dermatitis. Current 
opinion in allergy and clinical immunology. 2007 Oct;7(5):413-7. PubMed PMID: 17873581. 
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a general population. Journal of the American Academy of Dermatology. 1994 Jan;30(1):35-9. 
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correlated in patients with atopic dermatitis. Journal of Korean medical science. 2012 
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Laughter D, Istvan JA, Tofte SJ, Hanifin JM. The prevalence of atopic dermatitis in Oregon 
schoolchildren. J Am Acad Dermatol. 2000 Oct;43(4):649-55. 
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. 
Leung DY. Pathogenesis of atopic dermatitis. The Journal of allergy and clinical immunology. 
1999 Sep;104(3 Pt 2):S99-108. PubMed PMID: 10482860. 
Lewis-Jones MS, Finlay AY. The Children's Dermatology Life Quality Index (CDLQI): initial 
validation and practical use. The British journal of dermatology. 1995 Jun;132(6):942-9. 
PubMed PMID: 7662573. 
Luca NJ, Lara-Corrales I, Pope E J. Eczema herpeticum in children: clinical features and factors 
predictive of hospitalization. Pediatr. 2012 Oct;161(4):671-5. doi: 10.1016/j.jpeds.2012.03.057. 
Epub 2012 May 9. 
Mortz CG, Andersen KE, Dellgren C, et al. C Atopic dermatitis from adolescence to adulthood 
in the TOACS cohort: prevalence, persistence and comorbidities. Allergy. 2015 
Jul;70(7):836-45. doi: 10.1111/all.12619 
Mukai H, Noguchi T, Kamimura K, Nishioka K, Nishiyama S. Significance of elevated serum 
LDH (lactate dehydrogenase) activity in atopic dermatitis. J Dermatol. 1990 Aug;17(8):477-81. 
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Ong PY, Leung DYM. The infectious aspects of atopic dermatitis. Immunol Allergy Clin N Am 
2010;30:309-321. 
Proudfoot LE, Powell AM, Ayis S, et al, The European TREatment of severe Atopic eczema in 
children Taskforce (TREAT) survey. Br J Dermatol. 2013 Oct;169(4):901-9. doi: 
10.1111/bjd.12505. Erratum in: Br J Dermatol. 2013 Nov;169(5):1171. 
Schmitt J, Schmitt N, Meurer M. Cyclosporin in the treatment of patients with atopic eczema a 
systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2007; 21: 606–619. 
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. 
Silverberg JI, Simpson EL. Association between severe eczema in children and multiple 
comorbid conditions and increased healthcare utilization. Pediatr Allergy Immunol. 2013 
Aug;24(5):476-86. doi: 10.1111/pai.12095. 
Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 2003 
Dec;112(6 Suppl):S118-27. Review. 
Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its impact on the family and financial 
cost. Arch Dis Child. 1997 Feb;76(2):159-62. PubMed PMID: 9068310. Pubmed Central 
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Takeda K, Kishimoto T, Akira S. STAT6: its role in interleukin 4-mediated biological functions. 
J Mol Med 1997; 75:317–326. 
Thepen T, Langeveld-Wildschut EG, Bihari IC et al. Biphasic response against aeroallergen in 
atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: An 
immunocytochemical study. J Allergy Clin Immunol 1996;97:828-37. 
van der Hulst AE, Klip H, Brand PL Risk of developing asthma in young children with atopic 
eczema: a systematic review. J Allergy Clin Immunol. 2007 Sep;120(3):565-9. 
Wirnsberger G1, Hebenstreit D, Posselt G, Horejs-Hoeck J, Duschl A. IL-4 induces expression 
of TARC/CCL17 via two STAT6 binding sites. Eur J Immunol. 2006 Jul;36(7):1882-91. 
Yaghmaie P1, Koudelka CW, Simpson EL. Mental health comorbidity in patients with atopic 
dermatitis. J Allergy Clin Immunol. 2013 Feb;131(2):428-33. doi: 10.1016/j.jaci.2012.10.041. 
Epub 2012 Dec 13. 
Zheng T, Yu J, Oh MH, Zhu Z. The atopic march: progression from atopic dermatitis to allergic 
rhinitis and asthma. Allergy Asthma Immunol Res. 2011 Apr;3(2):67-73. doi: 
10.4168/aair.2011.3.2.67. 
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22. 
INVESTIGATOR’S AGREEMENT 
I 
have 
read 
the 
attached 
protocol: 
A 
RANDOMIZED, 
DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF 
DUPILUMAB 
ADMINISTERED 
CONCOMITANTLY 
WITH 
TOPICAL 
CORTICOSTEROIDS IN PATIENTS ≥6 TO <12 YEARS OF AGE, WITH 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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APPENDIX 1. 
FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF ADVERSE EVENTS 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 preclinical 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 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 preclinical data or prior 
clinical data 
NOTE: This list is not exhaustive.
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APPENDIX 2. 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 
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4 = Severe disease 
Severe erythema and severe papulation/infiltration 
Deep/dark red erythema; marked and extensive elevation 
(papulation/infiltration) 
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APPENDIX 3. POTENTIAL MAJOR PROTOCOL VIOLATIONS 
*Note: This is a preliminary list and the final list will be generated prior to database lock. 
Category 
Description of Protocol Deviation 
Inclusion Criteria not met 
but patient randomized 
Male or female not ≥6 to <12 years of age at time of screening visit 
Inclusion Criteria not met 
but patient randomized 
No diagnosis of AD according to the American Academy of Dermatology consensus 
criteria (Eichenfield 2003) at screening visit 
Inclusion Criteria not met 
but patient randomized 
Chronic AD not diagnosed at least 1 year prior to the screening visit 
Inclusion Criteria not met 
but patient randomized 
IGA <4 at the baseline visit 
Inclusion Criteria not met 
but patient randomized 
EASI <21 at the baseline visit 
Inclusion Criteria not met 
but patient randomized 
BSA <15% at the baseline visit 
Inclusion Criteria not met 
but patient randomized 
Baseline worst itch score weekly average score for maximum itch intensity <4 
Inclusion Criteria not met 
but patient randomized 
Without documented recent history (within 6 months before the baseline visit) of 
inadequate response to topical AD medication(s)   
Inclusion Criteria not met 
but patient randomized 
Has not applied a stable dose of topical emollient (moisturizer) twice daily for at least 
11 out of 14 doses during the 7 consecutive days immediately before the baseline visit 
Inclusion Criteria not met 
but patient randomized 
Not willing and able to comply with all clinic visits and study-related procedures 
Inclusion Criteria not met 
but patient randomized 
Patient, either alone or with help of parents/legal guardians, as appropriate, is not able 
to understand and complete study-related questionnaires 
Inclusion Criteria not met 
but patient randomized 
Parent or legal guardian did not provide signed informed consent. Patients have not 
provided separate informed assent to enroll in the study, and signed and dated either a 
separate informed assent form (IAF) or the informed consent form (ICF) was not 
signed by the parent/legal guardian (as appropriate based on local regulations and 
requirements). 
Exclusion Criteria met 
but patient randomized 
Participation in a prior dupilumab clinical study 
Exclusion Criteria met 
but patient randomized 
Treatment with a systemic investigational drug before 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 
Exclusion Criteria met 
but patient randomized 
Treatment with a topical investigational drug within 2 weeks prior to the baseline visit 
Exclusion Criteria met 
but patient randomized 
Treatment with crisabarole within 2 weeks prior to the baseline visit 
Exclusion Criteria met 
but patient randomized 
History of important side effects of medium-potency topical corticosteroids (eg, 
intolerance to treatment, hypersensitivity reactions*, significant skin atrophy, 
systemic effects), as assessed by the investigator or patient’s treating physician  
*If a patient has a history of hypersensitivity reaction to any particular TCS, 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 TCS drug product that does not have cross-reactivity to the 
drug product that caused the hypersensitivity. 
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Category 
Description of Protocol Deviation 
Exclusion Criteria met 
but patient randomized 
Treatment with a TCI within 2 weeks prior to the baseline visit 
Exclusion Criteria met 
but patient randomized 
Having used any of the following treatments within 4 weeks before the baseline visit, 
or any condition that, in the opinion of the investigator, is likely to require such 
treatment(s) during the first 4 weeks of study treatment: 
a. Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, 
cyclosporine, mycophenolate-mofetil, interferon gamma, Janus kinase inhibitors, 
azathioprine, methotrexate, etc) 
b. Phototherapy for AD 
Exclusion Criteria met 
but patient randomized 
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 before the baseline 
visit, whichever is longer 
Exclusion Criteria met 
but patient randomized 
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 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: 
 Patients for whom administration of live (attenuated) vaccine can be safely 
postponed would be eligible to enroll into the study. 
 Patients who have their vaccination preponed can enroll in the study only after a 
gap of 4 weeks following administration of the vaccine. 
Exclusion Criteria met 
but patient randomized 
Planned or anticipated use of any prohibited medications and procedures during study 
treatment 
Exclusion Criteria met 
but patient randomized 
Body weight <15 kg at baseline 
Exclusion Criteria met 
but patient randomized 
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) 
Exclusion Criteria met 
but patient randomized 
Regular use (more than 2 visits per week) of a tanning booth/parlor within 8 weeks of 
the baseline visit 
Exclusion Criteria met 
but patient randomized 
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 
Exclusion Criteria met 
but patient randomized 
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, 
other mycobacterial infections, 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 
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Category 
Description of Protocol Deviation 
Exclusion Criteria met 
but patient randomized 
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. 
Exclusion Criteria met 
but patient randomized 
Known history of human immunodeficiency virus (HIV) infection or HIV 
seropositivity at the screening visit 
Exclusion Criteria met 
but patient randomized 
With an established diagnosis of hepatitis B viral infection at the time of screening or 
is positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody 
(HBcAb) at the time of screening 
NOTE: Patients who have gained immunity for hepatitis B virus infection after 
vaccination (patients who are HBsAg negative, hepatitis B surface antibody [HBsAb] 
positive, and HBcAb negative) are eligible for the study.  
Exclusion Criteria met 
but patient randomized 
With an established diagnosis of hepatitis C viral infection at the time of screening or 
is positive for hepatitis C antibody at the screening visit 
Exclusion Criteria met 
but patient randomized 
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  
Exclusion Criteria met 
but patient randomized 
Presence of any 1 or more of the following abnormalities in laboratory test results at 
screening: 
 Platelets ≤100 × 103/μL 
 Neutrophils <1.5 × 103/μL 
 Creatine phosphokinase (CPK) >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. Only if the repeat test confirms the 
abnormality, the patient would be categorized as a screen failure. 
Exclusion Criteria met 
but patient randomized 
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. 
Exclusion Criteria met 
but patient randomized 
History of malignancy before the baseline visit 
Exclusion Criteria met 
but patient randomized 
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 
Exclusion Criteria met 
but patient randomized 
Severe concomitant illness(es) that, in the investigator’s judgment, would adversely 
affect the patient’s participation in the study. Examples include, but are not limited to 
patients with short life expectancy, patients with uncontrolled diabetes (hemoglobin 
A1c ≥9%), patients with cardiovascular conditions (eg, Class III or IV cardiac failure 
according to the New York Heart Association classification), severe renal conditions 
(eg, patients on dialysis), hepato-biliary conditions (eg, Child-Pugh class B or C), 
neurological conditions (eg, demyelinating diseases), active major autoimmune 
diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other 
severe endocrinological, gastrointestinal, metabolic, pulmonary, 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). 
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Category 
Description of Protocol Deviation 
Exclusion Criteria met 
but patient randomized 
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.). 
Exclusion Criteria met 
but patient randomized 
Planned major surgical procedure during the patient’s participation in this study 
Exclusion Criteria met 
but patient randomized 
Patient or his/her immediate family is a member of the dupilumab investigational 
team 
Exclusion Criteria met 
but patient randomized 
Patient is female who is pregnant, breastfeeding, or planning to become pregnant or 
breastfeed during the study 
Exclusion Criteria met 
but patient randomized 
Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities 
Exclusion Criteria met 
but patient randomized 
Patient is female of childbearing potential* and sexually active, who is unwilling to 
use highly effective methods of contraception prior to the initial dose, during the 
study and for at least 12 weeks after the last dose of study drug. Highly effective 
contraceptive measures include stable use of combined (estrogen and progestogen 
containing) hormonal contraception (oral, vaginal, transdermal) or progestogen-only 
hormonal contraception (oral, injectable, implantable) associated with inhibition of 
ovulation initiated 2 or more menstrual cycles prior to screening; intrauterine device 
(IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation; 
vasectomized partner; and or sexual abstinence**. 
* For the purpose of this study, any female who has had her first menstrual period 
(menarche) and is sexually active will be considered to be of childbearing 
potential. Female patients who are not of childbearing potential at the start of the 
study but have the onset of menarche during the course of the study and are 
sexually active will also have to follow adequate birth control methods to continue 
participation in the study.  
** Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the patient. 
NOTE:  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception. 
Visit not performed 
Visit 2 not performed (TCS Standardization) 
Visit not performed 
Visit 3 not performed (Baseline) 
Visit not performed 
V19/EOT or Early Termination visit not performed (protocol deviation not applicable 
for patients who completed EOT and rolled over to OLE) 
Visit performed out of 
window 
Visit 2 (TCS Standardization) visit is not within Days (-14 to -1) prior to Visit 3 
(Baseline) 
Procedure not performed 
IGA not performed at Screening, Baseline/Day 1 or Visit 19/EOT 
Procedure not performed 
EASI not performed at Screening, Baseline/Day 1 or Visit 19/EOT 
Procedure not performed 
BSA not performed at Screening or Baseline/Day 1 
Procedure not performed 
Physical Examination not performed at Screening 
Procedure not performed 
Electrocardiogram not performed at Screening 
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Category 
Description of Protocol Deviation 
Procedure not performed 
Serum Pregnancy testing not performed at Screening (must check WOCBP at 
Screening visit: if Yes, for WOCBP then must have results) 
Procedure not performed 
Pregnancy testing not performed at Baseline, Visits 5, 7, 11, 15, 22/EOS or ET (must 
check WOCBP at Screening visit: if Yes, for WOCBP then must have results).   
Procedure not performed 
HIV, HBsAg, HBsAb, HBcAb and Hepatitis C Ab not performed at Screening visit 
Procedure not performed 
Hematology not performed at Screening or Baseline/Day 1 
Procedure not performed 
Chemistry not performed at Screening or Baseline/Day 1 
Procedure not performed 
Medical History information not collected at Screening 
Procedure not performed 
Prior Atopic Dermatitis history information not collected at Screening 
Procedure not performed 
Ophthalmology Exam not performed during Screening period for patients with 
history of conjunctivitis, blepharitis, or keratitis within 12 months of screening 
Procedure not performed 
More than 1 scheduled study drug administration missed 
Dosing non compliance 
Study drug given to patient without being randomized 
Prohibited medications 
Treatment with Live (attenuated) vaccine during the study. Examples in section 7.8.1 
of the protocol 
Prohibited medications 
Treatment with Immunomodulating biologics during the study 
Prohibited medications 
Treatment with an investigational drug (other than dupilumab) during the study 
Prohibited medications 
Treatment with systemic nonsteroid immunosuppressant during the study. (may be 
used as rescue, see section 7.3 of protocol for details) 
Prohibited medications 
Treatment with systemic corticosteroids during the study. (may be used as rescue, see 
section 7.3 of protocol for details) 
Prohibited medications 
Treatment with crisabarole during the study.  
Prohibited medications 
Treatment with TCI 
Note: The use of TCI is prohibited during the 2-week standardization period leading 
up to the baseline visit, and the treatment and follow-up periods 
Prohibited medications 
Treatment with high-potency or very-high-potency TCS, (high-potency TCS may be 
used as rescue, see Section 7.3 for details) 
Prohibited medications 
Initiation of treatment of AD with prescription moisturizers 
Prohibited procedures 
Major elective surgical procedures 
Prohibited procedures 
Tanning in a bed/booth 
Prohibited procedures 
Phototherapy (UVA, UVB, nbUVB, high dose UVA and PUVA) 
Other: Randomization 
Mis-stratification of patient due to incorrectly entered weight group in IVRS 
Handling of 
Investigational Product 
was not performed in 
accordance with the 
protocol 
Investigational product (IP) has been destroyed without having an approval from the 
sponsor  
Handling of 
Investigational Product 
was not performed in 
accordance with the 
protocol 
Decision to unblind the IP treatment assignment has been made by an unauthorized 
personnel 
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CONFIDENTIAL 
Category 
Description of Protocol Deviation 
Handling of 
Investigational Product 
was not performed in 
accordance with the 
protocol 
Patient was dosed with IP that had a temperature excursion and was deemed 
unacceptable 
Inadequate Informed 
Consent administration 
Incorrect ICF (unapproved version, incorrect version, incorrect study, not patient's 
language) 
Inadequate Informed 
Consent administration 
ICF not signed by patient/parent, ICF not dated by patient/parent (incomplete date) or 
initialed (if applicable).  Consent and/or assent not obtained. 
Inadequate Informed 
Consent administration 
ICF signed after screening or any study procedures 
Inadequate Informed 
Consent administration 
Patient did not re-consent on new version(s) of ICF (to be done by the next following 
visit)  
Inadequate Informed 
Consent administration 
ICF missing for sub-study and DNA sample collected in the presence of a sample 
Inadequate source 
documents 
Patient laboratory not reviewed to confirm eligibility by PI 
Personnel not qualified 
and/or designated to 
perform study-related 
activities. 
Patient confidentiality not maintained 
Personnel not qualified 
and/or designated to 
perform study-related 
activities. 
Improper delegation of duties 
Personnel not qualified 
and/or designated to 
perform study-related 
activities. 
Site staff not properly trained to conduct study 
Personnel not qualified 
and/or designated to 
perform study-related 
activities. 
Staff inappropriately unblinded to study drug arm (except EU sites where unblinded 
information can be provided based on country requirements)  
Randomization error-
Patient Randomized to 
wrong treatment 
Patient was randomized and treated with study drug from the incorrect treatment 
group 
Randomization error-
Patient Randomized to 
wrong treatment 
Ineligible patient randomized/enrolled 
Other: Safety monitoring 
after study drug 
Study drug overdose has not been reported to the sponsor per protocol requirements 
Other: Safety monitoring 
after study drug 
Pregnancy has not been reported to sponsor per protocol requirements  
Other: ePRO compliance 
0 = or lesser than 60% compliance NRS 
Other: ePRO compliance 
0 = or lesser than 60% compliance TCS 
Other: ePRO compliance 
0 = or lesser than 60% compliance moisturizer. 
Other: ePRO compliance 
TCS not applied for at least 11 of 14 days consecutively prior to randomization. 
Other: Laboratory  
Expired lab kits used 
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CONFIDENTIAL 
Category 
Description of Protocol Deviation 
Other: Laboratory  
Improper collection/processing/shipping of Serum pregnancy, Urine pregnancy or 
HIV, HBsAg, HBsAb, HBcAb and Hepatitis C Ab lab samples 
Other: Laboratory  
Improper collection/processing/shipping of Hematology or Chemistry lab samples at 
Screening and Baseling visits 
Other: Laboratory  
Serum pregnancy, Urine pregnancy or HIV, HBsAg, HBsAb, HBcAb and Hepatitis C 
Ab lab samples were beyond stability and no results available.  
Other: Laboratory  
Hematology or Chemistry lab samples at Screening or Baseling visits were beyond 
stability and no results available.  
Other: AESI 
AESI not reported within protocol defined window 
Other: SAE 
SAE not reported within protocol defined window 
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CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Investigate 
the Efficacy and Safety of Dupilumab Administered Concomitantly with 
Topical Corticosteroids in Patients, ≥6 Years to <12 Years of Age, with 
Severe Atopic Dermatitis 
Protocol Number: 
R668-AD-1652, Amendment 3 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
                                        VV-RIM-00053769-2.0 Approved - 21 Nov 2018 GMT-5:00


Signature Page for VV-RIM-00053769 v2.0
Signature Page for VV-RIM-00053769 v2.0 Approved
ESig Approval
gement
21-Nov-2018 16:35:11 GMT+0000
ESig Approval
21-Nov-2018 16:54:07 GMT+0000
ESig Approval
21-Nov-2018 18:16:44 GMT+0000
ESig Approval
21-Nov-2018 18:36:09 GMT+0000
                                        VV-RIM-00053769-2.0 Approved - 21 Nov 2018 GMT-5:00

SAP_001.pdf: 
Clinical and Regulatory Development 
Biostatistics and Data Management 
STATISTICAL ANALYSIS PLAN 
Title: A randomized, double-blind, placebo-controlled study to investigate the efficacy and 
safety of dupilumab administered concomitantly with topical corticosteroids in patients, > 
6 years to <12 years of age, with severe Atopic Dermatitis 
Protocol: R668-AD-1652.03 
Investigational product: Dupilumab (REGN668) 
Sponsor: Regeneron Pharmaceuticals, Inc. 
Statistician: 
 
Study Medical Director: 
 
Clinical Trial Manager: 
 
Version/Date: Version 1.0 / 07May2019 
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Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 2 of 83 
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. 
 
Study Biostatistician  
 
(Author) 
 
Print Name  
Signature 
Date (DDMMMYYYY) 
Study Medical Director 
 
(Approver) 
 
Print Name  
Signature 
Date (DDMMMYYYY) 
Head of BDM or designee 
 
(Approver) 
 
Print Name  
Signature 
Date (DDMMMYYYY) 
 
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Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
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TABLE OF CONTENTS 
1. 
OVERVIEW ....................................................................................................... 8 
1.1. Background and Rationale .................................................................................. 8 
1.2. Study Objectives ................................................................................................. 9 
1.2.1. 
Primary Objective .................................................................................... 9 
1.2.2. 
Secondary Objectives ............................................................................... 9 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ............. 9 
2. 
INVESTIGATIONAL PLAN ........................................................................... 10 
2.1. Study Design and Randomization ..................................................................... 10 
2.2. Sample Size and Power Considerations ............................................................ 11 
2.3. Study Plan ......................................................................................................... 12 
3. 
ANALYSIS POPULATIONS .......................................................................... 14 
3.1. The Efficacy Analysis Sets ............................................................................... 14 
3.2. The Safety Analysis Set (SAF) ......................................................................... 14 
3.3. The Pharmacokinetic Analysis Set (PKAS) ..................................................... 15 
3.4. The Immunogenicity Analysis Set (AAS) ........................................................ 15 
4. 
ANALYSIS VARIABLES ............................................................................... 16 
4.1. Demographic and Baseline Characteristics ...................................................... 16 
4.2. Medical History and Atopic Disease Medical History ..................................... 16 
4.3. Prior / Concomitant Medications and Procedures ............................................ 16 
4.4. Efficacy Variables ............................................................................................. 18 
4.4.1. 
Primary Efficacy Variable ...................................................................... 18 
4.4.2. 
Secondary Efficacy Variables ................................................................ 19 
4.4.3. 
Other Efficacy Variables ........................................................................ 23 
4.5. Safety Variables ................................................................................................ 25 
4.5.1. 
Adverse Events and Serious Adverse Events Variables ........................ 25 
4.5.2. 
Laboratory Safety Variables................................................................... 28 
4.5.3. 
Vital Sign Variables ............................................................................... 29 
4.5.4. 
Body Weight and Height ........................................................................ 29 
4.5.5. 
Physical Examination Variables ............................................................ 29 
4.5.6. 
12-Lead Electrocardiography (ECG) Variables ..................................... 29 
4.6. Pharmacokinetic (PK) Variables....................................................................... 30 
4.7. Immunogenicity Variables ................................................................................ 30 
4.8. Biomarkers Variables........................................................................................ 30 
5. 
STATISTICAL METHODS ............................................................................. 31 
5.1. Demographics and Baseline Characteristics ..................................................... 31 
5.2. Medical and AD History ................................................................................... 31 
5.3. Pre-treatment/Concomitant Medications/Procedures ....................................... 31 
5.4. Subject Disposition ........................................................................................... 32 
5.5. Dose administration .......................................................................................... 32 
5.6. Treatment Exposure and Observation Period ................................................... 33 
5.7. Analyses of Efficacy Variables ......................................................................... 33 
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Statistical Analysis Plan 
 
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CONFIDENTIAL 
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5.7.1. 
Analysis of Primary Efficacy Variable .................................................. 35 
5.7.2. 
Analyses of Secondary Efficacy Variables ............................................ 36 
5.7.3. 
Subgroup Analysis ................................................................................. 38 
5.7.4. 
Analyses of Other Efficacy Variables .................................................... 38 
5.8. Analysis of Safety Data .................................................................................... 39 
5.8.1. 
Adverse Events ....................................................................................... 39 
5.8.2. 
Analysis of Clinical Laboratory Measurements ..................................... 40 
5.8.3. 
Analysis of Vital Signs ........................................................................... 41 
5.8.4. 
Analysis of Physical Exams ................................................................... 41 
5.8.5. 
Analysis of 12-Lead ECG ...................................................................... 41 
5.9. Analysis of Pharmacokinetic Data .................................................................... 41 
5.10. Analysis of Immunogenicity Data .................................................................... 42 
5.10.1. Analysis of ADA Data ........................................................................... 42 
5.10.2. Analysis of Neutralizing Antibodies (NAb)........................................... 43 
5.11. Association of Immunogenicity with Exposure, Safety and Efficacy .............. 43 
5.11.1. Immunogenicity and Exposure .............................................................. 43 
5.11.2. Immunogenicity on Safety and Efficacy ................................................ 43 
5.12. Analysis of Biomarker Data.............................................................................. 44 
6. 
DATA CONVENTIONS .................................................................................. 46 
6.1. Definition of Baseline for Efficacy/Safety Variables ....................................... 46 
6.2. General Data Handling Conventions ................................................................ 46 
6.3. Data Handling Convention Missing Data ......................................................... 46 
6.4. Analysis Visit Window ..................................................................................... 48 
7. 
INTERIM ANALYSIS ..................................................................................... 50 
8. 
SOFTWARE ..................................................................................................... 50 
9. 
REFERENCES ................................................................................................. 51 
10. 
APPENDIX ....................................................................................................... 52 
10.1. Summary of Statistical Analyses ...................................................................... 52 
10.2. Schedule of Events ............................................................................................ 55 
10.3. Potential Major Protocol Violations ................................................................. 66 
10.4. Criteria for Treatment-Emergent Potentially Clinical Significant Value for Pediatric 
Patients (>=6 to <11 years old) ................................................................................. 73 
10.5. Search Criteria for TEAE of Special Interest/TEAE Syndrome1 ..................... 78 
10.6. Algorithm for RESCUE TREATMENTS ........................................................ 80 
10.7. PROMIS Scoring Tables................................................................................... 82 
 
 
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Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
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LIST OF TABLES 
Table 1: 
Schedule of Events (Screening, TCS Standardization, Baseline, and 
Treatment Period) .......................................................................................................55 
Table 2: Schedule of Events (Follow-Up Period, Unscheduled Visits, and Early 
Termination) ...............................................................................................................61 
 
LIST OF FIGURES 
Figure 1: 
Randomization Scheme ..............................................................................................11 
Figure 2: 
Study Flow Diagram ...................................................................................................12 
 
  
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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 
CMH 
Cochran-Mantel-Haenszel 
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 
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 
IGA 
Investigator global assessment 
IL 
Interleukin 
IgE 
Immunoglobulin E 
LDH 
Lactate dehydrogenase  
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
NAb 
Neutralizing antibody 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
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Statistical Analysis Plan 
 
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CONFIDENTIAL 
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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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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 
realize the analysis of data for the R668-AD-1652 study. 
This plan 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. These revisions will be 
based on blinded review of the study and data.  This plan will be finalized prior to the final 
database lock. 
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. Phase 3 of the International Study of Asthma and Allergies in Childhood (ISAAC) 
showed a 1-year period prevalence rate for AD in the 6 to 7 year age group to be 15% or more in 
Australia, England, and Scandinavia.  A study conducted in the United States (US) in school-
going children aged 5 to 9 years old showed similar prevalence rate of around 17%. 
There is currently a high unmet medical need for a safe and effective therapy for AD in young 
children.  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.  The more effective TCI products (tacrolimus 0.1%) 
are not approved for use in children aged 6 to 11 years old.  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 (refer to products’ US prescribing 
information). 
Systemic agents are used off-label in children aged 6 to 11 years old (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. 
All of these systemic agents have significant side effects in children, including stunted growth, 
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CONFIDENTIAL 
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diabetes, cutaneous atrophy, hypertension, osteoporosis, and rebound exacerbation after 
discontinuation 
(corticosteroids), 
myelosuppression 
and 
hepatotoxicity 
(methotrexate), 
nephrotoxicity and hypertension (cyclosporine), increased risk of malignancies (cyclosporine, 
azathioprine), 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. 
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. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
The primary objective of the study is to demonstrate the efficacy of dupilumab administered 
concomitantly with TCS in patients, ≥6 years to <12 years of age, with severe AD. 
1.2.2. 
Secondary Objectives 
The secondary objective of the study is to assess the safety of dupilumab administered 
concomitantly with TCS in patients ≥6 years to <12 years of age with severe AD. 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
None. 
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2. 
INVESTIGATIONAL PLAN 
2.1. 
Study Design and Randomization 
This is a randomized, double-blind, placebo-controlled, parallel-group study in which study 
treatments (dupilumab/placebo) will be administered concomitantly with TCS. The study 
population will include patients ≥6 years to <12 years of age with severe AD whose disease 
cannot be adequately controlled with topical medications. Approximately 330 study patients are 
planned to be enrolled in the study. 
Patients who continue to meet eligibility criteria at baseline will undergo day 1/baseline 
assessments and will be randomized in a 1:1:1 ratio stratified by baseline body weight (<30 kg 
and ≥30 kg) (Figure 1) and region (North America, Europe) as follows:   
 dupilumab Q2W treatment group combined with TCS (dupilumab Q2W + TCS):   
 Patients with baseline weight <30 kg will receive Q2W SC injections of 100 mg 
dupilumab (0.7 mL of a 150 mg/mL solution) from week 2 to week 14, following 
a loading dose of 200 mg on day 1.  
 Patients with baseline weight ≥30 kg will receive Q2W SC injections of 200 mg 
dupilumab (1.14 mL of a 175 mg/mL solution) from week 2 to week 14, 
following a loading dose of 400 mg on day 1  
 dupilumab Q4W treatment group combined with TCS (dupilumab Q4W + TCS):  all 
patients regardless of weight will receive Q4W SC injections of 300 mg dupilumab (2 
mL of a 150 mg/mL solution) from week 4 to week 12, following a loading dose of 
600 mg on day 1.  
 placebo treatment group combined with TCS (Placebo + TCS): Patients will receive 
matching placebo (including doubling the amount of placebo on day 1 to match the 
loading dose).  In order to maintain blinding, the patients in the <30 kg weight 
stratum will be randomly assigned to receive, in a 1:1 ratio, either Q2W SC injections 
of placebo (0.7 mL) matching the 100 mg dupilumab (including doubling the amount 
of placebo on day 1 to match the loading dose) or Q4W SC injections of placebo (2 
mL) matching the 300 mg dupilumab (including doubling the amount of placebo on 
day 1 to match the loading dose).  In the ≥30 kg weight stratum, the patients 
randomized to the placebo group will receive, in a 1:1 ratio, either Q2W SC injections 
of placebo (1.14 mL) matching the 200 mg dupilumab (including doubling the 
amount of placebo on day 1 to match the loading dose) or Q4W SC injections of 
placebo (2 mL) matching the 300 mg dupilumab (including doubling the amount of 
placebo on day 1 to match the loading dose).   
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Figure 1: Randomization Scheme  
 
Arm A consists of patients receiving Q2W treatment, either 100 mg for patients weighing <30 kg or 200 mg for 
patients weighing ≥30 kg. Arm B consists of patients receiving Q4W treatment , 300 mg regardless of weight. Arm 
C consists of patients receiving placebo treatment Q2W and Q4W and matching the dupilumab Q2W and Q4W dose 
regimens. 
2.2. 
Sample Size and Power Considerations 
Due to an inadvertent operational error, 68 patients were potentially unblinded. Details about the 
error and why it may have been unblinding will be described in the clinical study report. An 
additional approximately 90 patients were added to the study to ensure that the original number 
of blinded patients for all treatment groups is available for sensitivity analyses that exclude the 
potentially unblinded patients. This will maintain study balance and power.  
Initially it is estimated that with 80 patients per group, at the 2-sided 5% significance level, the 
study will have a power table shown as below: 
 
Placebo 
+ TCS 
(N=80) 
Dupilumab 100mg/200mg 
Q2W + TCS 
(N=80) 
Dupilumab 300mg Q4W + 
TCS 
(N=80) 
Q2W 
+ TCS 
Treatment 
Difference Power 
Q4W 
+ TCS 
Treatment 
Difference Power 
Proportion of patients 
with IGA score 0 or 1 
at week 16 (%) 
5% 
28% 
23% 
97% 
22% 
17% 
87% 
Proportion of patients 
with EASI-75 at week 
16 (%) 
17% 
68% 
51% 
99% 
62% 
45% 
99% 
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The significance level is set to 2-sided, 0.05 level. At the time the study was designed, there were 
no data available on the effects of dupilumab in pediatric patients. The assumptions used for the 
power calculations were estimated based on results from the R668-AD-1224 study (phase 3 
combination study with TCS for adult AD patients) and R668-AD-1021 study (a phase 2b dose-
ranging study in adults with AD) for patients with IGA=4 at baseline. Based on the result from 
the R668-AD-1021 study, the efficacy profile for dupilumab 200 mg Q2W was similar to 
dupilumab 300 mg Q2W. Therefore, the adult efficacy results from dupilumab 300 mg Q2W 
were used to assume the treatment effect for dupilumab 100mg/200mg Q2W in the study. This 
was a conservative assumption as it was expected that the effect of dupilumab in children would 
be greater than that seen in adults. The sample size calculations were done using nQuery 
(Version 7.0). 
Adding 90 patients, the total sample size of the study will be up to approximately 330 patients 
(110 patients per group), or approximately 262 patients (80, 91 and 91 in Q2W, Q4W, and 
placebo group, respectively) if the potentially unblinded patients are excluded. With the sample 
size of 330 patients or 262 patients, the power for the co-primary endpoints will be greater than 
90%.  
2.3. 
Study Plan 
The study will consist of the following periods (Figure 2):  
1. Screening of up to 9 weeks,  
2. TCS standardization period of 2 weeks,   
3. Treatment period of 16 weeks, and   
4. Follow-up of 12 weeks (for patients who do not enter the OLE)  
Figure 2: Study Flow Diagram 
 
D = study day; W = study week  
Note:  The length of the screening period is not fixed, but the screening period and TCS standardization must not 
exceed 77 days.  The length of the TCS standardization period is fixed at 14 days.  
1 For patients who enter the OLE, week 16 is the end of study.  
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After the parents or legal guardians provide informed consent and patients provide assent, the 
patients will be assessed for study eligibility at the screening visit.  During the screening period, 
systemic treatments for AD will be washed out, as applicable, according to the eligibility 
requirements.  The use of TCS (±TCI) will be permitted at the discretion of the investigator 
during the screening period until day -14. Starting on day -14, all patients will initiate a 
standardized TCS treatment regimen according to the guidelines.  Patients may be rescreened, 
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. 
Patients who continue to meet eligibility criteria at baseline will undergo day 1/baseline 
assessments and will be randomized in a 1:1:1 ratio stratified by baseline body weight (<30 kg 
and ≥30 kg) (Figure 1) and region (North America, Europe).  
During the treatment period, patients will have weekly in-clinic visits through week 4, and then 
in-clinic visits Q4W through week 16 with weekly telephone visits in between the in-clinic 
visits.  Parents/caregivers will be trained on injecting study drug during in-clinic visit 3 (day 1), 
visit 5 (week 2), and visit 7 (week 4) (this only applies to patients who will receive Q2W 
treatment during the study).  During weeks in which no in-clinic visit is scheduled, the 
parent/caregiver will administer study drug to the patient. In case the parent/caregiver does not 
want to administer study drug to patient, they may have the clinic staff administer all the study 
drug injections in the clinic.  Safety, laboratory, and clinical assessments will be performed at 
specified clinic visits, as noted in Appendix 10.2.  The end of treatment period visit will occur at 
week 16, two weeks after the last dose of study drug for patients randomized to the Q2W 
treatment group or placebo Q2W group, and 4 weeks after the last dose of study drug for patients 
randomized to the Q4W treatment or placebo Q4W group.  The co-primary endpoints will be 
assessed at this visit.  If patients prematurely discontinue study treatment, the patients will be 
encouraged to stay in the study to have data collected at all remaining scheduled visits until 
completion of the planned end of study visit.  Patients who participate in the study may 
subsequently be eligible to participate in an OLE study.  All patients will be offered the 
opportunity to screen for entry into the OLE study at the end of the treatment period (week 16).  
Patients who decline to enroll in the OLE study or those who fail eligibility criteria for the OLE 
study will have a 12-week follow-up period.  For these patients, after week 16, follow-up visits 
will occur every 4 weeks from week 20 to week 28.  During the follow-up period, patients will 
be monitored for safety and tolerability and have laboratory and clinical assessments as noted in 
Appendix 10.2. 
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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 Efficacy Analysis Sets 
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 considered to be the primary analysis set.  
The modified full analysis set (mFAS) includes all randomized patients but excludes potentially 
unblinded patients. The primary endpoint, co-primary endpoint, and selected secondary 
endpoints will be evaluated in the mFAS as sensitivity analyses.  
The per protocol set (PPS) includes all patients in the FAS except for those who are excluded 
because of major protocol violations. A preliminary list of potential major protocol violations is 
provided in Appendix 10.3 and a final list will be generated prior to database lock. The PPS will 
also exclude potentially unblinded patients.  
The primary and co-primary endpoints will also be evaluated in the PPS.  
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who receive at least one injection 
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: 
Randomized to 
Treatment Received 
Treatment Assignment 
Dupilumab (any regimen) All placebo 
Placebo 
Dupilumab (any regimen) ≥ 1 Dupilumab (any regimen) 
Original randomization group 
Placebo 
1 Dupilumab (any regimen) 
Dupilumab regimen received 
Placebo 
> 1 Dupilumab (any regimen) 
First Dupilumab regimen received 
[1] 
[1] For example, a patient was randomized to Placebo group but received one 100mg Dupilumab and one 200mg 
Dupilumab accidently. This patient will be assigned to 100mg Q2W Dupilumab treatment group. 
In addition:  
 Nonrandomized but treated patients will not be part of the safety population; 
however, their safety data will be presented separately. 
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 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:  
 Week 16 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  
 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 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 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. 
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 (AAS) 
The ADA population will consist of all patients who received any study drug and who had at 
least one non-missing ADA result after first dose of the study drug. Patients will be analyzed 
according to the treatment actually received.The NAb analysis set includes all patients who 
received any study drug and who are negative in the ADA assay or with at least one non-missing 
result in the NAb assay [patients who are ADA negative are set to negative in the NAb analysis 
set]. 
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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 (≥6 to <9, ≥9 to <12), sex, 
ethnicity, race, baseline weight (kg) with grouping (<30 kg,  >=30 kg), height (m), 
BMI (kg/m2) with grouping (<20, >=20) 
 Baseline characteristics: Duration of AD disease with grouping (< 5 years, >=5 
years), worst itch score, Investigator’s Global Assessment (IGA) score, Eczema Area 
and Severity Index (EASI) score, SCORing Atopic Dermatitis (SCORAD) score, 
Body Surface Area (BSA) affected by Atopic Dermatitis, Patient global impression of 
disease, Patient Oriented Eczema Measure (POEM), Children's Dermatology Life 
Quality Index (CDLQI), Global Individual Signs score (GISS), Dermatitis Family 
Index (DFI) and Patient Reported Outcomes Measurements Information Systems 
(PROMIS) anxiety and depression score 
4.2. 
Medical History and Atopic Disease Medical History 
Medical history will be coded to a Preferred Term (PT), High Level Term (HLT) and associated 
primary System Organ Class (SOC) according to the latest available version of MedDRA at the 
coding CRO. Information on conditions related to AD 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. 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 to the ATC level 2 (therapeutic main group) and ATC 
level 4 (chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary (WHODD) at the coding CRO. Patients will be counted once in all ATC categories 
linked to the medication. 
Procedures will be coded to a Preferred Term (PT), High Level Term (HLT) and associated 
primary System Organ Class (SOC) according to the latest available version of MedDRA at the 
coding CRO. 
Prior medications/procedures: medications taken or procedures performed prior to administration 
of the first study drug. 
Concomitant medications/procedures: medications taken or procedures performed following the 
first dose of study drug through the EOS visit.  
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 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 week 16 visit date is missing. Medications/procedures taken 
during the 16 week treatment period and continued afterwards into 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 
 Treatment with immunomodulating biologics 
 Treatment with an investigational drug (other than dupilumab) 
 Treatment with systemic nonsteroidal immunosuppressant (may be used as rescue) 
 Treatment with systemic corticosteroids (may be used as rescue) 
 Treatment with crisabarole 
 Treatment with TCI 
Note: The use of TCI is prohibited during the 2-week standardization period leading up to the 
baseline visit, and the treatment and follow-up periods 
 Treatment with high-potency or very high potency TCS, (high potency TCS may be 
used as rescue) 
 Initiation of treatment of AD with prescription moisturizers 
The following concomitant procedures are prohibited during study participation: 
 Major elective surgical procedures 
 Tanning in a bed/booth 
 Phototherapy (UVA, UVB, nbUVB, high dose UVA and PUVA) 
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. 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 = 4 or have intolerable symptoms.  If possible, investigators are encouraged to consider 
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. 
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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. 
Blinded adjudication of rescue treatments will be implemented before database locks by 
considering the type of medication or procedure, indication, timing, frequency and the potential 
impact of the use of the prohibited medication or procedure. The rescue treatments will be 
adjudicated by the clinical study director and the adjudication procedure will be documented. 
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 EMA and EMA 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 10.2. 
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 using the weights. For patients of age >=8 years, the weights are 10% = head, 20% = upper 
extremities, 30% = trunk, 40% = lower extremities. For patients of age <8 years, the weights are 
20% = head, 20% = upper extremities, 30% = trunk, 30% = lower extremities.  The minimum 
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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 10.2. 
4.4.2. 
Secondary Efficacy Variables 
The key secondary endpoints are: 
 Proportion of patients with EASI-75 (≥75% improvement from baseline) at week 16 
(this is not a secondary endpoint for ex-US countries as it is already a co-primary 
endpoint) 
 Percent change in EASI score from baseline to week 16 
 Percent change from baseline to week 16 in weekly average of daily worst itch score 
Worst itch scale 
The worst itch scale is a simple assessment tool that patients will use to report the intensity of 
their pruritus (itch). This tool is composed of two questions and each question is an 11-point 
scale (0 to 10) in which 0 indicates no itching while 10 indicates worst itching possible. Patients 
will be asked the following 2 questions: 
 “What was the worst itch you had today?” 
 “What was the worst itch you had last night?” 
Patients will be asked to provide answers to these 2 questions daily throughout the entire study 
(screening period, treatment period, and follow-up period; see time point in Appendix 10.2 ). The 
daily worst itch score will be calculated as the worse of the scores for the 2 questions on a given 
day. Any day with one score only should be discarded as a “missing score day”. 
Patients will be instructed on using the patient diary to record their worst itch score at the 
screening and baseline visits. Clinical sites will check and remind patients to complete the diary 
at each visit. 
The baseline worst itch scale score is defined as the prorated average of the worst itch scale 
scores reported continuously for 7 days right before the baseline visit (i.e. study day -7 to day -
1). A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average 
score. For post-baseline worst itch scale score, the weekly mean of daily worst itch score is 
calculated as the prorated average of the reported daily worst 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 endpoints are: 
 Change from baseline to week 16 in weekly average of daily worst itch score  
 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 
 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   
 Time to onset of effect on pruritus during the 16-week treatment period (≥4 point 
reduction of weekly average of daily worst itch score from baseline) 
 Time to onset of effect on pruritus during the 16-week treatment period (≥3 point 
reduction of weekly average of daily worst itch score from baseline) 
 Change from baseline to week 16 in CDLQI 
 Change from baseline to week 16 in POEM 
 Change from baseline to week 16 in Dermatitis Family Index (DFI) 
 Change from baseline to week 16 in Patient Reported Outcomes Measurements 
Information Systems (PROMIS) pediatric anxiety short form scale score 
 Change from baseline to week 16 in PROMIS pediatric depressive symptoms short 
form scale score 
 Topical treatment for AD – proportion of TCS medication-free days from baseline to 
week 16 
 Mean weekly dose of TCS in grams for low or medium potency TCS from baseline to 
week 16 
 Mean weekly dose of TCS in grams for high potency TCS from baseline to week 16 
 Incidence of skin-infection TEAEs (excluding herpetic infections) through week 16* 
 Incidence of serious TEAEs through week 16  
*Adjudicated by study medical director. 
Body Surface Area (BSA) Involvement of Atopic Dermatitis 
Body surface area affected by AD will be assessed for each section of the body and will be 
reported as a percentage of all major body sections combined. The possible highest score for 
each region is:  
Head 
Torso 
Lower Extremities 
Upper Extremities 
Genitals 
Age 10 and older 
9% 
36% 
36% 
18% 
1% 
Age 9 
10% 
36% 
36% 
18% 
0% 
Age 8 
11% 
36% 
35% 
18% 
0% 
Age 7 
12% 
36% 
34% 
18% 
0% 
Age 6 
13% 
36% 
33% 
18% 
0% 
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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 10.2 _Schedule_of_Events. 
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. 
Patients will undergo this assessment at the scheduled and unscheduled clinic visits according to 
Appendix 10.2 . 
Children’s Dermatology Life Quality Index (CDLQI) 
The CDLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to 
assess the impact of AD disease symptoms and treatment on Quality of Life (QoL) in children. 
The format is a simple response to 10 items, which assess QoL over the past week. For each 
item, the scale is rated as follows: 0=’not at all’=’not relevant’; 1=’only a little’; 2=’quite a lot’; 
3=’very much’=’yes’=”prevent school” in question 7, with an overall scoring system of 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 10.2 . 
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 can 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 should not be scored: 
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Symptoms and feelings 
Questions 1,2  
Score maximum 6 
Leisure 
Questions 4, 5 and 6 
Score maximum 9 
School or holidays 
Question 7 
Score maximum 3 
Personal relationships 
Questions 3 and 8  
Score maximum 6 
Sleep 
Question 9 
Score maximum 3 
Treatment 
Question 10 
Score maximum 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. 
This questionnaire asks the caregiver to report their perception of patient’s AD symptoms. It is 
therefore completed by the caregiver. 
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, 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 10.2. 
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Handling missing items from DFI: 
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. 
PROMIS Anxiety and Depression Scales 
The PROMIS Anxiety instrument measures self-reported fear (fearfulness, panic), anxious 
misery (worry, dread), hyperarousal (tension, nervousness, restlessness), and somatic symptoms 
related to arousal (racing heart, dizziness). The PROMIS Depression instrument assesses 
self-reported negative mood (sadness, guilt), views of self (self-criticism, worthlessness), and 
social cognition (loneliness, interpersonal alienation), as well as decreased positive affect and 
engagement (loss of interest, meaning, and purpose). This questionnaire asks the caregiver to 
report their perception of the patient’s anxiety and depressive symptoms. It is therefore 
completed by the caregiver. 
Each question has five response options ranging in value from 1 to 5 (1= Never, 2= Almost 
never, 3=Sometimes, 4= Often, 5= Almost Always). For an 8-item form, the lowest possible total 
raw score is 8; the highest possible total raw score is 40. For a 6-item form, the lowest possible 
total raw score is 6; the highest possible total raw score is 30. The scoring algorithm is as 
follows. 
1. Calculate the total raw score as the sum of values of response to each question answered.  
2. If some questions are not answered, calculate the pro-rated raw score as 
raw sum*number of items on the form
number of items that were actually answered  
1. Locate the applicable score conversion table in Appendix 10.7  and use this table to 
translate the total raw score or pro-rated score into a T-score for each participant. The T-
score rescales the raw score into a standardized score with a mean of 50 and a standard 
deviation (SD) of 10. Therefore a person with a T-score of 40 is one SD below the mean. 
The standardized T-score is reported as the final score for each participant.  
The PROMIS will be assessed at time points according to Appendix 10.2 . 
4.4.3. 
Other Efficacy Variables 
Other 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 
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 Patient global impression of disease: proportion of patients with not itchy at all and 
proportion of patients with not itchy at all or a little itchy at week 16 
 Patient global impression of change: proportion of patients who rate their eczema 
symptoms as “much better” at week 16 
 Proportion of patients who achieve reduction of IGA score by ≥2 from baseline to 
week 16 
 Change from baseline to week 16 in GISS (erythema, infiltration/papulation, 
excoriations, lichenification) 
 Number of missed school days during the treatment period 
 Number of caregiver missed workdays during the treatment period 
 Mean VAS score of injection site pain as assessed by Faces pain scale for all visits 
through week 16 
 Change from baseline to week 16 in sleep quality evaluation  
 Proportion of patients with IGA score 0 or 1 or EASI-90 at week 16 
Patient Global Impression of Disease  
Patients will rate their disease based on a 5-point Likert scale. Patients will be asked: “In general, 
how itchy have you been during the last 7 days?”. Response choices are: “Not itchy at all” (1); 
“A little itchy” (2); “Medium itchy” (3); “Pretty itchy” (4); “Very itchy” (5). Patients will 
undergo this assessment at time points according to Appendix 10.2. 
Patient Global Impression of Change  
Patients will rate their satisfaction with the study treatment based on a 5-point Likert scale. 
Patients will be asked: “Since you started your study medication, how has your itching 
changed?” Response choices are: “Much better” (1); “A little better” (2); “No difference” (3); “A 
little worse” (4); “Much worse” (5). Patients will undergo this assessment at time points 
according to Appendix 10.2. 
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 will be ranged from 0 to 12. The GISS will be assessed at the scheduled and unscheduled 
clinic visits according to Appendix 10.2. 
Faces pain scale - Revised  
The Faces Pain Scale – Revised (FPS-R) is a self-report measure of pain intensity developed for 
children. It was adapted from the Faces Pain Scale to make it possible to score the sensation of 
pain on the widely accepted 0 to 10 metric. The possible pain scale are 0, 2, 4, 6, 8 and 10. The 
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instrument will be used to assess injection site pain at the time points specified at visits according 
to Appendix 10.2. 
Assessment of Missed School Days 
Patients who are enrolled in school will be asked to report the number of missed school days 
since the last study assessment. Patients will undergo this assessment at time points according to 
Appendix 10.2. This questionnaire is completed by the caregiver. 
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 the time points according to 
Appendix 10.2. 
Sleep Disturbance 
Sleep disturbance will be evaluated using 3 scores as listed below: 
 Assessment of sleeplessness from SCORAD (score ranged from 0 to 10)  
 Question 9 “Over the last week, how much has your sleep been affected by your skin 
problem?” from CDLQI (score ranged from 0 to 3)  
 Question 2 “Over the last week, on how many nights has your sleep been disturbed 
because of the eczema?” from POEM (score ranged from 0 to 4) 
SCORAD, CDLQI and POEM will be assessed at time points according to Appendix 10.2. 
4.5. 
Safety Variables  
4.5.1. 
Adverse Events and Serious Adverse Events Variables 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then 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, latest version). 
An Adverse Event 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. 
AEs also include: any worsening (i.e. 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; 
abnormal laboratory findings considered by the investigator to be clinically significant; and any 
untoward medical occurrence. 
A Serious Adverse Event is any untoward medical occurrence that at any dose results in death; 
is life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; 
results in persistent or significant disability/ incapacity; is a congenital anomaly/ birth defect; or 
is an important medical event. 
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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. 
The pre-treatment AE and treatment emergent AE (TEAE) are defined as following:  
 Pre-treatment signs and symptoms (Pre-treatment AEs) are AEs that developed or 
worsened in severity during pre-treatment period. 
 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 the 
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 as 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 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 study. 
Adverse event of special interest (AESI)/TEAE category 
 Systemic or extensive hypersensitivity reactions, including anaphylactic reactions 
 Malignancy 
 Helminthic infections 
 Suicide-related events  
 Conjunctivitis (any type or etiology), keratitis or blepharitis (only events that are 
either severe or serious will be reported as AESIs) 
Appendix 10.5 provides a list of AESIs search criteria. 
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Other adverse events: 
 Narrow conjunctivitis is defined as the following PT terms 
 Conjunctivitis 
 Conjunctivitis allergic 
 Conjunctivitis bacterial 
 Conjunctivitis viral 
 Atopic Keratoconjunctivitis 
 Broad conjunctivitis is defined as the following PT terms 
 Conjunctivitis, Conjunctivitis allergic 
 Conjunctivitis bacterial 
 Conjunctivitis viral 
 Atopic Keratoconjunctivitis 
 Blepharitis 
 Dry eye 
 Eye irritation 
 Eye pruritus 
 Lacrimation increased 
 Eye discharge 
 Foreign body sensation in eyes 
 Photophobia, Xerophthalmia 
 Ocular hyperaemia 
 Conjunctival hyperaemia 
 Keratitis is defined as the following PT terms 
 Keratitis 
 Allergic keratitis 
 Ulcerative keratitis 
 Corneal infection  
 Atopic keratoconjunctivitis 
 Herpes ophthalmic 
 Eczema Herpeticum is defined as the following PT terms 
 Eczema herpeticum 
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 Herpes Zoster is defined as the following PT terms 
 Herpes zoster 
 Ophthalmic herpes zoster 
 Muco-cutaneous herpes simplex infections is defined as the following PT terms 
 Oral herpes 
 Genital herpes 
 Herpes simplex 
 Herpes virus infection 
 Nasal herpes 
4.5.2. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory.  
Samples for laboratory testing will be collected according to visit schedule (Appendix 10.2). 
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 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
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Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast  
Other Laboratory Tests 
Serum and urine pregnancy testing will be performed for all female patients of childbearing 
potential at time points according to Appendix 10.2. 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). 
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) 
Vital signs including temperature, sitting blood pressure, heart rate, and respiration, will be 
collected predose at every in-clinic visit. At the first 3 administrations of study drug (day 1, week 
2, and week 4 for patients receiving Q2W treatment and day 1, week 4, and week 8 for patients 
receiving Q4W treatment), sitting blood pressure, heart rate, and respiratory rate will also be 
assessed at 30 (±10) minutes postdose and then at 2 hours (±15 minutes). See Appendix 10.2 for 
assessment time points. 
4.5.4. 
Body Weight and Height 
Body weight and height will be measured at time points according to Appendix 10.2. 
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 visit schedule 
(Appendix 10.2). 
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] and QTc Bazett [QTcB]=QT/[RR0.5]) ECG 
status: normal, abnormal not clinical significant or abnormal clinical significant. See 
Appendix 10.2 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 10.2 . 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 will be collected at time points according to visit schedule 
(Appendix 10.2 ). ADA analysis will be conducted on samples collected at baseline, EOT and 
EOS. ADA sample at Week 4 will only be analyzed for ADA in patients positive for ADA in a 
later visit such as EOT or EOS. 
4.8. 
 Biomarkers Variables  
Biomarkers to be analyzed in this study are:  
 TARC  
 Total serum IgE  
 Immunoglubin profiling 
 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 10.2 . 
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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 3 treatment groups (i.e. dupilumab q2w dose, dupilumab q4w 
dose and placebo).  
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group for FAS. 
Listing of demographics and baseline characteristics will be presented. 
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. 
Information on conditions related to AD 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. will be summarized. 
5.3. 
Pre-treatment/Concomitant Medications/Procedures 
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 groups. 
Patients will be counted only once for each medication class (ATC level 2 and 4) linked to the 
medication. 
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 combined dupilumab treatment groups. Patients will be counted 
only once for each SOC and PT linked to the procedure. 
Prior medications or procedures started before screening visit and started between screening visit 
and first injection date will be summarized separately.  
Number and proportion of patients taking adjudicated rescue treatment (concomitant topical 
treatments (high potency TCS/TCI), systemic immune-suppressants) and other treatments 
(emollients/ antihistamines) will also be summarized separately. 
Kaplan Meier curves for time to first rescue use will be generated. 
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The compliance 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 
Listing of medications and procedures will be provided. 
5.4. 
Subject Disposition 
The following summaries by table will be provided: 
 The total number of screened patients 
 The total number of randomized patients: 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 
 The total number of patients who completed the study treatment and discontinued the 
study treatment with the reason of discontinuation 
 The total number of patients who continued in pediatric open label extension study 
 The total number of patients who entered into follow-up period and their study 
completion status with reason of discontinuation 
 The total number of patients potentially unblinded 
 
The following listings will be provided: 
 Listing of patient disposition including: date of randomization, date of the last visit, 
received dose, completed study drug or discontinued by reason, completed study or 
discontinued by reason 
 A listing of patients randomized but not treated, and patients randomized but not 
treated as randomized 
 A listing of patients prematurely discontinued from the study or treatment, along with 
reasons for discontinuation 
 Summary table with listing of protocol deviations will be provided 
 A listing of patients potentially unblinded 
5.5. 
Dose administration 
The compliance with study treatment 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% 
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%. 
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Listing of dose administration: including date/time, study day, number of injections, locations of 
injections, dosing information, and whether or not the total dose is administered for each dose 
will be presented. 
5.6. 
Treatment Exposure and Observation Period 
The duration of treatment exposure during the study in day is calculated as: 
Q2W dosing: (Date of last study drug injection – date of first study drug injection) + 14 days  
Q4W dosing: (Date of last study drug injection – date of first study drug injection) + 28 days 
The calculations are regardless of temporary dosing interruption. The duration of exposure 
during the study will be summarized by treatment group using number of patients, means, SD, 
minimums, Q1, medians, Q3 and maximums. 
In addition, the duration of exposure will be summarized categorically by counts and percentages 
for each of the following categories and cumulatively by these categories as well: ≥ 14 days, ≥ 
28 days, ≥ 42 days, ≥ 56 days, ≥ 70 days, ≥ 84 days, ≥ 98 days, and ≥ 112 days. 
The duration of observation period during the study in day is calculated as: 
(Date of the last visit – date of the first study drug injection) +1. 
The number (%) of patients with observation periods will be presented by specific time periods. 
The time periods of interest is specified as: < 8 days, ≥ 8 days, ≥ 15 days, ≥ 22 days, ≥ 29 days, 
≥50 days, ≥ 57 days, ≥ 85 days, ≥99 days, ≥113 days, ≥141 days, ≥169 days, ≥183 days and 
≥197 days. 
5.7. 
Analyses of Efficacy Variables 
For all efficacy variables, the analysis will be comparisons of each dupilumab regimen and the 
placebo treatment groups. The following null and alternative hypotheses for the primary 
endpoint will be tested for each dupilumab regimen group and the placebo group: 
H0:  𝑝𝑑𝑢𝑝𝑖𝑙𝑢𝑚𝑎𝑏 =  𝑝𝑝𝑙𝑎𝑐𝑒𝑏𝑜, where 𝑝 stands for the percent of responders in a treatment group 
H1: 𝑝𝑑𝑢𝑝𝑖𝑙𝑢𝑚𝑎𝑏 ≠  𝑝𝑝𝑙𝑎𝑐𝑒𝑏𝑜. 
The analyses of efficacy variables are described in the subsections below and summarized in 
Appendix 10.1 . 
Subgroups are defined by key baseline factors recorded on the CRF and listed to be considered 
for primary and key secondary efficacy analyses: 
 Age group (≥6 to <9, ≥9 to <12)  
 Sex (Male, Female) 
 Ethnicity: Hispanic or Latino (no/yes) 
 Race (White, Black or African American, Asian, Other) 
 Duration of AD (< 5 years, ≥5 years) 
 Age of disease onset (<2 years, ≥2 years 
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 Age of disease onset (<5 years, ≥5 years) 
 Family history of atopic disease (Yes/No) 
 Baseline weight group (<30 kg,  ≥30 kg) 
 BMI (<20, ≥20) 
 Region (North America, Europe) 
 Baseline severe EASI (<25, ≥25) 
 Baseline moderate-to-severe EASI (<20, >=20) 
 Baseline worst 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 usage of methotrexate (MTX) (Yes, No) 
 Previous usage of Azathioprine (Aza) (Yes, No) 
 Previous use of systemic immunosuppressants for AD (Yes, No) 
 History of asthma (Yes, No) 
 History of nasal polys (Yes, No) 
 History of allergic rhinitis (Yes, No) 
 History of food allergies (Yes, No) 
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5.7.1. 
Analysis of Primary Efficacy Variable 
The Cochran-Mantel-Haenszel (CMH) test adjusted by randomization strata (baseline weight 
group (<30 kg or >30kg) and region (North America or Europe) will be used for the analysis of 
percentage of patients with IGA 0 or 1 at week 16 or percentage of patients with EASI-75 at 
week 16. The Mantel-Fleiss (MF) criterion will be performed, and if it is not met while using the 
option CMH (MF) in SAS procedure PROC PREQ, sensitivity analyses including each factor 
separately in CMH test will be conducted. 
All efficacy data, regardless of whether the patient remains on study treatment or discontinues 
the study treatment but remains in the study, will be used for analysis. Specifically, if a patient 
stays in the study until the end of the study planned placebo-controlled treatment period, all 
efficacy data collected up to the study planned end of treatment visit will be included in the 
primary analysis, regardless of whether the patient is on treatment or not. 
Handling of dropouts or adjudicated rescue treatment or missing value for the binary response 
variables as the primary analysis 
 If a patient withdraws from the study, 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 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, then it will be counted as a non-
responder at week 16. 
Sensitivity analyses  
1. Post-baseline Last Observation Carried Forward (LOCF) approach after censoring for 
rescue treatment use or study withdrawal to determine patient’s status at week 16 will be 
conducted to assess the robustness of the primary efficacy analysis with regards to 
handling of missing data. 
2. All observed data, regardless if rescue treatment is used or data is collected after 
withdrawal from study treatment will be included for analysis. Patients with missing 
value will be counted as non-responder. 
The primary efficacy analyses will be performed on the FAS, which will be considered as the 
primary analysis. Evaluation of primary and co-primary endpoints in the mFAS and PPS will be 
considered as sensitivity analyses.  
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5.7.2. 
Analyses of Secondary Efficacy Variables 
All secondary endpoints will be evaluated on the FAS. Selected secondary endpoints will be 
evaluated in the mFAS as sensitivity analyses. 
The binary secondary efficacy endpoints will be analyzed using the same approaches used for the 
analysis of the primary endpoints.  
The continuous endpoints will be analyzed using analysis of covariance (ANCOVA) model as 
the primary analysis method with multiple imputation (MI) method for missing data. Patients’ 
efficacy data through week 16 after the rescue treatment use will be set to missing first, and then 
be imputed by MI method. 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 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 
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 and region) 
 Measured endpoint values at every clinic visit (i.e. week 1, 2, 3, 4, 8, 12 and week 16) 
Categorical variables included in above model (i.e., treatment group and randomization strata) 
are not expected to be missing. 
To account for the impact of rescue treatment on the efficacy effect: 
 Continuous efficacy endpoints: if a patient receives rescue treatment that specifies the 
patient as a non-responder according to the above rules for binary efficacy endpoints, 
the data collected after rescue treatment is initiated will be treated as missing. 
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Sensitivity analyses 
In addition to the MI method described previously, sensitivity analyses for the continuous 
endpoints for EASI and/or Pruritus worst itch scale will be conducted as described below. 
1. The sensitivity analysis based on all observed data regardless if rescue treatment is used 
or data is collected after withdrawal from study treatment using MI method will be 
performed. 
2. This sensitivity analysis will use ANCOVA model, including the treatment group, the 
baseline value and the randomization strata. The efficacy data will be set to missing after 
rescue treatment is used. The post-baseline LOCF method will then be used to impute 
missing values. 
3. This sensitivity analysis will use ANCOVA model, including the treatment group, the 
baseline value and the randomization strata. The efficacy data will be set to missing after 
rescue treatment is used. The post-baseline worst observation carried forward (WOCF) 
method will then be used to impute missing values. 
Time to onset of effect on pruritus as measured by proportion of patients with improvement 
(reduction) of weekly average of daily Pruritus worst itch scale >=4 and >=3 from baseline 
during the 16-week treatment period will be calculated for each patient as the date of having the 
first event - the first study drug dose date + 1 day. Patients not having either event during the 
treatment period will have their time censored at the end of treatment period. These times to 
onset of effect on pruritus will be analyzed using the Cox proportional hazards model including 
treatment and randomization strata as factors, The hazards ratio, its 95% confidence interval and 
p-value will be reported. Kaplan-Meier curves will be provided.  
The mean weekly dose of TCS use during the treatment period endpoints will be analyzed using 
an ANCOVA model with treatment, randomization strata (baseline weight group and region) and 
relevant baseline included in the model. 
Analysis of incidence of TEAE-related variables 
 Incidence of skin infection TEAE (excluding herpetic infections) from baseline 
through week 16 
 Incidence of treatment-emergent serious adverse events from baseline through 
week 16 
These endpoints will be analyzed for patient in SAF. The week 16 treatment period is defined in 
Section 3.2. The Cochran-Mantel-Haenszel test adjusted for randomization strata will be used for 
the percentage of patients with events described above through week 16. 
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 across 
the 2 dupilumab dose regimens 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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Endpoints 
Dupilumab 
 
q4w group 
q2w group 
Primary endpoint  Proportion of patients with IGA 0 to 1 (on a 5-point 
scale) at week 16 
7 
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 
 
8 
 
2 
Secondary 
endpoints 
Percent change in EASI score from baseline to week 16 
9 
3 
Proportion of patients with EASI-50 at week 16 
10 
4 
Percent change from baseline to week 16 in weekly 
average of daily worst itch score 
11 
5 
Proportion of patients with improvement (reduction) of 
weekly average of daily worst itch score ≥4 from 
baseline at week 16 
12 
6 
Proportion of patients with improvement (reduction) of 
weekly average of daily worst itch score ≥3 from 
baseline at week 16 
15 
13 
Proportion of patients with EASI-90 at week 16 
16 
14 
Change from baseline to week 16 in POEM 
20 
17 
Change from baseline to week 16 in CDLQI 
21 
18 
Percent change from baseline to week 16 in SCORAD 
22 
19 
 
 
 
 
5.7.3. 
Subgroup Analysis 
Subgroup for the primary endpoint and key secondary efficacy will be analyzed based on FAS. 
The analysis method for the subgroup will be the same as the primary analysis described in 
Section 5.7.1 and Section 5.7.2. Interactions between the subgroups and treatment groups will 
also be tested using the logistic regression model for the categorical endpoints, and using the 
ANCOVA model for the continuous endpoints. The model will include randomization strata, 
treatment group, subgroup, treatment by randomization strata interaction and treatment by 
subgroup interaction as factors. P-values for the interaction term will be reported. We will 
consider interaction effect as significant if P-value is greater than 0.1. 
Forest plots of the primary and key secondary efficacy endpoints across subgroups will be 
generated.   
5.7.4. 
Analyses of Other Efficacy Variables 
The analyses of other efficacy variables will be the same as the primary analysis described in 
Section 5.7.1 and Section 5.7.2. 
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5.8. 
Analysis of Safety Data 
The summary of safety and tolerability will be performed based on 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 10.4. Treatment-emergent PCSV is 
any PCSV developed or worsened in severity compared to the baseline during the treatment and 
follow-up period. 
The time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
Subgroups are defined by key baseline factors recorded on the CRF and listed to be considered 
for safety analyses: 
 Age group (≥6 to <9, ≥9 to <12)  
 Sex (Male, Female) 
 Ethnicity: Hispanic or Latino (no/yes) 
 Race (White, Black, Asian, Other) 
 Duration of AD (< 5 years, ≥5 years) 
 Baseline BMI (<20, ≥20) 
 Baseline weight group (<30 kg,  ≥30 kg) 
5.8.1. 
Adverse Events 
Listings of TEAEs, serious TEAEs, and TEAEs resulting in death and study drug discontinuation 
will be generated. 
Number and proportions of patients reporting TEAEs will be summarized for 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 based on the overall incidence for the combined dupilumab 
treatment groups. 
Summaries of TEAEs will include: 
 TEAEs 
 TEAEs by SOC/PT 
 TEAEs by SOC/HLT/PT 
 TEAEs by PT 
 Common TEAEs by SOC/HLT/PT (incidence with PT ≥5%) 
 Common TEAEs by SOC/HLT/PT (incidence with PT ≥2%) 
 TEAEs by severity by SOC/PT 
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 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/HLT/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 
 Death by SOC/PT 
 AESI by AESI category (see Appendix 10.4 ) and SOC/PT 
The time to first AESIs (TEAE category), serious TEAE, or TEAE leading to permanent 
treatment discontinuation during the treatment period 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 treatment period.  
5.8.2. 
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 
 The number (n) and percentage (%) of patients with abnormal lab value during study 
whose screening and baseline values are normal (overall and per each lab parameter) 
 The number (n) and percentage (%) of patients with treatment-emergent PCSVs 
overall during the study, during the treatment period and during the follow-up period  
 Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
Listing of all laboratory parameters normal range, abnormal flag and treatment-emergent PCSV 
by patient and visit will be provided. 
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5.8.3. 
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 
Listings of vital sign will be provided with flags indicating the treatment-emergent PCSVs. 
5.8.4. 
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. A 
summary of treatment-emergent abnormal findings will be provided. 
5.8.5. 
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 
Listings of ECG will be provided with flags indicating PCSVs. 
5.9. 
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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5.10. 
Analysis of Immunogenicity Data 
5.10.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.7 will be summarized using descriptive 
statistics in the ADA analysis set. Frequency tables of the proportion of patients with pre-
existing immunoreactivity, treatment-emergent, treatment-boosted, persistent ADA responses, 
and titer categories will be presented as absolute occurrence (n) and percent of patients (%) by 
treatment groups. 
ADA response categories and titer categories are defined as follows: 
 Pre-existing immunoreactivity, defined as either an ADA positive response in the 
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 over baseline titer 
levels 
 Treatment-emergent response, defined as a positive response in the ADA assay post 
first dose when baseline results are negative or missing.  The treatment-emergent 
responses will 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 greater than 
12-week period, with no ADA negative samples in between 
 Indeterminate Response - as a treatment-emergent response with only the last 
collected sample positive in the ADA assay 
 Transient Response - a treatment emergent ADA positive assay response that is 
not considered persistent or indeterminate. 
 Treatment-boosted response, defined as a positive response in the 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 Values (Titer value category) 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000)   
The following summaries will be provided based on AAS: 
 Number (%) of ADA-negative patients 
 Number (%) of patients with pre-existing immunoreactivity by treatment group and 
ADA titer categories   
 Number (%) of treatment-emergent ADA-positive patients by treatment group and 
ADA titer categories 
 Number (%) of persistent treatment-emergent ADA-positive patients 
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 Number (%) of indeterminate treatment-emergent ADA-positive patients 
 Number (%) of transient treatment-emergent ADA-positive patients 
 Number (%) of treatment-boosted ADA-positive patients 
 Listing of all ADA peak titer levels will be provided for treatment emergent and 
treatment boosted ADA response subjects and the neutralizing antibody status will be 
provided for subjects positive in the ADA assay. 
 Scatter plot of ADA titers by ADA assessment time point indicated in Appendix 10.2 
 Number (%) of patients in the three ADA titer categories by treatment group  
5.10.2. 
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.  
5.11. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.11.1. 
Immunogenicity and Exposure 
Association between ADA 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) on PK. 
5.11.2. 
Immunogenicity on Safety and Efficacy 
Association between ADA response categories and safety events will focus on the following 
events: 
 Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
 Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Number (%) of patients with the above mentioned safety events will be summarized by 
treatment-emergent, treatment-boosted, persistent ADA response status, and neutralizing 
antibody status during the TEAE period.  
Association between ADA and the primary and key secondary efficacy endpoints may be 
explored and summarized in SAF using individual patient spaghetti plots.  
 
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 
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 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: 
                              - High, 
                              - Moderate, 
                              - Low 
5.12. 
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, IgG subclasses) 
 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 on 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 value will be imputed by LOCF method for visits between post-baseline to 
week 16. After week 16, no imputation will be made. P-value for difference from placebo will be 
provided. 
Correlation of baseline TARC (measured value) and IgE (measured value) 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 to indicate significance of the correlation/association. 
 Percent change from baseline to week 16 in EASI score 
 Percent change from baseline to week 16 in weekly average of worst itch scale 
 Change from baseline to week 16 in percent BSA 
 Percent change from baseline to week 16 in SCORAD 
Correlation of baseline TARC (measured value) and IgE (measured value) with the following 
clinical endpoints will be explored using the logistic model. The model includes the 
responder/nonresponder of 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 to indicate significance of the 
correlation/association. 
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 IGA 0-1 at week 16 
 EASI-75 at week 16 
 improvement (reduction) of weekly average of worst itch scale ≥4 from baseline to 
week 16 
Association of positivity to at least one antigen-specific IgE with the following clinical endpoints 
will be explored using CMH test stratified by weight. 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 itch scale ≥4 from baseline to 
week 16 
Correlation/association will be implemented on the placebo, dupilumab Q2W, dupilumab Q4W 
and combined dupilumab (dupilumab Q2W and Q4W) groups, respectively. 
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 are 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.  
For the biomarkers with at least 5 evaluable patients in both the dupilumab and placebo 
treatment groups at Week 16, a Cochran-Mantel-Haenszel test will be conducted to compare the 
proportion of patients achieving normalized status across treatment groups, stratified by 
randomization strata (baseline weight group and region), for both the main (LOCF) and 
sensitivity (OC) analysis approaches. The test statistic p-values for the comparison of the 
dupilumab groups versus placebo and point estimate with 95% confidence interval will be 
provided. The proportions will be also summarized by treatment group at each assessment visit. 
 
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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 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 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 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 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 to in line with the 
protocol which specifies to collect up to 2 years 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 post-baseline PCSV but missing baseline value will be regarded as having 
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 and end of treatment (EOT)/end of study 
(EOS) have the potential to be summarized. No analysis visit windows will be applied for the 
study scheduled visits.  
The following analysis visit windows will be used to map the unscheduled visits, ET and 
EOT/EOS visits, based on the study day: 
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Visit 
Target Day 
Analysis Time Window 
Based on Study day* 
Screening 
<1 
<1 
Baseline 
1 
1 
Week 1 
8 
[2,11] 
Week 2 
15 
[12,18] 
Week 3 
22 
[19,25] 
Week 4 
29 
[26, 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 day is calculated relative to the date of first study drug injection. 
In general, the following order will be used to select the record for analysis at given visit: 
1. Scheduled visit  
2. Early termination (ET) or end of study (EOS), whichever comes first if scheduled visit 
not available  
3. Unscheduled visit if both scheduled visit and ET/EOT/EOS are not available 
For the multiple measurements of the same test in the same window, the following rules will be 
used to pick up the analysis value: 
 If multiple valid values of a variable within an analysis visit window, the closest from 
the target study day will be selected.  
 If the difference is a tie, the value after the targeted study day will be used.  
 If multiple available values of a variable exist within a same day, then the first value 
of the day will be selected. 
Both scheduled and unscheduled measurements will be considered for determining 
abnormal/PCSV values from laboratory, vital sign or ECG as well as the baseline values.  
For the daily collected ePRO data, 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. 
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7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
A first-step 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 first-step analysis. The assessment of primary and 
secondary endpoints performed during the analysis will be the final analysis of the primary 
endpoint and secondary endpoints. Hence, there will be no need for alpha adjustment due to the 
first-step 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 first-step analysis, a 
dissemination plan will be written. This plan will clearly identify the team (including the 
statistician) that will perform the first-step 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 9.2 or above. 
 
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9. 
REFERENCES 
Desai N, Poindexter G, Monthrope YM et al. A pilot quality-of-life instrument for pruritus. J Am 
Acad Dermatol 2008;59:234-44. 
Hanifin JM, Thurston M, Omoto M et al. The eczema area and severity index (EASI): 
assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001;10: 11-
18. 
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. 
Kaufmann R, Bieber T, Helgesen AL et al. Onset of pruritus relief with pimecrolimus cream 1% 
in adult patients with atopic dermatitis: a randomized trial. Allergy 2006;61: 375-381. 
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. 
No authors listed. Severity scoring of atopic dermatitis: the SCORAD index: consensus report of 
the European task force on atopic dermatitis. Dermatology 1993;186: 23-31. 
Zigmond AS, Snaith RP: The Hospital Anxiety And Depression Scale. Acta Psychiatr Scand 
1983, 67:361-70 
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Statistical Analysis Plan 
 
May 07, 2019 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Parameter(s) 
Endpoints 
Primary Statistical Method 
Supportive/Sensit
ivity Statistical 
Method 
Subgroup 
Analysis 
Investigator’s Global 
Assessment (IGA) 
 
 
IGA 0 to 1 
 
reduction of ≥2 points from 
baseline 
• CMH test adjusted by randomization strata 
Yes for IGA 0 to 1, 
Cochran-Mantel-
Haenszel test on OC 
or LOCF, and on PPS 
Yes for IGA 
0 to 1, 
Eczema Area and Severity 
Index (EASI) 
 
EASI 75 
 
EASI 50 
 
EASI 90 
 
% change from baseline 
 
Change from baseline 
• CMH test adjusted by randomization strata 
for categorical variables 
• multiple imputation (MI) with ANCOVA for 
continuous variables 
Yes for EASI-75 and 
% change, MMRM, 
ANCOVA for 
continuous variable, 
CMH on OC or LOCF 
for categorical 
variable 
Yes for 
EASI-75 and 
% change 
Pruritus worst itch score 
 
% change from baseline 
 
reduction of ≥4 points from 
baseline 
 
reduction of ≥3 points from 
baseline 
 
Change from baseline 
 
Time to event 
• CMH test adjusted by randomization strata 
for categorical variables 
• multiple imputation (MI) with ANCOVA for 
continuous variables 
• Cox model for time to event endpoint. 
 
Yes for % change and 
reduction >=4 
Yes for % 
change and 
reduction 
>=4 
Body Surface Area (BSA) 
Involvement of Atopic 
Dermatitis 
 
% change from baseline 
 
Change from baseline 
• multiple imputation (MI) with ANCOVA 
No 
No 
Parameter(s) 
Endpoints 
Primary Statistical Method 
Supportive/Sensit
ive Statistical 
Method 
Subgroup 
Analysis 
SCORing Atopic Dermatitis 
(SCORAD) 
 
 
% change from baseline 
 
Change from baseline 
 
SCORAD50 
• multiple imputation (MI) with ANCOVA for 
continuous variables 
• CMH test adjusted by randomization strata 
No 
No 
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 
SCORAD75 
 
SCORAD90 
for categorical variables 
 
Dermatitis Family Index( 
DFI)  
 
% change from baseline 
Change from baseline 
• multiple imputation (MI) with ANCOVA 
No 
No 
Global Individual Signs 
Score (GISS) 
 
% change from baseline 
 
Change from baseline 
• multiple imputation (MI) with ANCOVA for 
continuous variables 
No 
No 
Patient Oriented Eczema 
Measure (POEM) 
 
 
% change from baseline 
 
Change from baseline 
 
reduction of ≥3 points from 
baseline 
 
reduction of ≥4 points from 
baseline 
• multiple imputation (MI) with ANCOVA for 
continuous variables 
• CMH test adjusted by randomization strata 
for categorical variables 
No 
No 
Children Dermatology Life 
Quality Index (CDLQI) 
 
Change from baseline 
• multiple imputation (MI) with ANCOVA for 
continuous variables 
No 
No 
PROMIS anxiety and 
depression score 
 
% change from baseline 
 
Change from baseline 
 
 
• multiple imputation (MI) with ANCOVA for 
continuous variables 
• CMH test adjusted by randomization strata 
for categorical variables 
No 
No 
Parameter(s) 
Endpoints 
Primary Statistical Method 
Supportive/Sensit
ive Statistical 
Method 
Subgroup 
Analysis 
Patient Global Impression of 
disease 
 
 
Number (%) of patients with not 
itchy at all 
 
Number (%) of patients with not 
itchy at all or a little itchy 
• CMH test adjusted by randomization strata 
 
No 
No 
Patient Global Impression of 
Change 
 
 
Number (%) of patients who rate 
their eczema symptoms as “much 
better” 
• CMH test adjusted randomization strata 
 
No 
No 
Assess sick-leave/missed 
school days 
 
Number of days 
• Descriptive statistics by visit/time 
No 
No 
Assess caregiver missed 
workdays 
 
Number of days 
• Descriptive statistics by visit/time 
No 
No 
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Faces Pain Scale 
 
 
Mean VAS score of injection site 
pain 
• Descriptive statistics by visit/time 
No 
No 
TCS 
 
Proportion of TCS medication-
free days from baseline to week 
16 
 
Mean weekly dose of TCS in 
grams for low or medium 
potency TCS from baseline to 
week 16 
 
Mean weekly dose of TCS in 
grams for high potency TCS 
from baseline to week 16 
• CMH test adjusted randomization strata 
 
• ANCOVA for continuous variables 
No 
No 
 
Safety Analyses: 
 
Analysis 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Populations 
Method 
Analysis 
Analysis 
Analyses 
 
 
 
 
 
 
Adverse Events 
SAF 
Descriptive statistics and model-
based analyses 
No 
Yes for 
selected AE 
summary 
No 
Laboratory Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
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10.2. 
Schedule of Events 
Table 1: Schedule of Events (Screening, TCS Standardization, Baseline, and Treatment Period)  
 
Screening  
Treatment Period 
 
 
TCS 
standar
dization 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V
6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W2 
W
3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to 
D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient and/or 
parents/caregiver diary 
training3 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection 
training/observation 
(patients receiving Q2W 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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May 07, 2019 
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Screening  
Treatment Period 
 
 
TCS 
standar
dization 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V
6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W2 
W
3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to 
D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
treatment)4 
Study drug 
administration (patients 
receiving Q2W 
treatment) 
 
 
X5 
 
X5 
 
X5 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Injection observation 
(patients receiving Q4W 
treatment)5 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Study drug 
administration (patients 
receiving Q4W 
treatment) 
 
 
X5 
 
 
 
X5 
 
 
 
X5 
 
 
 
X 
 
 
 
 
Patient and/or 
parents/caregiver diary 
completion to record 
self-admin of study 
drug (patients receiving 
Q2W treatment) 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Study drug dispensing 
(patients receiving Q2W 
treatment) 6 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Study drug 
accountability (patients 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
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May 07, 2019 
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Screening  
Treatment Period 
 
 
TCS 
standar
dization 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V
6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W2 
W
3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to 
D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
receiving Q2W 
treatment) 
Review home diary 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
TCS application7  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TCS dispensing  
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
TCS accountability8  
 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Patient and 
parents/caregiver 
counseling for diary 
completion 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Patient recording of 
TCS use via diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient recording of 
emollient use via diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient assessment of 
pruritus intensity using 
worst itch score via 
diary (daily)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient global 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
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Screening  
Treatment Period 
 
 
TCS 
standar
dization 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V
6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W2 
W
3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to 
D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
impression of 
disease,10,11  
Patient global 
impression of 
change10,11 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CDLQI10,11 POEM,10,11 
DFI12, PROMIS 
anxiety and 
depression scale10,11 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
IGA, EASI, GISS, 
SCORAD, BSA 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Faces pain scale for 
injection pain  
 
 
X 
 
X13 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Assess missed school 
days 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Assess caregiver missed 
workdays 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Photograph AD areas 
(select sites) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Screening  
Treatment Period 
 
 
TCS 
standar
dization 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V
6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W2 
W
3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to 
D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Vital signs5 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Chemistry 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test, 
WOCBP only 
Ser 
 
Ur 
 
Ur16 
 
Ur 
 
 
 
Ur 
 
 
 
Ur 
 
 
 
 
HIV, HBsAg, HBsAb, 
HBcAb, Hep C Ab, 
TB15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TARC 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Immunoglobulin 
profiling 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening  
Treatment Period 
 
 
TCS 
standar
dization 
BL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOT17 
In-clinic Visit (V) or 
Phone Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V
6 
V7 
PV 
81 
PV 
91  
PV 
101 
V 
11 
PV 
121 
PV 
131 
PV 
141 
V 
15 
PV 
161 
PV 
171 
PV 
181 
V 
19 
Week (W) 
 
 
W1 
W2 
W
3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W 
12 
W 
13 
W 
14 
W 
15 
W 
16 
Study Day (D) 
D 
-77 
to 
D 
-14 
D 
-14 to 
D-1 
D1 
D8 
D 
15 
D 
22 
D 
29 
D 
36 
D 
43 
D 
50 
D 
57 
D 
64 
D 
71 
D 
78 
D 
85 
D 
92 
D 
99 
D 
106 
D 
113 
Window in days 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Drug Concentration 
and ADA:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional dupilumab 
concentration sample 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ADA sample 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
BL = baseline; Ser = serum; Ur = urine; WOCBP = women of childbearing potential; TB = tuberculosis 
Note:  The length of the screening period is not fixed, but must not exceed 77 days.  The length of the TCS standardization period is fixed at 14 days. 
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Table 2: Schedule of Events (Follow-Up Period, Unscheduled Visits, and Early Termination) 
Study Procedure 
Follow-Up Period7 
Unscheduled Visit8 
Early Termination Visit 
 
 
 
EOS 
In-clinic Visit (V) 
V20 
V21 
V22 
 
 
Week (W) 
W20 
W24 
W28 
 
 
Study Day (D) 
D141 
D169 
D197 
 
 
Window in days 
±4 
±4 
±4 
 
 
Treatment: 
 
 
 
 
 
Study drug accountability 1 
 
 
 
X 
X 
TCS application  
X 
X 
X 
 
 
TCS dispensing 
X 
X 
 
X 
 
TCS accountability  
X 
X 
X 
X 
X 
Patient recording of TCS use via diary 
X 
X 
X 
X 
X 
Patient recording of emollient use via diary 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
Efficacy:2  
 
 
 
 
 
Patient assessment of pruritus intensity using worst itch score 
via diary (daily)  
X 
X 
X 
X 
X 
Patient global impression of disease  
X 
X 
X 
X 
X 
Patient global impression of change  
X 
X 
X 
X 
X 
Patient-reported CDLQI3,4, POEM3,4, DFI5, PROMIS anxiety 
and depression scale3,4 
X 
X 
X 
X 
X 
IGA, EASI, GISS, SCORAD, BSA 
X 
X 
X 
X 
X 
Assess missed school days 
X 
X 
X 
X 
X 
Assess caregiver missed work days 
X 
X 
X 
X 
X 
Photograph AD areas (select sites) 
 
 
X 
 
X 
Safety 
 
 
 
 
 
Weight 
 
 
X 
 
X 
Height 
 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
Physical examination 
 
 
X 
X 
X 
ECG 
 
 
X 
X 
X 
Adverse events9 
X 
X 
X 
X 
X 
Laboratory Testing:6 
 
 
 
 
 
Hematology 
 
 
X 
X 
X 
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Study Procedure 
Follow-Up Period7 
Unscheduled Visit8 
Early Termination Visit 
 
 
 
EOS 
In-clinic Visit (V) 
V20 
V21 
V22 
 
 
Week (W) 
W20 
W24 
W28 
 
 
Study Day (D) 
D141 
D169 
D197 
 
 
Window in days 
±4 
±4 
±4 
 
 
Chemistry 
 
 
X 
X 
X 
Urinalysis 
 
 
X 
X 
X 
Pregnancy test, WOCBP only 
 
 
Urine 
Urine 
Urine 
Biomarker:  
 
 
 
 
 
TARC 
 
 
X 
X 
X 
Immunoglobulin profiling 
 
 
X 
X 
X 
Drug Concentration and ADA Samples:  
 
 
 
 
 
Functional dupilumab concentration sample 
 
X 
X 
X 
X 
ADA sample 
 
 
X 
X 
X 
EOS = End of Study 
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CONFIDENTIAL 
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Footnotes for Schedule of Events Table 1 
1. The site will contact the patient or parents/caregiver by telephone to conduct these visits. The parents/caregiver may administer 
study drug during phone visits. Patients who receive study drug outside the study center will complete a dosing diary to 
document compliance with study drug administration and to document any related issues. 
 
 
. 
3. Training of patients and parents/caregiver regarding completion of diary to record (a) administration of each dose of drug 
outside the clinic by parent/caregiver; (b) completion of the assessment of pruritus using worst itch scale; (c) emollient use; (d) 
TCS use 
4. Parents/caregivers will be trained on how to administer study drug. This will enable administration at home in between clinic 
visits.  
5. Patients will be monitored at the study site at visits 3, 5, and 7 (for patients receiving Q2W treatment) and at visits 3, 7, and 11 
(for patients receiving Q4W treatment) for a minimum of 2 hours after study drug administration. Vital signs (sitting blood 
pressure, heart rate, respiratory rate, and body temperature) and AEs will be assessed at 30 minutes (±10 minutes) post-
injection and then at 2 hours (±15 minutes). 
6. Starting at visit 7, study drug will be dispensed to the parents (or caregivers) for the dose that will be administered before the 
next clinic visit. Parents (or caregivers) will return the study kit box (for prefilled syringes) at each subsequent in-clinic visit.  
At these in-clinic visits, sites will perform accountability assessment for the study drug that the parents (or caregivers) have 
returned to the site. 
7. As per standardized regimen outlined in protocol Section 7.2 
8. 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. 
9. Assessments/procedures should be conducted in the following order: patient reported outcomes (other than patient assessment 
of injection pain), investigator assessments, safety and laboratory assessments (including sample collection for ADA, PK, 
biomarker, 
), administration of study drug, and assessment of injection pain.  
10. The questionnaires will be administered only to the subset of patients or parents/caregivers who speak fluently the language in 
which the questionnaire is presented (based on availability of validated translations in participating countries). 
11. Refer to protocol Section 8.2.2 for details on who (parent or caregiver) is required to complete the specific questionnaires. 
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CONFIDENTIAL 
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12. DFI is to be completed by parent/caregiver.  
13. Injection pain assessment at week 2 will only be performed for patients on Q2W treatment 
14. Samples will be collected before the injection of study drug 
15. TB testing will be performed on a country-by-country basis, according to local guidelines if required by regulatory authorities 
or ethics boards. 
16. Urine pregnancy testing at week 2 will only be performed for patients who receive Q2W treatment. 
17. EOT is end of study for patients who enter the OLE. 
18. Patients who experience adverse events of special interest related to eye disorders (refer to Protocol Section 9.4.3) 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. 
 
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Statistical Analysis Plan 
 
Septebmer  15, 2017 
CONFIDENTIAL 
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Footnotes for Schedule of Events Table 2 
1. Starting at visit 4, study drug will be dispensed to the parents (or caregivers) for the dose that will be administered before the 
next clinic visit. Parents (or caregivers) will return the study kit box (for prefilled syringes) at each subsequent in-clinic visit.  
At these in-clinic visits, sites will perform accountability assessment for the study drug that the parents (or caregivers) have 
returned to the site. 
2. Assessments/procedures should be conducted in the following order: patient reported outcomes (other than patient assessment 
of injection pain), investigator assessments, safety and laboratory assessments (including sample collection for ADA, PK, 
biomarker, 
), administration of study drug, and assessment of injection pain.  
3. The questionnaires will be administered only to the subset of patients or parents/caregivers who speak fluently the language in 
which the questionnaire is presented (based on availability of validated translations in participating countries). 
4. Refer to protocol Section 8.2.2 for details on who (parent or caregiver) is required to complete the specific questionnaires. 
5. DFI is to be completed by parent/caregiver.  
6. Samples will be collected before the injection of study drug 
7. Only for patients who do not enter the OLE. 
8. Specific assessments to be performed at the unscheduled visit will depend upon the reason for the unscheduled visit. 
9. Patients who experience adverse events of special interest related to eye disorders (refer to Section 9.4.3) 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. 
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CONFIDENTIAL 
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10.3. 
Potential Major Protocol Violations  
*Note: This is a preliminary list and the final list will be generated prior to database lock.  
Category  
Description of Protocol Deviation  
Inclusion Criteria not met 
but patient randomized  
Male or female not ≥6 to <12 years of age at time of screening visit  
Inclusion Criteria not met 
but patient randomized  
No diagnosis of AD according to the American Academy of Dermatology consensus 
criteria (Eichenfield 2003) at screening visit  
Inclusion Criteria not met 
but patient randomized  
Chronic AD not diagnosed at least 1 year prior to the screening visit  
Inclusion Criteria not met 
but patient randomized  
IGA <4 at the baseline visit  
Inclusion Criteria not met 
but patient randomized  
EASI <21 at the baseline visit  
Inclusion Criteria not met 
but patient randomized  
BSA <15% at the baseline visit  
Inclusion Criteria not met 
but patient randomized  
Baseline worst itch score weekly average score for maximum itch intensity <4  
Inclusion Criteria not met 
but patient randomized  
Without documented recent history (within 6 months before the baseline visit) of 
inadequate response to topical AD medication(s)    
Inclusion Criteria not met 
but patient randomized  
Has not applied a stable dose of topical emollient (moisturizer) twice daily for at least 
11 out of 14 doses during the 7 consecutive days immediately before the baseline visit  
Inclusion Criteria not met 
but patient randomized  
Not willing and able to comply with all clinic visits and study-related procedures  
Inclusion Criteria not met 
but patient randomized  
Patient, either alone or with help of parents/legal guardians, as appropriate, is not able 
to understand and complete study-related questionnaires  
Inclusion Criteria not met 
but patient randomized  
Parent or legal guardian did not provide signed informed consent. Patients have not 
provided separate informed assent to enroll in the study, and signed and dated either a 
separate informed assent form (IAF) or the informed consent form (ICF) was not 
signed by the parent/legal guardian (as appropriate based on local regulations and 
requirements).  
Exclusion Criteria met but 
patient randomized  
Participation in a prior dupilumab clinical study  
Exclusion Criteria met but 
patient randomized  
Treatment with a systemic investigational drug before 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  
Exclusion Criteria met but 
patient randomized  
Treatment with a topical investigational drug within 2 weeks prior to the baseline visit  
Exclusion Criteria met but 
patient randomized  
Treatment with crisabarole within 2 weeks prior to the baseline visit  
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CONFIDENTIAL 
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Exclusion Criteria met but 
patient randomized  
History of important side effects of medium-potency topical corticosteroids (eg, 
intolerance to treatment, hypersensitivity reactions*, significant skin atrophy, 
systemic effects), as assessed by the investigator or patient’s treating physician  *If 
a patient has a history of hypersensitivity reaction to any particular TCS, 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 TCS drug product that does not have cross-reactivity to the 
drug product that caused the hypersensitivity.  
Exclusion Criteria met but 
patient randomized  
Treatment with a TCI within 2 weeks prior to the baseline visit  
Exclusion Criteria met but 
patient randomized  
Having used any of the following treatments within 4 weeks before the baseline visit, 
or any condition that, in the opinion of the investigator, is likely to require such 
treatment(s) during the first 4 weeks of study treatment:  
a. Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, 
cyclosporine, mycophenolate-mofetil, interferon gamma, Janus kinase inhibitors, 
azathioprine, methotrexate, etc)  
b. Phototherapy for AD  
Exclusion Criteria met but 
patient randomized  
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 before the baseline 
visit, whichever is longer  
Exclusion Criteria met but 
patient randomized  
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 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:  
• Patients for whom administration of live (attenuated) vaccine can be safely 
postponed would be eligible to enroll into the study.  
• Patients who have their vaccination preponed can enroll in the study only after a gap 
of 4 weeks following administration of the vaccine.  
Exclusion Criteria met but 
patient randomized  
Planned or anticipated use of any prohibited medications and procedures during study 
treatment  
Exclusion Criteria met but 
patient randomized  
Body weight <15 kg at baseline – all countries except Germany 
Body Weight <30 kg for Germany 
Exclusion Criteria met but 
patient randomized  
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)  
Exclusion Criteria met but 
patient randomized  
Regular use (more than 2 visits per week) of a tanning booth/parlor within 8 weeks of 
the baseline visit  
Exclusion Criteria met but 
patient randomized  
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  
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Exclusion Criteria met but 
patient randomized  
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, other 
mycobacterial infections, histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, chronic mucocutaneous candidiasis, etc or otherwise recurrent 
infections of abnormal frequency or prolonged duration suggesting an 
immunecompromised status, as judged by the investigator  
Exclusion Criteria met but 
patient randomized  
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.  
Exclusion Criteria met but 
patient randomized  
Known history of human immunodeficiency virus (HIV) infection or HIV 
seropositivity at the screening visit  
Exclusion Criteria met but 
patient randomized  
With an established diagnosis of hepatitis B viral infection at the time of screening or 
is positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody 
(HBcAb) at the time of screening  
NOTE: Patients who have gained immunity for hepatitis B virus infection after 
vaccination (patients who are HBsAg negative, hepatitis B surface antibody [HBsAb] 
positive, and HBcAb negative) are eligible for the study.   
Exclusion Criteria met but 
patient randomized  
With an established diagnosis of hepatitis C viral infection at the time of screening or 
is positive for hepatitis C antibody at the screening visit  
Exclusion Criteria met but 
patient randomized  
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   
Exclusion Criteria met but 
patient randomized  
Presence of any 1 or more of the following abnormalities in laboratory test results at 
screening:  
• Platelets ≤100 × 103/μL  
• Neutrophils <1.5 × 103/μL  
• Creatine phosphokinase (CPK) >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. Only if the repeat test confirms the abnormality, the 
patient would be categorized as a screen failure.  
Exclusion Criteria met but 
patient randomized  
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.  
Exclusion Criteria met but 
patient randomized  
History of malignancy before the baseline visit  
Exclusion Criteria met but 
patient randomized  
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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Exclusion Criteria met but 
patient randomized  
Severe concomitant illness(es) that, in the investigator’s judgment, would adversely 
affect the patient’s participation in the study. Examples include, but are not limited to 
patients with short life expectancy, patients with uncontrolled diabetes (hemoglobin 
A1c ≥9%), patients with cardiovascular conditions (eg, Class III or IV cardiac failure 
according to the New York Heart Association classification), severe renal conditions 
(eg, patients on dialysis), hepato-biliary conditions (eg, Child-Pugh class B or C), 
neurological conditions (eg, demyelinating diseases), active major autoimmune 
diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other 
severe endocrinological, gastrointestinal, metabolic, pulmonary, 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).  
Exclusion Criteria met but 
patient randomized  
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.).  
Exclusion Criteria met but 
patient randomized  
Planned major surgical procedure during the patient’s participation in this study  
Exclusion Criteria met but 
patient randomized  
Patient or his/her immediate family is a member of the dupilumab investigational team  
Exclusion Criteria met but 
patient randomized  
Patient is female who is pregnant, breastfeeding, or planning to become pregnant or 
breastfeed during the study  
Exclusion Criteria met but 
patient randomized  
Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities  
Exclusion Criteria met but 
patient randomized  
Patient is female of childbearing potential* and sexually active, who is unwilling to 
use highly effective methods of contraception prior to the initial dose, during the study 
and for at least 12 weeks after the last dose of study drug. Highly effective 
contraceptive measures include stable use of combined (estrogen and progestogen 
containing) hormonal contraception (oral, vaginal, transdermal) or progestogen-only 
hormonal contraception (oral, injectable, implantable) associated with inhibition of 
ovulation initiated 2 or more menstrual cycles prior to screening; intrauterine device  
(IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation; 
vasectomized partner; and or sexual abstinence**.  
* For the purpose of this study, any female who has had her first menstrual period 
(menarche) and is sexually active will be considered to be of childbearing potential. 
Female patients who are not of childbearing potential at the start of the study but 
have the onset of menarche during the course of the study and are sexually active 
will also have to follow adequate birth control methods to continue participation in 
the study.   
** Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical trial and the preferred and usual lifestyle of 
the patient.  
NOTE:  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception.  
Visit not performed  
Visit 2 not performed (TCS Standardization)  
Visit not performed  
Visit 3 not performed (Baseline)  
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Visit not performed 
Visit 19 not performed (End of Treatment) 
Visit not performed 
Early Termination visit not performed (PD not applicable for patients who completed 
EOT and rolled over to OLE) 
Procedure not performed  
IGA not performed at Screening, Baseline/Day 1 or Visit 19/EOT  
Procedure not performed  
EASI not performed at Screening, Baseline/Day 1 or Visit 19/EOT  
Procedure not performed  
BSA not performed at Screening or Baseline/Day 1  
Procedure not performed  
Physical Examination not performed at Screening  
Procedure not performed  
Electrocardiogram not performed at Screening  
Procedure not performed 
Serum Pregnancy testing not performed at Screening (must check WOCB at 
Screening visit: if Yes, for WOCB then must have results) 
Procedure not performed 
Urine Pregnancy testing not performed at Baseline, Visits 5, 7, 11, 15, 22/EOS or ET 
(must check WOCB at Screening visit: if Yes, for WOCB then must have results).  
Major if no pregnancy performed at all.  Minor if serum performed instead of urine 
per protocol. 
Procedure not performed 
HIV, HBsAg, HBsAb, HBcAb and Hepatitis C Ab not performed at Screening visit 
Procedure not performed 
Hematology not performed prior to treatment with study drug at Baseline/V3 
Procedure not performed 
Chemistry not performed prior to treatment with study drug at Baseline/V3 
Procedure not performed 
Medical History information not collected at Screening 
Procedure not performed 
Prior Atopic Dermatitis history information not collected at Screening 
Procedure not performed 
Ophthalmology Exam not performed during Screening period for patients with history 
of conjunctivitis, blepharitis, or keratitis with 12 months of screening. 
Procedure not performed 
Any dose missed for non safety-related reasons for patients on Q4W. 
Procedure not performed 
> 1 dose missed for non safety-related reasons for patients on Q2W 
Dosing non compliance 
Study drug given to subject without being randomized 
Prohibited medications 
Treatment with Live (attenuated) vaccine during the study. Examples in section 7.8.1 
of the protocol 
Prohibited medications 
Treatment with Immunomodulating biologics during the study 
Prohibited medications 
Treatment with an investigational drug (other than dupilumab) during the study 
Prohibited medications 
Treatment with systemic nonsteroid immunosuppressant during the study. (may be 
used as rescue, see section 7.3 of protocol for details) 
Prohibited medications 
Treatment with systemic corticosteroids during the study. (may be used as rescue, see 
section 7.3 of protocol for details) 
Prohibited medications 
Treatment with crisabarole during the study.  
Prohibited medications 
Treatment with TCI 
Note: The use of TCI is prohibited during the 2-week standardization period leading 
up to 
the baseline visit, and the treatment and follow-up periods 
Prohibited medications 
Treatment with high-potency or very high potency TCS, (high potency TCS may be 
used as rescue, see Section 7.3 for details) 
Prohibited medications 
Initiation of treatment of AD with prescription moisturizers 
Prohibited procedures 
Major elective surgical procedures 
Prohibited procedures 
Tanning in a bed/booth 
Prohibited procedures 
Phototherapy (UVA, UVB, nbUVB, high dose UVA and PUVA) 
Other: Randomization 
Mis-stratification of subject due to incorrectly entered weight group in IVRS 
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Handling of 
Investigational Product 
was not performed in 
accordance with the 
protocol 
IP has been destroyed without having an approval from the sponsor  
Handling of 
Investigational Product 
was not performed in 
accordance with the 
protocol 
Decision to unblind the IP treatment assignment has been made by an unauthorized 
personnel 
Handling of 
Investigational Product 
was not performed in 
accordance with the 
protocol 
Patient was dosed with IP that had a temperature excursion and deemed unacceptable 
Inadequate Informed 
Consent administration 
Incorrect ICF (unapproved version, incorrect version, incorrect study, not subject's 
language) 
Inadequate Informed 
Consent administration 
ICF not signed by subject/parent, ICF not dated by subject/parent (incomplete date) or 
initialed (if applicable).  Consent and/or assent not obtained. 
Inadequate Informed 
Consent administration 
ICF signed after screening or any study procedures 
Inadequate Informed 
Consent administration 
Subject did not re-consent on new version(s) of ICF (to be done by the next following 
visit)  
Inadequate Informed 
Consent administration 
ICF missing for sub-study and DNA sample collected in the presence of a sample 
Inadequate source 
documents 
Subject laboratory not reviewed to confirm eligibility by PI 
Personnel not qualified 
and/or designated to 
perform study-related 
activities. 
Subject confidentiality not maintained 
Personnel not qualified 
and/or designated to 
perform study-related 
activities. 
Improper delegation of duties 
Personnel not qualified 
and/or designated to 
perform study-related 
activities. 
Site staff not properly trained to conduct study 
Personnel not qualified 
and/or designated to 
perform study-related 
activities. 
Staff inappropriately unblinded to study drug arm (except EU sites where unblinded 
information can be provided base on country requirements)  
Randomization error-
Subject Randomized to 
wrong treatment 
Subject was randomized and treated with study drug from the incorrect treatment 
group 
Randomization error-
Subject Randomized to 
wrong treatment 
Ineligible subject randomized/enrolled 
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Other: Safety monitoring 
after study drug 
Study drug overdose has not been reported to the sponsor per protocol requirements 
Other: Safety monitoring 
after study drug 
Pregnancy has not been reported to sponsor per protocol requirements  
Other: Laboratory  
Expired lab kits used 
Other: Laboratory  
Pregnancy test; HIV; HBsAg; HBsAb; Hep C lab results unable to be analyzed to 
determine eligibility prior to treatment with study drug at Baseline/V3  
Other: Laboratory  
Hematology or Chemistry lab samples  were unable to be analyzed to determine 
eligibility prior to treatment with study drug at Baseline/V3 
Other: AESI 
AESI not reported within protocol defined window 
Other: SAE 
SAE not reported within protocol defined window 
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10.4. 
Criteria for Treatment-Emergent Potentially Clinical Significant 
Value for Pediatric Patients (>=6 to <11 years old) 
Parameter 
Treatment Emergent PCSV1 
Comments 
Clinical Chemistry 
ALT 
≥3 and < 5 ULN and baseline < 3 ULN 
≥5 and < 10 ULN and baseline < 5 ULN 
≥10 and < 20 ULN and baseline < 10 ULN 
≥20 ULN and baseline < 20 ULN 
Enzyme activity must be expressed in ULN, 
not in IU/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Each category is calculated independently. 
AST 
≥3 and < 5 ULN and baseline < 3 ULN 
≥5 and < 10 ULN and baseline < 5 ULN 
≥10 and < 20 ULN and baseline < 10 ULN 
≥20 ULN and baseline < 20 ULN 
Enzyme activity must be expressed in ULN, 
not in IU/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Each category is calculated independently. 
Alkaline 
Phosphatase 
≥1.5 ULN and baseline < 1.5 ULN 
Enzyme activity must be expressed in ULN, 
not in IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
 
Total Bilirubin 
≥1.3 ULN and baseline < 1.3 ULN 
Must be expressed in ULN, not in µmol/L or 
mg/L. 
Based on normal range: <1 mg/dL,  CF = mg 
x 1.7 = μmol 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
 
Conjugated 
Bilirubin 
(Direct Bilirubin >35% Total Bilirubin and Total 
Bilirubin ≥1.3 ULN)  
Conjugated bilirubin will be measured when 
the total bilirubin is above the ULN 
Based on normal range: 0 to 0.4 mg/dL 
ALT and Total 
Bilirubin 
(ALT≥3 ULN and TBILI≥2 ULN) and baseline 
(ALT <3 ULN and TBILI <2 ULN) 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
 
CPK 
≥3 ULN and baseline < 3ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
 
                                                 
1 The ULN is based upon central lab reference ranges. The reference range might be different for 
different age-groups. For the purpose of this study in a particular patient the reference range based upon 
age at baseline will be used as reference throughout the study for determining PCSVs 
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Parameter 
Treatment Emergent PCSV1 
Comments 
Creatinine 
≥90µmol/L and baseline < 90µmol/L (or ≥1.1 
mg/dL and baseline <1.1 mg/dL) 
 
>=30%  change from baseline 
 
 Benichou C., 1994 
Two independent criteria 
Uric Acid 
Hyperuricemia 
 
Hypouricemia 
  
 
>8.0 mg/dL and <8.0 mg/dl at baseline ( or >476 
µmol/L and <476 µmol/L at baseline 
≤2 mg/dL and >2 mg/dL at baseline (or ≤119 
µmol/L and baseline > 119 µmol/L) 
 
 
 
Blood Urea 
Nitrogen 
≥20 mg/dL and <20 mg/dL at baseline (or 
>=7.14 mmol/L and <7.14 mmol/L at baseline) 
 
  
Chloride 
Hypochloremia 
Hyperchloremia 
 
<80 mmol/L and baseline ≥ 80 mmol/L  
≥115 mmol/L and baseline < 115 mmol/L  
Two independent criteria  
Reference ranges are same in adolescents (12-
17 yrs. old) and adults 
Sodium 
Hyponatremia 
Hypernatremia 
 
<129 mmol/L  and baseline ≥ 129 mmol/L  
≥150 mmol/L  and baseline <150 mmol/L  
Two independent criteria 
Reference ranges are similar in adolescents 
(12-17 yrs. old) and adults 
 
Potassium 
Hypokalemia 
Hyperkalemia 
 
≤3.5 mmol/L and baseline >3.5 mmol/L  
≥5.5 mmol/L and baseline <5.5 mmol/L  
FDA Feb 2005. 
Two independent criteria 
Reference ranges are similar in adolescents 
(12-17 yrs. old) and adults 
 
Calcium total 
<2 mmol/L and baseline ≥2 mmol/L   
(or ≤ 8 mg/dL and baseline >8 mg/dL) 
≥2.9 mmol/L and baseline <2.9 mmol/L  
(or ≥11.6 mg/dL and baseline <11.6 mg/dL) 
 
LDL Cholesterol 
≥4.91 mmol/Land <4.91 mmol/L at baseline 
(≥ 190 mg/dl and <190 mg/dl at baseline) 
Threshold for therapeutic intervention with 
pharmacotherapy in children 
(Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in 
Children and Adolescents; 2011). 
Total cholesterol 
≥6.20 mmol/Land < 6.20 mmol/L at baseline  
(or ≥ 240 mg/dL and < 240 mg/dL at baseline) 
 
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Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1652 
Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 75 of 83 
Parameter 
Treatment Emergent PCSV1 
Comments 
Triglycerides 
Fasting level ≥ 5.64 mmol/Land < 5.64 mmol/L 
at baseline 
(or ≥ 500 mg/dL and < 500 mg/dL at baseline) 
Threshold for therapeutic intervention with 
pharmacotherapy in children. (Expert Panel 
on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and 
Adolescents; 2011). 
CF = g x 1.14 = mmol 
Glucose 
Hypoglycaemia 
 
Hyperglycaemia 
 
<2.7 mmol/L and ≥2.7 mmol/L at baseline (or < 
50 mg/dL and ≥ 50 mg/dL at baseline)  
≥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) 
 
 
HbA1c 
>6.5% and <= 6.5% at baseline 
WHO 2006/2011 
ADA 2003 and 2012 
Albumin 
≤25 g/L and >25 g/L at baseline 
Reference ranges are same in children (6-17 
yrs. old) and adults 
Hematology 
WBC 
<5.0 Giga/L and ≥5.0 Giga/L at baseline  
>17.0 Giga/L and ≤17.0 Giga/L at baseline 
 
Lymphocytes 
<1.0 Giga/L and ≥1.0 Giga/L at baseline  
>8.0 Giga/L and ≤ 8.0 Giga/L at baseline 
 
Neutrophils 
<1.2 Giga/L and ≥1.2 Giga/L at baseline  
>ULN and baseline ≤ ULN 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
FDA criteria. 
 
Monocytes 
>0.7 Giga/L and <= 0.7 Giga/L at baseline 
 
Eosinophils 
(>0.5 Giga/L and >ULN) and (<=0.5 Giga/L or 
<= ULN at baseline) 
Harrison- Principles of internal Medicine 17th 
Ed., 2008. 
Hemoglobin 
<10 g/dL and >10 g/dL at baseline (or <100 g/L 
and >=100 g/L at baseline) or any decrease ≥ 2 
g/dL 
 
≥20 g/dL and <20 g/dL at baseline (or >=200 
g/L and <200 g/L at baseline) 
 
Two criteria are independent 
 
.  
Hematocrit 
< 32% and ≥ 32% at baseline 
>47% and ≤ 47% at baseline 
Two Criteria are independent 
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1652 
Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 76 of 83 
Parameter 
Treatment Emergent PCSV1 
Comments 
Platelets 
<100 Giga/L and ≥100 Giga/L at baseline 
>700 Giga/L and ≤ 700 Giga/L at baseline 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
Two independent criteria 
Urinalysis 
Ketonuria 
Presence and absence at baseline 
Semi-quantitative methods 
Glycosuria 
Presence and absense at baseline 
Semi-quantitative methods 
Microscopic 
Hematuria 
> 5 RBCs/ HPF and ≤5 RBCs/ HPF at baseline Semi-quantitative methods 
Proteinuria 
≥ 1+ and <1 at baseline 
Semi-quantitative methods, ≥ 1+ means 
concentration >=30 mg/dL 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
>120 bpm and increase from baseline≥20 bpm 
 
SBP 
≤80 mmHg and decrease from baseline ≥ 
20mmHg 
≥108 mmHg and increase from baseline ≥ 
20mmHg 
 
DBP 
≤48 mmHg and decrease from baseline ≥ 
10mmHg 
≥72 mmHg and increase from baseline ≥ 
20mmHg 
 
Temperature 
Rectal, ear: >100.4 °F/38.0 °C 
Oral: >99.5 °F/37.5 °C  
Axillary: >99 °F/37.2 °C 
 
Respiratory rate 
<16 per minute and ≥16 per minute at baseline 
>30 per minute and ≤30 per minute at baseline 
 
Weight 
≥5% decrease 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. 
ECG 
Ref.: CPMP 1997 guideline. 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
 
PR 
≥170 ms and <170 ms at baseline 
 
QRS 
≥100 ms and <100 ms at baseline 
 
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1652 
Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 77 of 83 
Parameter 
Treatment Emergent PCSV1 
Comments 
QTc 
 
Absolute values (ms)  
Borderline: 431-450 ms and < 431ms at baseline 
Prolonged: >450 ms and ≤ 450 ms at baseline  
Additional: ≥500 ms and < 500 ms at baseline 
 
AND 
 
Increase from baseline 
Borderline: Increase from baseline 30-60 ms 
Prolonged: Increase from baseline >60 ms 
Bazett’s formula (measured QT interval 
divided by the square root of the R-R) to be 
applied to arrive at corrected QT value 
interval) 
 
To be applied to QTcF; QTc prolonged and 
QTc>60 ms are the PCSA to be identified in 
individual patient listings 
 
Independent criteria 
 
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1652 
Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 78 of 83 
10.5. 
Search Criteria for TEAE of Special Interest/TEAE Syndrome1 
AESI 
Search Criteria 
Anaphylactic reactions  
 
For SMQ “anaphylactic reaction” An algorithmic approach will be used. 
A case must include either:  
1. A narrow term (a term from Category A);  
2. Patient with both a term from Category B AND a term from Category 
C;  
3. Patient with a term from Category D AND { a term from Category B -  
OR a term from Category C } 
For bullets 2 and 3, the search terms that are included under the SMQ for 
a particular event need to have the same start date (for e.g. if search shows 
cough (category B term) occurring at day 3 and urticaria (category C 
term) occurring at day 7, this event is not adjudicated as anaphylactic 
reaction as this is inconsistent with the clinical presentation of 
anaphylaxis as an acute event with simultaneous involvement of 2 or 
more body systems. 
Note:  manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
Systemic or severe 
hypersensitivity reactions  
 
Hypersensitivity: Narrow SMQ for hypersensitivity excluding preferred 
term equal to dermatitis atopic or eczema  
For systemic hypersensitivity, events in which 2 or more body systems are 
involved (as defined by System Organ Class) would be considered for 
adjudication based on further medical judgement 
For severe hypersensitivity, an additional search will be done; 
- HLT = Injection site reactions and Severity = “severe”  
- HLT = Allergies to foods, food additives, drugs and other chemicals 
and Severity = “severe” or Serious=”Yes” 
Note:  manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
Malignancy 
 SMQ “Malignant tumours” 
 SMQ “Tumours of unspecified malignancy” 
Helminthic infections2 
-HLT = Cestode infections 
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1652 
Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 79 of 83 
-HLT = Helminthic infections NEC 
-HLT = Nematode infections 
-HLT = Trematode infection 
Suicidal behavior 
Include the following PTs 
 Completed suicide 
 Suicidal ideation 
 Suicide attempt 
 Depression suicidal 
 Suicidal behavior 
Any type of conjunctivitis 
or blepharitis (severe or 
serious) 
broad CMQ conjunctivitis (Conjunctivitis, Conjunctivitis allergic, 
Conjunctivitis bacterial, Conjunctivitis viral, Atopic keratoconjunctivitis, 
Blepharitis, Dry eye, Eye irritation, Eye pruritus, Lacrimation increased, 
Eye discharge, Foreign body sensation in eyes, Photophobia, Ocular 
hyperaemia, Conjunctival hyperaemia, Xerophthalmia) 
Blepharitis PTs (Blepharitis, blepharitis allergic) 
 
AND 
Serious AE= “Yes” OR Severity= “severe” 
Note: manual adjudication of relevant PTs will be required by the 
study medical monitor, before database lock. 
Keratitis 
Any of the following PTs: 
a. Keratitis 
b. Allergic keratitis 
c. Ulcerative keratitis 
d. Atopic keratoconjunctivitis 
e. Herpes ophthalmic  
f. − Ophthalmic herpes simplex  
Note: manual adjudication of relevant PTs will be required by the 
study medical monitor, before database lock. 
1 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 
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1652 
Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 80 of 83 
10.6. 
Algorithm for RESCUE TREATMENTS 
1. Not required to adjudicate rescue treatment:  
Post-baseline medications (WHODD-coded) given for indications consistent with AD 1  
a. Always considered rescue: 
 ATC2 = CORTICOSTEROIDS FOR SYSTEMIC USE 
 ATC2 = IMMUNOSUPPRESSANTS 
 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 
 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) 
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1652 
Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 81 of 83 
 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 
 Preferred Drug Name = TRIAMCINOLONE ACETONIDE 
1 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.  
1. Require 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 
 
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1652 
Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 82 of 83 
10.7. 
PROMIS Scoring Tables 
Anxiety 8a - Pediatric v2.0 
Short Form Conversion Table 
Raw 
Score 
T-Score 
SE* 
8 
33.5 
5.9 
9 
38.0 
4.9 
10 
40.6 
4.7 
11 
43.0 
4.4 
12 
44.9 
4.2 
13 
46.7 
4.0 
14 
48.3 
3.9 
15 
49.8 
3.8 
16 
51.2 
3.8 
17 
52.5 
3.7 
18 
53.8 
3.7 
19 
55.1 
3.7 
20 
56.3 
3.7 
21 
57.5 
3.7 
22 
58.7 
3.7 
23 
59.9 
3.7 
24 
61.0 
3.7 
25 
62.2 
3.7 
26 
63.4 
3.7 
27 
64.5 
3.7 
28 
65.7 
3.6 
29 
66.9 
3.6 
30 
68.1 
3.6 
31 
69.3 
3.7 
32 
70.6 
3.7 
33 
71.8 
3.7 
34 
73.2 
3.7 
35 
74.6 
3.8 
36 
76.0 
3.8 
37 
77.6 
3.9 
38 
79.3 
4.0 
39 
81.1 
3.9 
40 
83.3 
3.8 
SE* = Standard Error on T-Score 
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1652 
Statistical Analysis Plan 
 
May 07, 2019 
CONFIDENTIAL 
Page 83 of 83 
 
Pediatric v2.0 - Depressive 
Symptoms 8a 
Short Form Conversion Table 
Raw Score T-Score 
SE* 
6 
36.2 
5.9 
7 
42.1 
4.4 
8 
45.4 
4.0 
9 
48.0 
3.6 
10 
50.2 
3.4 
11 
52.1 
3.3 
12 
53.9 
3.2 
13 
55.6 
3.1 
14 
57.2 
3.1 
15 
58.9 
3.1 
16 
60.5 
3.1 
17 
62.1 
3.1 
18 
63.7 
3.1 
19 
65.3 
3.1 
20 
66.8 
3.1 
21 
68.4 
3.1 
22 
70.0 
3.1 
23 
71.5 
3.0 
24 
73.1 
3.0 
25 
74.7 
3.0 
26 
76.3 
3.1 
27 
78.1 
3.2 
28 
80.2 
3.3 
29 
82.5 
3.4 
30 
84.7 
3.2 
SE* = Standard Error on T-Score 
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00


Signature Page for VV-RIM-00078151 v2.0
Signature Page for VV-RIM-00078151 v2.0 Approved
ESig Approval
gement
10-May-2019 14:29:14 GMT+0000
ESig Approval
10-May-2019 14:33:46 GMT+0000
ESig Approval
ment
10-May-2019 16:24:17 GMT+0000
                                        VV-RIM-00078151-2.0 Approved - 10 May 2019 GMT-5:00