Conditions: Moderate-to-Severe Atopic Dermatitis Dermatitis, Dermatitis Atopic Eczema, Skin Diseases, Skin Diseases Genetic, Genetic Diseases Inborn, Skin Disease, Eczematous Skin Hypersensitivity, Immediate Hypersensitivity, Immune System Diseases Dermatitis, Atopic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 251
Healthy volunteers: no

Brief summary:
The primary objective of the study was to demonstrate the efficacy of dupilumab as a monotherapy in participants ≥12 years to \<18 years of age with moderate-to-severe atopic dermatitis (AD). The secondary objective of the study was to assess the safety of dupilumab as a monotherapy in participants ≥12 years to \<18 years of age with moderate-to-severe AD.

Detailed description:

Arms:
arm 1: Participants received placebo matching dupilumab once every 2 weeks (Q2W) (including doubling the amount of placebo on day 1 to match the loading dose). In order to maintain blinding for the study, participants in the \<60 kilogram (kg) weight stratum received, in a 1:1 ratio, either placebo matching 200 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose) or placebo matching 300 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose). In the ≥60 kg weight stratum, the participants randomized to the placebo group received placebo matching 300 mg dupilumab (including doubling the amount of placebo on day 1 to match the loading dose). arm 2: Participants received once every 4 weeks (Q4W) subcutaneous (SC) injections of 300 milligrams (mg) dupilumab following a loading dose of 600 mg on day 1. In order to maintain blinding, all participants received an injection once every 2 weeks (Q2W) from day 1 to week 14. Participants received placebo 2 milliliter (mL) injection at the weeks dupilumab was not given. arm 3: Participants with baseline weight \<60 kg received once every 2 weeks (Q2W) subcutaneous (SC) injections of 200 milligrams (mg) dupilumab following a loading dose of 400 mg on day 1. Participants with baseline weight ≥60 kg received Q2W SC injections of 300 mg dupilumab following a loading dose of 600 mg on day 1.

Interventions: intervention 1: Dupilumab intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous injection among the different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms. intervention 2: Subcutaneous injection among the different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.

Protocol document:
Prot_000.pdf: 
VV-RIM-00038275-2.0 Approved - 23 Feb 2018 GMT-5:00 
 
NCT03054428 
 
 
 
 
IND Number: 107969 
EudraCT Number: 2015-004458-16 
Regeneron Pharmaceuticals, Inc. 
 
 
 
Clinical Study Protocol 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO INVESTIGATE THE EFFICACY AND SAFETY OF DUPILUMAB 
MONOTHERAPY IN PATIENTS ≥12 TO <18 YEARS OF AGE, WITH 
MODERATE-TO-SEVERE ATOPIC DERMATITIS 
 
 
 
Compound: 
Dupilumab 
 
Clinical Phase: 
3 
 
 
 
 
Protocol Number: 
R668-AD-1526 
 
Protocol Version: 
R668-AD-1526 Amendment 3 
 
Amendment 3 Date of Issue: 
See appended electronic signature page 
 
Amendment 2 Date of Issue: 
05 July 2017 
 
Original Date of Issue: 
29 October 2015 
 
 
 
 
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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Amendment 3 
AMENDMENT HISTORY 
 
The following table outlines the changes made to the protocol and the affected sections: 
 
Change 
Section Changed 
1. Moved the following endpoint from other secondary to 
key secondary endpoints: 
Proportion of patients with improvement (reduction) 
of weekly average of daily peak Pruritus NRS ≥3 
from baseline to week 16 
Rationale:    The sponsor will conduct a post-hoc 
responder analysis to determine the relevant threshold 
for the adolescent population.  The sponsor believes that 
an improvement in Pruritus NRS by 3 points may be 
clinically relevant especially in a pediatric population; 
hence, this endpoint has been prespecified in the 
protocol. 
2. Added  the  following  endpoint  to  the  list  of  other 
endpoints: 
Time to onset of effect on pruritus as measured by 
proportion of patients with improvement (reduction) 
of weekly average of daily peak Pruritus NRS ≥3 
from baseline during the 16-week treatment period 
Rationale:  The sponsor believes that this endpoint is 
clinically relevant; hence, should be prespecified in the 
protocol. 
3. Made changes to the statistical hierarchy for multiplicity 
control. 
Rationale: The order of testing for certain endpoints was 
re-arranged based on further internal review and 
discussions. This was based on review of the power 
calculation assumptions and the perceived clinical 
relevance of the endpoints. 
Synopsis, Secondary endpoints 
Section 8.2.2 Secondary Endpoints 
Section 9.5.2.3 Multiplicity Considerations 
Table 3 Statistical Hierarchy for Multiplicity 
Control 
Revision was made in Inclusion Criterion #8 for clarification 
purpose  based  on  clarification  letter  previously  sent  to 
investigators,  regulatory  authorities,  ethic  committees  and 
independent review boards. 
Section 4.2.1, Inclusion Criteria,  #8 
The     biomarker     sample     type     was     changed     from 
“serum/plasma” to “serum” based on clarification letter 
previously sent to investigators, regulatory authorities, ethic 
committees and independent review boards. 
Table 1 Schedule of Events (Screening, 
Baseline, and Treatment Period) – row for 
Biomarker Samples 
Table 2 Schedule of Events (treatment Period 
cont, Follow-Up Period, Unscheduled Visits, 
and Early Termination) - row of Biomarker 
Samples 
Section 6.2.5 Biomarker Procedures 


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Amendment 2 
 
The following table outlines the changes made to the protocol and the affected sections: 
 
Change 
Section Changed 
Added   an   exclusion   criterion   #9   of   “Treatment   with 
crisaborole within 2 weeks prior to the baseline visit.” 
Crisaborole was recently approved in the US for the treatment 
of mild to moderate AD in patients 2 years and older. This 
exclusion criterion has been added to ensure that patients will 
be completely washed off this topical therapy before baseline 
assessments and to minimize any carry-over effects into the 
treatment period. This will minimize any confounding of 
efficacy assessment for the study drug. 
Section 4.2.2 Exclusion Criteria 
Revised exclusion criteria #19: 
Creatine phosphokinase (CPK) >2.5× ULN to Creatine 
phosphokinase (CPK) >5× ULN. 
The criterion for temporary discontinuation of drug for 
elevated CPK levels (section 5.4.2.2  of protocol) has also 
been modified accordingly. Increases in CPK levels which are 
transient and not clinically significant are well known after 
strenuous exercise, especially in adolescent patients. 
Moreover, based on data gathered from studies with 
dupilumab in adult patients and in pediatric patients (R668- 
AD-1412), there is no evidence that dupilumab per se has any 
impact on CPK levels in blood. The drug is not expected to 
have such an effect based on its mechanism of action.  The 
sponsor believes that this should be the optimal threshold 
which while ensuring patient safety will not be overly 
restrictive and not negatively impact patient recruitment and 
retention during the study. This would ensure that pediatric 
patients are not unnecessarily deprived of a potentially useful 
therapy for a disease with high unmet medical need. 
Section 4.2.2 Exclusion Criteria 
Section 5.4.2.2 Reasons for Temporary 
Discontinuation of Study Drug 
Corrected  the  expellable  volume  for  200  mg  to  1.14  mL 
instead of 1.0 mL. 
Section 5.1 Investigational and Reference 
Treatments 
Clarified  the  text  indicating  where  moisturizers  should  be 
applied by the deletion of the following text in the third 
sentence “on the area(s) of nonlesional skin desigated for such 
assessments” 
Section 5.2 Background Treatment 
Added  the  medication  crisaborole  to  the  list  of  prohibited 
agents  because  it  is  a  treatment  for  atopic  dermatitis  and 
would interfere with the efficacy evaluation.  Crisaborole has 
been added to the list of prohibited medications to prevent any 
confounding of efficacy assessment for the study drug. 
Section 5.7.1 Prohibited Medications and 
Procedures 


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Change 
Section Changed 
In original version of protocol, there were certain criterion 
that were needed to be met before patients could be offered 
roll-over into OLE at end of treatment period. Patients who 
did not meet these criteria would be followed up during the 
12 week follow up period before they were allowed entry into 
OLE. 
In the amended version, all patients would be offered entry 
into OLE at end of treatment. The patients who decline OLE 
will be followed up for 12 weeks. 
The primary purpose of the 12 week follow up period was to 
gather off-treatment efficacy and safety data in pediatric 
patients. However, this provision is now built in the OLE 
protocol as patients who have been exposed to drug for 52 
weeks, and have achieved clinical response will be taken off 
treatment and efficacy/safety will be observed in these 
patients. 
Moreover, seamless transition into OLE will prevent pediatric 
patients from developing flares of disease during the follow 
up period. Continuous treatment is also expected to minimize 
the development of ADAs due to treatment interruption. 
Section 3.1 Study Description and Duration 
Section 5.8 Continuation of Dupilumab 
Treatment in an Open-Label Extension Study 
Added the provision: If baseline/day 1 visit occurs within 14 
days of screening, hematology and serum chemistry do not 
need to be repeated at the baseline/day 1 visit as long as these 
assessments were performed at the screening visit. 
This would help minimize blood volumes collected in this 
pediatric population. 
Section 6.1 Schedule of Events, Table 1 
Removed hematology and chemistry assessments at week 2 
and week 12. 
This has been done to minimize the volume of blood collected 
in a pediatric population. These assessments would still be 
being conducted at screening, baseline, week 4, week 8, week 
16, and end of study, which should be sufficient to allow 
detection of any clinically significant abnormality in these lab 
parameters within a reasonable time frame.  Moreover, data 
from dupilumab studies in adult patients and the phase 2 study 
in pediatric patients (R668-AD-1412) does not suggest that 
dupilumab has an impact on any of the lab parameters being 
evaluated under serum hematology and chemistry. 
Section 6.1 Schedule of Events, Table 1 
Removed the Pain Assessment with Visual Analogue Scale 
(VAS) from phone visit 16 for accuracy. 
Section 6.1 Schedule of Events, Table 2 
Corrected the text related to the The Total Nasal Symptoms 
Score (TNSS) to state “The Total Nasal Symptom Score 
(TNSS) will be used to assess the effect of study drug on 
symptoms of allergic rhinitis. The summed score will include 
the following 5 4 nasal symptoms: rhinorrhea, nasal 
congestion, nasal itching, and sneezing, and difficulty in 
sleeping, each rated...” 
Section 6.2.2.9 – Total Nasal Symptom Score 
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. 
Section 6.2.2.11  Investigator’s Global 
Assessment 


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Change 
Section Changed 
Added that the investigator will also assess whether the AES 
are related to any study procedures (as listed in Tables 1 and 
2).  This will allow better characterization of adverse events 
during the study. 
Deleted the heading “Relationship of AEs to Study Drug” 
since the section is also referring to relationship to 
procedures. 
Section 7.3.2 Evaluation of Causality 
The list of AESIs has been revised across the dupilumab 
program in AD and incorporates the data gathered from adult 
phase 3 studies, the dupilumab risk profile, and regulatory 
feedback. This will enable focus of pharmacovigilance 
activities on identified and potential risks with this drug. 
Section 7.2.3 Other Events that Require 
Accelerated Reporting 
As per FDA request, added that 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.  This methodology was added to 
further clarify the testing. 
Section 9.5.2.1 Primary Efficacy Analysis 
Synopsis (Statistical Plan) 


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Change 
Section Changed 
As per FDA request, provided further details on the 
methodology for multiple imputation of the continuous 
endpoints and deleted text related to missing data from the 
FAS. 
For continuous endpoints, added that the multiple imputation 
(MI) with analysis of covariance (ANCOVA) model will be 
used “as the primary analysis method.” 
Added the following text to clarify the methodology: 
“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 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. 
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 (disease severity, 
weight group), 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 (disease severity, 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 the 40 
analyses using Rubin’s formula.” 
Deleted the following text:  “Missing data from the FAS will 
be imputed multiple 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 (baseline disease severity 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.” 
Section 9.5.2.2 Secondary Efficacy Analysis 
Synopsis (Statistical Plan) 


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Change 
Section Changed 
As per FDA request, added the hierarchy for testing 
procedures for primary and secondary endpoints across the 
two dupilumab dose regimens to further clarify the testing. 
The following text was added: 
“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).” 
The following text was deleted: 
“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 hierarchy of testing procedure will be provided 
in the SAP.” 
Added an endpoint table to clarify the statistical changes for 
the Primary endpoint, Co-primary endpoint for ex-US 
countries, key secondary for US, Key Secondary endpoints, 
and Secondary Endpoints. 
Section 9.5.2.3 Multiplicity Considerations 
Synopsis (Statistical Plan) 
Minor editorial changes 
Section 5.4.2.1 Reasons for Permanent 
Discontinuation of Study Drug 


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AMENDMENT 1 
 
NOTE: This is the first version of the protocol that will be implemented. 
The objectives of amendment 1 are to: 
• Add a 200 mg every 2 week (Q2W) regimen (with a loading dose of 400 mg on 
day 1) to the Q2Wtreatment group.  Patients below 60 kg will receive 200 mg Q2W, 
while patients ≥60 kg will receive 300 mg Q2W (with a loading dose of 600 mg on 
day 1).  This weight-adjusted dosing better fulfills the conventional therapeutic 
objective to utilize the minimum effective dose. This tiered weight-based approach 
will reduce difference in exposure levels between patients with different body 
weights. In addition, it will allow assessment of a dose regimen that involves 
injection of lower volume of drug product (1 mL). A lower volume injection may be 
better tolerated by pediatric patients. 
 
• Increase sample size from 180 patients to 240 patients. Assumptions for power 
calculations in the original protocol were based on phase 2b trial in adults. Since then, 
results from Phase 3 trials in adults (SOLO) have become available in which a higher 
placebo response was seen. Accordingly, assumptions for power calculations were 
updated and an increase in sample size is required to keep the study adequately 
powered for the primary endpoint (Proportion of patients achieving IGA 0/1). 
Increasing the sample size will enable a more rigorous assessment of the therapeutic 
profile of dupilumab in this patient population. 
 
• Change duration of treatment period from 12 weeks to 16 weeks.  The treatment 
duration was increased to enable detection of maximum therapeutic effect of 
dupilumab and maximize the likelihood to detect a statistically significant difference 
versus placebo on the primary endpoint. The study design was originally informed by 
results from adult phase 2b trial (study R668-AD-1021), which suggested efficacy of 
dupilumab had plateaued at week 12 with no incremental efficacy between week 12 
and week 16.  However, recently available results from phase 3 studies in adults 
showed an increase in efficacy for dupilumab treatment arms between week 12 and 
week 16. 
 
• Revise the fourth bullet point under inclusion criterion number 8 from "… If 
documentation is inadequate, potential patients may be rescreened after such 
documentation is obtained (ie, patients are shown to fail a 28-day course of 
mid-to-higher potency TCS [±TCI])" to "… If documentation is inadequate, potential 
patients may be offered a course of treatment with a daily regimen of TCS of medium 
or higher potency (±TCI as appropriate), applied for at least 28 days during the 
screening period, or for the maximum duration recommended by the product 
prescribing information, whichever is shorter. Patients who demonstrate inadequate 
response during this period, as defined above, will be eligible for inclusion in the 
study, following appropriate washout".  The language in original protocol was 
ambiguous as it suggested that all patients were to be re-screened if they were offered 
a course of TCS to demonstrate inadequate response.  However, there might be some 
patients who would be able to enroll into the study as part of the initial screening as 


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long as they are able to complete the course of TCS within the screening period of 
35 days.  The revised text serves to clarify this ambiguity. 
 
• Revise inclusion criterion number 11 from “Patient either alone or with the help of 
their parents/legal guardians, as appropriate, must be able to understand and complete 
study-related questionnaires” to “Able to understand and complete study-related 
questionnaires”. The objective of making this change is to ensure that patient 
reported outcome questionnaires are completed by patients alone, as assistance from 
parents or caregivers might bias the interpretation and response to questions in the 
instrument. 
 
• Revise exclusion criterion number 2 from “Treatment with an investigational drug 
before the baseline visit” to “Treatment with a systemic investigational drug before 
the baseline visit”, and add another exclusion criterion (criterion number 3) in this 
context: “Treatment with a topical investigational drug within 4 weeks or within 
5 half-lives (if known), whichever is longer, before the baseline visit”. The previous 
exclusion criterion was too restrictive and would have prevented patients who had 
received topical investigational agents for AD, at any time prior to screening visit, 
from being enrolled in this study. The updated exclusion criterion enables such 
patients to be enrolled in this trial, conditional upon a 4-week or a period of 5-half- 
lives washout for the topical investigational agent. 
 
• Revise exclusion criterion number 4 (old criterion number 3 in the original protocol) 
from “Treatment with TCS or topical calcineurin inhibitors (TCI) within 1 week 
before the baseline visit (patients may be rescreened)” to “Treatment with TCS or 
topical calcineurin inhibitors (TCI) within 2 weeks before the baseline visit (patients 
may be rescreened)”. The duration of a washout period for TCS and TCIs has been 
increased to 2 weeks to ensure that patients are completely washed off these topical 
therapies before baseline assessments and to prevent any carry-over effects from 
these agents into the treatment period. 
 
• Revise exclusion criterion number 12 (old criterion number 11 from the original 
protocol) from “Active chronic or acute infection requiring treatment with systemic 
antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before the 
screening visit, or superficial skin infections within 1 week before the screening visit” 
to “Active chronic or acute infection requiring treatment with systemic antibiotics, 
antivirals, antiprotozoals, or antifungals within 2 weeks before the baseline visit”. 
The objective of this exclusion criterion in the original protocol was to prevent 
patients with active infections from receiving the study drug and to allow a sufficient 
duration between the resolution of infection and first administration of study drug. 
Since first administration of study drug will take place at baseline and not screening, 
the baseline visit and not the screening visit is the relevant reference time point for the 
purpose of implementation of this criterion. Data from the phase 3 program in adults 
has shown that dupilumab actually reduces the risk of superficial skin infections. 
Hence, the exclusion criterion around superficial skin infections was removed. 


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• Change exclusion criterion number 18 (old criterion number 17 from the original 
protocol) to exclude patients with laboratory abnormalities at screening consistent 
with Common Terminology Criteria for Adverse Events (CTCAE) grade 2 and above. 
Changes were made to the exclusionary values for neutrophil count (previously 
<1000/µl, revised <1500/ µl), serum creatinine value (previously 2mg/dl, revised 
>1.5 ULN) and serum creatine phosphokinase (CPK) level (previouly >10 ULN, 
revised 2.5 ULN) at screening. The criteria for temporary discontinuation of study 
drug due to laboratory abnormalities were updated to be consistent with the exclusion 
criteria. This change has been made to address a regulatory agency request to make the 
exclusion criterion around lab parameters more stringent. 
 
• Revise exclusion criterion number 22 (old criterion number 21 from the original 
protocol) from “History of alcohol or drug abuse within 2 years before the screening 
visit” to “History of alcohol or drug abuse within 2 years before the screening visit or 
evidence of such abuse as documented by a positive result in laboratory test of 
alcohol and/or drug panel conducted at screening”. Excluding patients on basis of an 
objective lab test will be a more reliable way to assess ongoing alcohol or drug use. 
 
Also, added a clarifying note that patients who have a positive drug test due to a 
prescription drug being used for medical reasons, will still be eligible for enrollment 
into the study. 
 
• Revise the schedule of events: 
 
 Add a blood sample at week 4, visit 6 for assessment for anti-drug antibody 
(ADA) to Table 1.  This change has been made based on a Health Authority 
request. It will allow further characterization of the immunogenicity of the study 
drug. 
 
 Add injection training/observation at week 12, visit 14 to Table 1 
 
 Add “Assess missed school days” assessment to Table 1 and Table 2.  This 
patient reported outcome allows evaluation of effect of study drug on school 
related productivity. 
 
 Add “Total Nasal Symptom Score (TNSS)” assessment to Table 1 and Table 2 
and add footnote “k” to Table 1 and footnote “h” to Table 2 to state that “TNSS 
will be administered only to patients with medical history of allergic rhinitis 
throughout the screening period (at least 7 days before baseline/day 1) and only 
for 7 days preceding visit 6, visit 18 (EOT), and visit 21 (EOS).”  This patient 
reported outcome allows evaluation of effect of study drug on symptoms of 
Allergic Rhinitis, a commonly seen co-morbidity in patients with AD. 
 
 Add “Patient Assessment of Injection Pain Using Visual Analogue Scale (VAS)” 
assessment to Table 1 and Table 2.  This patient reported outcome enables 
evaluation of tolerability of dupilumab injections in an adolescent population. 
 
 Add “Patient/parent(s) or caregiver paper diary training for dosing” to Table 1 and 
add “Review home ediary” to Table 1 and Table 2 


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 Revise footnote “g” of Table 1 and footnote “d” of Table 2 to further clarify that at 
“in-clinic visits, sites will perform accountability assessment for the study drug 
that the patients or parents/caregivers have returned to the site.” 
 
 Remove SNOT questionnaire from Table 1 and Table 2 and delete from footnote 
“j” of Table 1 and footnote “e” of Table 2 that SNOT-22 will be administered 
only to patients with a history of chronic (rhino) sinusitis or nasal polyps. 
 
 Revise footnote “h” of Table 1 and footnote “e” of Table 2 to clarify that patient- 
reported assessments are to be completed only by the patient. 
 
 Revise footnote "j" of Table 1 and footnote "g" of Table 2 to clarify that ACQ-5 
will only be administered to patients with on-going asthma (in the original 
protocol, ACQ-5 was planned in patients with medical history of asthma). 
 
 Add “Study drug administration” and “Patient dosing paper diary completion” at 
week 14, visit 15 to Table 2. 
 
 Rename “Research samples (serum/plasma)” to “Biomarker samples 
(serum/plasma)” and move under Biomarker (Table 1 and Table 2). 
 
 
 Add that “Samples positive in the ADA assay will be analyzed in the Neutralizing 
antibody (NAb) assay.” to footnote “c” of Table 2. 
 
• Remove the endpoint hierarchy under Multiplicity Considerations; details will be 
specified in the SAP. 
 
• Include a description of the possible first-step analysis 
 
• Make the following change to the list of “Primary Endpoints”: 
 
 Update all endpoints previously being assessed at 12 weeks to be assessed at 
16 weeks (to align with increase in duration of treatment period from 12 weeks to 
16 weeks). 
 
• Make the following changes to the list of “Secondary Endpoints”: 
 
 Update all endpoints previously being assessed at 12 weeks to be assessed at 
16 weeks (to align with increase in duration of treatment period from 12 weeks to 
16 weeks) 
 
 Rearrange the order of the key secondary endpoints 
 
 Add the following endpoint: 
 
▪ Percent change in EASI score from baseline to week 16 


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 Revise the following endpoints (to harmonize with adult phase 3 trials): 
 
▪ “Percent change from baseline to week 12 in Pruritus Numerical Rating 
Scale (NRS)” to “Percent change from baseline to week 16 in weekly 
average of daily peak Pruritus NRS” 
 
▪ “Proportion of patients with improvement (reduction) of Pruritus NRS ≥4 
from baseline to week 12” to “Proportion of patients with improvement 
(reduction) of weekly average of daily peak Pruritus NRS ≥4 from 
baseline to week 16” 
 
▪ “Proportion of patients with improvement (reduction) of Pruritus NRS ≥3 
from baseline to week 12” to “Proportion of patients with improvement 
(reduction) of weekly average of daily peak Pruritus NRS ≥3 from 
baseline to week 16” AND move this endpoint to the list of “Other 
Secondary Endpoints” 
 
• Make the following changes to the list of “Other Secondary Endpoints”: 
 
 Update all endpoints previously being assessed at 12 weeks to be assessed at 
16 weeks (to align with increase in duration of treatment period from 12 weeks to 
16 weeks) 
 
 Rearrange the order of other secondary endpoints 
 
 Change all "pruritus NRS" to "peak pruritus NRS" 
 
 Add the following endpoints: 
 
▪ Change from baseline to week 16 in weekly average of daily peak Pruritus 
NRS 
 
▪ Proportion of patients with EASI-50 at week 16 
 
▪ Proportion of patients with EASI-90 at week 16 
 
▪ Time to onset of effect on pruritus as measured by proportion of patients 
with improvement (reduction) of weekly average of daily peak Pruritus 
NRS ≥4 from baseline during the 16-week treatment period 
 
▪ Proportion of patients with improvement (reduction) of weekly average of 
daily peak Pruritus NRS ≥4 from baseline to week 4 
 
▪ Incidence of skin-infection treatment-emergent adverse events (TEAEs) 
(excluding herpetic infections) through week 16 
 
▪ Incidence of serious treatment-emergent adverse events (TEAEs) through 
week 16 
 
 Remove the following endpoint: Proportion of patients with SCORing Atopic 
Dermatitis (SCORAD)-50 (≥50% reduction in SCORAD from baseline) response 
at week 12 


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 Remove the following endpoint: Change from baseline to week 12 in Global 
Individual Signs Score (GISS; erythema, infiltration, papulation, excoriations, 
lichenification) 
 
 Revise the following endpoints: 
 
▪ “Percent change in EASI score from baseline to week 12” to “Percent 
change in EASI score from baseline to week 16” AND move this endpoint 
to the list of “Key Secondary Endpoints” 
 
▪ “Percent change from baseline to week 2 in Pruritus NRS” to “Percent 
change from baseline to week 4 in weekly average of daily peak Pruritus 
NRS” 
 
• Removed the list of “Other Endpoints and Assessments” and noted that these will be 
specified in the Statistical Analysis Plan (SAP), as applicable. 
 
• Revise the number of imputations used to generate a complete data set for missing 
data from the full analysis set (FAS) from 50 times to multiple times. 
 
• Add a description of the power calculations based on the key secondary endpoint 
“Proportion of patients with improvement (reduction) of weekly average of daily 
peak Pruritus NRS ≥4 from baseline to week 16” 
 
• Add language to section 9.5.2.1 “Primary Efficacy Analysis” to clarify that data 
collected after study drug discontinuation will also be used in all analyses. 
 
• Correct the IND number 
 
• Add that “Regulatory approvals will also be obtained where required by local 
legislation.” 
 
• Update the Introduction to include more current information about completed and 
ongoing trials in the dupilumab program 
 
• Update reasons for temporary discontinuation of study drug 
 
• Make the following changes to section 5.8 “Continuation of Dupilumab Treatment in 
an Open-Label Extension Study”: 
 
 Remove the first bullet point “Patients have completed at least 6 weeks of study 
treatment and the remaining assessments during the treatment period (through 
week 12)” and replace with, “The patient needs to have completed at least 5 on 
site visits (including completing the study assessments and procedures planned for 
each of those visits), during the 16-week treatment period. 
 
AND 
 
The patient needs to have completed at least 6 study drug administrations during 
the 16-week treatment period.” 
 
 Clarify that the screening visit for the open-label extension may be completed on 
the same day as the early termination visit 


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 Revise the requirement of BSA affected by AD lesions from >10% to ≥10% 
 
 Clarify that patients who experience a flare during the follow-up period and 
would otherwise require treatment with systemic corticosteroids or 
immunosuppressive drugs can be directly enrolled into the open-label extension 
study at the investigator’s discretion. 
 
 Clarify that study drug administration refers to injections of dupilumab or 
placebo. 
 
• Clarify that patients will be trained at screening and baseline on using ediaries to 
record Pruritus NRS score, pruritus categorical scale score, assessment of Total Nasal 
Symptom Score (TNSS), and emollient usage, and at visit 6/week 4 on using a paper 
diary to record administration of each dose of study drug outside the clinic 
 
• Add language to section 6.2 “Study Procedures” indicating the order in which 
assessments/procedures should be performed at study visits 
 
• Revise the list of AESIs.  The list of AESIs has been revised across the dupilumab 
program in AD and incorporates the data gathered from adult phase 3 studies, the 
dupilumab risk profile, and regulatory feedback. This will enable focus of 
pharmacovigilance activities on identified and potential risks with this drug. 
 
• Revise the Biomarker Procedures section to align with the new procedures for 
collection, use, and storage of biomarker serum and plasma samples 
 
 
• Revise the definition of concomitant medications and procedures 
 
• Delete the section on Cytochrome P450.  Data became available recently from a 
phase 1 study to examine the Effects of Dupilumab on the Pharmacokinetics of 
Selected Cytochrome P450 Substrates in Adult Patients with Moderate to Severe 
Atopic Dermatitis. The results of this study showed no evidence for a clinically 
meaningful effect of dupilumab on the PK of a cocktail of prototypic substrates, 
indicating that blockade of IL4/13 signaling does not have a clinically relevant effect 
on the activity of CYP3A, CYP2C19, CYP2C9, CYP1A2 or CYP2D6, in adult 
patients with moderate to severe AD. 
 
• Revise the definition of “total number of patients with treatment-emergent ADA 
response in ADA assay” from “total number of patients with treatment-emergent ADA 
response in ADA assay – defined as either a positive response in ADA assay 
postbaseline when baseline results are negative, or any postbaseline positive response 
in ADA assay with a titer ≥4-fold over the baseline titer level.” to “total patients with 
treatment-emergent response – defined as a positive response in the ADA assay post 
first dose when baseline results are negative or missing”. This change was made to 
harmonize with the definition used for ADA analysis performed in phase 3 adult 
studies. 


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• Revise the definition of “persistent ADA response” from “a treatment-emergent ADA 
positive response with 2 or more consecutive positives in the ADA assay separated by 
at least a 12-week period” to “a treatment-emergent ADA positive response with 2 or 
more consecutive ADA positive sampling time points, separated by greater than a 
12-week period (with no ADA negative samples in between)”. This change was 
made to harmonize with the definition used for ADA analysis performed in phase 3 
adult studies. 
 
• Clarify the definition of the ADA analysis set from “all treated patients who received 
any study drug and who had at least 1 qualified result in the ADA assay after the first 
dose of the study drug” to “all treated patients who received any study drug and who 
had at least 1 non-missing reportable ADA result (either “ADA negative” or “ADA 
positive”) after first dose of the study drug”. This change was made to harmonize 
with the definition used for ADA analysis performed in phase 3 adult studies. 
 
• Include that ADA positive samples will be further characterized for the presence of 
neutralizing antibody response 
 
• Clarify that ADA variables will be summarized using descriptive statistics by 
treatment groups 
 
• Make editorial changes for clarity and consistency 


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CLINICAL STUDY PROTOCOL SYNOPSIS 
 
Title 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO INVESTIGATE THE EFFICACY AND SAFETY OF DUPILUMAB 
MONOTHERAPY IN PATIENTS ≥12 TO <18 YEARS OF AGE, WITH 
MODERATE-TO-SEVERE ATOPIC DERMATITIS 
 
Site Locations 
 
Principal Investigator 
Multiple sites in North America; other regions may be included. 
 
To be determined 
 
Objectives 
The primary objective of the study is to demonstrate the efficacy of dupilumab 
as a monotherapy in patients ≥12 years to <18 years of age with 
moderate-to-severe atopic dermatitis (AD). 
 
The secondary objective of the study is to assess the safety of dupilumab as a 
monotherapy in patients ≥12 years to <18 years of age with moderate-to-severe 
AD. 
 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group study to 
investigate the efficacy and safety of dupilumab monotherapy in pediatric 
patients with moderate-to-severe AD. The study population will include patients 
≥12 years to <18 years of age with moderate-to-severe AD whose disease cannot 
be adequately controlled with topical medications or for whom topical treatment 
is medically inadvisable (eg, intolerance, other important side effects or safety 
risks). Approximately 240 study patients are planned to be randomized to 1 of the 
following treatment groups: 
 
• 
Dupilumab every 2 weeks (Q2W) treatment group: 200 mg Q2W 
(patients <60 kg) or 300 mg Q2W (patients ≥60 kg) 
 
• 
Dupilumab every 4 weeks (Q4W) treatment group: 300 mg Q4W, 
irrespective of weight 
 
• 
Placebo group 
 
The study will consist of the following 3 periods: screening of up to 5 weeks, 
treatment period of 16 weeks, and follow-up of 12 weeks. 
 
After the parents or legal guardians/patients provide informed consent and 
informed assent (as appropriate), the patients will be assessed for study eligibility 
at the screening visit. During the screening period, systemic and topical 
treatments for AD will be washed out, as applicable, according to the eligibility 
requirements. Patients may be rescreened once if they fail the screening 
evaluation for reasons related to incidental transitory conditions, unless the 
reason for the screen failure is related to failing the disease severity inclusion 
criteria. Patients will be required to apply moisturizers twice daily for at least 
7 days before randomization and continue throughout the study. 


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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 weight group (<60 kg and ≥60kg; each weight stratum will enroll 
approximately 120 patients) and baseline disease severity (moderate 
[Investigator’s Global Assessment (IGA=3)] vs. severe [IGA=4] AD) as follows: 
 
• 
Dupilumab Q2W treatment group: Patients with baseline weight <60 kg 
will receive Q2W subcutaneous (SC) injections of 200 mg dupilumab 
following a loading dose of 400 mg on day 1.  Patients with baseline 
weight ≥60 kg will receive Q2W SC injections of 300 mg dupilumab 
following a loading dose of 600 mg on day 1. 
 
• 
Dupilumab Q4W treatment group:  Patients 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 placebo matching 
dupilumab Q2W (including doubling the amount of placebo on day 1 to 
match the loading dose). In order to maintain blinding for the study, 
patients in the <60 kg weight stratum will receive, in a 1:1 ratio, either 
placebo matching 200 mg dupilumab (including doubling the amount of 
placebo on day 1 to match the loading dose) or placebo matching 
300 mg dupilumab (including doubling the amount of placebo on day 1 
to match the loading dose). In the ≥60 kg weight stratum, the patients 
randomized to the placebo group will receive placebo matching 300 mg 
dupilumab (including doubling the amount of placebo on day 1 to match 
the loading dose). 
 
In order to maintain blinding, all patients will receive an injection Q2W from 
day 1 to week 14. Patients will receive placebo injection at the weeks dupilumab 
is not given. 
 
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. Patients and/or parents/caregivers (as 
deemed appropriate based on age of patient) will be trained on injecting study 
drug during in-clinic visit 2 (day 1) to visit 6 (week 4). During weeks in which no 
in-clinic visit is scheduled, patients will either self-inject study drug or the 
parent/caregiver will administer study drug to the patient. In case patients do not 
want to self-inject and the parent/caregiver do not want to administer study drug 
to patient, patients 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, two weeks after the last dose of study drug. The co-primary endpoints 
will be assessed at this visit. 
 
  
Patients who participate in the study may subsequently be eligible to participate  
 


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in an open-label extension study. 
 
Study Duration 
The duration of the study for each patient is approximately 28 weeks, excluding 
the screening period. 
 
Population 
 
Sample Size: 
Approximately 240 patients are planned to be enrolled into 3 groups (80 per 
group): dupilumab Q2W treatment group (200 mg Q2W or 300 mg Q2W), 
dupilumab Q4W treatment group (300 mg Q4W), or placebo group. 
 
Target Population: 
The study population includes pediatric patients (aged ≥12 to <18 years at the 
time of baseline) who have moderate-to-severe AD that cannot be adequately 
controlled with topical AD medications or for whom topical treatment is 
medically inadvisable (eg, intolerance, other important side effects or safety 
risks). 
 
Treatments Study Drug 
Dose/Route/Schedule: 
 
 
Dupilumab will be given every other week or every 4 weeks: 
 
• 
Dupilumab Q2W treatment: 
 
o SC injections of dupilumab, 400 mg loading dose on day 1, then 
200 mg Q2W from week 2 to week 14, or 
 
o SC injections of dupilumab, 600 mg loading dose on day 1, then 
300 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; in order to 
maintain the blind, there will be an SC injection of placebo in between 
dupilumab doses during the week 2 to week 14 dosing period so the injection 
frequency will match the other 2 groups. 
 
Placebo 
 
Route/Schedule: 
Matching placebo 
 
SC injections of placebo matching dupilumab Q2W (including doubling the 
amount of placebo on day 1 to match the loading dose). In order to maintain 
blinding for the study, patients in the <60 kg weight stratum who are randomized 
to the placebo group will receive, in a 1:1 ratio, either placebo matching 200 mg 
dupilumab (including doubling the amount of placebo on day 1 to match the 
loading dose) or placebo matching 300 mg dupilumab (including doubling the 
amount of placebo on day 1 to match the loading dose). 
 
Background Treatment 
 
Dose/Route/Schedule: 
All patients are required to 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 on the area(s) of  
 


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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 or moisturizers containing additives 
during the screening period or during the study. Patients may continue using 
stable doses of such moisturizers if initiated before the screening visit. 
 
Endpoints 
 
Primary (for US): 
•   Proportion of patients with IGA 0 to 1 (on a 5-point scale) at week 16 
 
Co-primary (for ex-US 
countries): 
•   Proportion of patients with Eczema Area and Severity (EASI)-75 
(≥75% improvement from baseline) at week 16 
 
•   Proportion of patients with IGA 0 to 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 peak 
Pruritus NRS 
 
•   Proportion of patients with improvement (reduction) of weekly average of 
daily peak Pruritus NRS ≥3 from baseline to week 16 
 
•   Proportion of patients with improvement (reduction) of weekly average of 
daily peak Pruritus NRS ≥4 from baseline to week 16 
 
Other Secondary Endpoints: 
 
•   Proportion of patients with EASI-50 at week 16 
 
•   Proportion of patients with EASI-90 at week 16 
 
•   Time to onset of effect on pruritus during the 16-week treatment period 
(≥3 point reduction of weekly average of peak Pruritus NRS from baseline) 
 
•   Time to onset of effect on pruritus during the 16-week treatment period 
(≥4 point reduction of weekly average of peak Pruritus NRS from baseline) 
 
•   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) 
 
•   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  
 


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(POEM) 
 
•   Change from baseline to week 16 in weekly average of daily peak Pruritus 
NRS 
 
•   Percent change from baseline to week 4 in weekly average of daily peak 
Pruritus NRS 
 
•   Change from baseline to week 16 in Hospital Anxiety and Depression Scale 
(HADS) 
 
•   Proportion of patients with improvement (reduction) of weekly average of 
daily peak Pruritus NRS ≥4 from baseline to week 4 
 
•   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 
investigator-reported assessments (including IGA that rates the overall severity 
of AD, EASI that measures the extent and severity of AD, SCORAD, BSA 
affected by AD, and GISS). In addition, patient-reported assessments (including 
Pruritus NRS, Pruritus PCS, patient global assessment of disease, patient global 
assessment of treatment, CDLQI, POEM, HADS, 5-question version of Asthma 
Control Questionnaire [ACQ-5], Total Nasal Symptom Score [TNSS], patient 
assessment of injection pain using Visual Analogue Scale [VAS], and patient 
assessment of missed school days [for patients who are enrolled in school]) will 
be used to assess their related endpoints. 
 
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. 
 
Statistical Plan 
Sample size Consideration: 
 
It is estimated that with 80 patients per group, at the 2-sided 5% significance 
level, the study will have: 
 
•   98% power to detect a difference of 28% between dupilumab Q2W and 
placebo treatment in the percentage of patients who achieve an IGA score 0 to 
1 at week 16, assuming that the percentages are 37% and 9% for dupilumab 
Q2W and placebo, respectively. 
 
•   88% power to detect a difference of 20% between dupilumab Q4W treatment 
and placebo treatment in the percentage of patients who achieve an IGA score 
0 to 1 at week 16, assuming that the percentages are 29% and 9% for 
dupilumab Q4W and placebo, respectively. 
 
•   99% power to detect a difference of 35% between dupilumab Q2W treatment 
  
and placebo treatment in the percentages of patients achieving EASI-75  
 


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response at week 16, assuming that the percentages are 48% and 13% for 
dupilumab Q2W and placebo, respectively. 
 
•   99% power to detect a difference of 32% between dupilumab Q4W treatment 
and placebo treatment in percentages of patients achieving EASI-75 response 
at week 16, assuming that the percentages are 45% and 13% for dupilumab 
Q4W and placebo, respectively. 
 
Additional power calculation based on the key secondary endpoint “proportion of 
patients with improvement (reduction) of Pruritus NRS ≥4 from baseline to week 
16”, with 80 patients per group, the study will provide: 
 
•   97% power at a 0.05 level to detect a difference of 27% in the percentages of 
patients achieving Pruritus NRS reduction ≥4 at week 16, assuming that the 
percentages are 38% and 11% for dupilumab Q2W and placebo, respectively. 
 
•   95% power at a 0.05 level to detect a difference of 25% in the percentages of 
patients achieving weekly average of daily peak Pruritus NRS reduction ≥4 at 
week 16, assuming that the percentages are 36% and 11% for dupilumab 
Q4W and placebo, respectively. 
 
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). 
 
The per protocol set (PPS) includes all patients in the FAS except for those who 
are excluded because of major efficacy-related protocol violations. A major 
protocol violation is one that may affect the interpretation of study results. 
 
Analysis Methods: 
 
Primary Efficacy Analyses 
 
The Cochran-Mantel-Haenszel (CMH) test adjusted by randomization strata 
(baseline disease severity and weight group) 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. 
 
All efficacy data, regardless of the patient being 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 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 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, 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   


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for endpoints after withdrawal. 
 
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. 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 CMH 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. 
 
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 (baseline 
disease severity 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 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 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 vs placebo. Each hypothesis will 
be formally tested only if the preceding one is significant at the 2-sided 0.05 
significance level. 


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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.............................................................................16 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................30 
 
1. 
INTRODUCTION AND RATIONALE.....................................................................33 
 
1.1. 
Introduction.................................................................................................................33 
 
1.2. 
Rationale .....................................................................................................................35 
 
1.2.1. 
Rationale for Study Design.........................................................................................35 
 
1.2.2. 
Rationale for Dose Selection ......................................................................................36 
 
1.2.3. 
Safety Considerations .................................................................................................37 
 
2. 
STUDY OBJECTIVES ..............................................................................................38 
 
2.1. 
Primary Objective .......................................................................................................38 
 
2.2. 
Secondary Objective ...................................................................................................38 
 
3. 
STUDY DESIGN .......................................................................................................38 
 
3.1. 
Study Description and Duration .................................................................................38 
 
3.1.1. 
End of Study Definition..............................................................................................40 
 
3.2. 
Planned Interim Analysis............................................................................................40 
 
3.3. 
Study Committees.......................................................................................................40 
 
3.3.1. 
Independent Data Monitoring Committee ..................................................................40 
 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............41 
 
4.1. 
Number of Patients Planned .......................................................................................41 
 
4.2. 
Study Population.........................................................................................................41 
 
4.2.1. 
Inclusion Criteria ........................................................................................................41 
 
4.2.2. 
Exclusion Criteria .......................................................................................................43 
 
4.3. 
Premature Withdrawal from the Study .......................................................................46 
 
4.4. 
Replacement of Patients .............................................................................................46 
 
5. 
STUDY TREATMENTS............................................................................................46 
 
5.1. 
Investigational and Reference Treatments..................................................................46 
 
5.2. 
Background Treatment ...............................................................................................48 
 
5.3. 
Rescue Treatment .......................................................................................................48 
 
5.4. 
Dose Modification and Study Drug Discontinuation Rules .......................................48 
 
5.4.1. 
Dose Modification ......................................................................................................48 


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5.4.2. 
Study Drug Discontinuation .......................................................................................49 
 
5.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................49 
 
5.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................50 
 
5.5. 
Method of Treatment Assignment ..............................................................................50 
 
5.5.1. 
Blinding ......................................................................................................................51 
 
5.5.2. 
Emergency Unblinding ...............................................................................................51 
 
5.6. 
Treatment Logistics and Accountability.....................................................................51 
 
5.6.1. 
Packaging, Labeling, and Storage ..............................................................................51 
 
5.6.2. 
Supply and Disposition of Treatments .......................................................................51 
 
5.6.3. 
Treatment Accountability ...........................................................................................52 
 
5.6.4. 
Treatment Compliance................................................................................................52 
 
5.7. 
Concomitant Medications and Procedures .................................................................52 
 
5.7.1. 
Prohibited Medications and Procedures .....................................................................52 
 
5.7.2. 
Permitted Medications and Procedures ......................................................................53 
 
5.8. 
Continuation of Dupilumab Treatment in an Open-Label Extension Study ..............53 
 
6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS.........................54 
 
6.1. 
Schedule of Events .....................................................................................................54 
 
6.2. 
Study Procedures ........................................................................................................61 
 
6.2.1. 
Procedures Performed only at the Screening/Baseline Visit ......................................61 
 
6.2.2. 
Efficacy Procedures ....................................................................................................61 
 
6.2.2.1. 
Patient Assessment of Pruritus Using Numerical Rating Scale..................................61 
 
6.2.2.2. 
Patient Assessment of Pruritus Using Pruritus Categorical Scale ..............................62 
 
6.2.2.3. 
Patient Global Assessment of Disease........................................................................62 
 
6.2.2.4. 
Patient Global Assessment of Treatment....................................................................62 
 
6.2.2.5. 
Children's Dermatology Life Quality Index ...............................................................63 
 
6.2.2.6. 
Patient Oriented Eczema Measure ..............................................................................63 
 
6.2.2.7. 
Patient-Assessed Hospital Anxiety and Depression Scale .........................................63 
 
6.2.2.8. 
Juniper Asthma Control Questionnaire – 5 ................................................................64 
 
6.2.2.9. 
Total Nasal Symptom Score .......................................................................................64 
 
6.2.2.10. 
Injection Site Pain Visual Analogue Scale .................................................................64 
 
6.2.2.11. 
Investigator’s Global Assessment...............................................................................64 
 
6.2.2.12. 
Eczema Area and Severity Index................................................................................65 


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6.2.2.13. 
Global Individual Signs Score ....................................................................................65 
 
6.2.2.14. 
SCORing Atopic Dermatitis .......................................................................................65 
 
6.2.2.15. 
Body Surface Area Involvement of Atopic Dermatitis ..............................................66 
 
6.2.2.16. 
Assessment of Missed School Days ...........................................................................66 
 
6.2.2.17. 
Atopic Dermatitis Area Photographs ..........................................................................66 
 
6.2.3. 
Safety Procedures .......................................................................................................66 
 
6.2.3.1. 
Vital Signs ..................................................................................................................66 
 
6.2.3.2. 
Body Weight and Height ............................................................................................66 
 
6.2.3.3. 
Physical Examination .................................................................................................66 
 
6.2.3.4. 
Electrocardiogram.......................................................................................................66 
 
6.2.3.5. 
Laboratory Testing......................................................................................................67 
 
6.2.4. 
Pharmacokinetic and Antibody Procedures ................................................................68 
 
6.2.4.1. 
Drug Concentration Measurements and Samples .......................................................68 
 
6.2.4.2. 
Anti-Drug Antibody Measurements and Samples ......................................................68 
 
6.2.5. 
Biomarker Procedures ................................................................................................68 
 
6.2.6. 
Future Biomedical Research .......................................................................................69 
 
 
 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................70 
 
7.1. 
Definitions ..................................................................................................................70 
 
7.1.1. 
Adverse Event.............................................................................................................70 
 
7.1.2. 
Serious Adverse Event................................................................................................70 
 
7.2. 
Recording and Reporting Adverse Events..................................................................71 
 
7.2.1. 
Adverse Events ...........................................................................................................71 
 
7.2.2. 
Serious Adverse Events ..............................................................................................71 
 
7.2.3. 
Other Events that Require Accelerated Reporting......................................................72 
 
7.2.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................72 
 
7.2.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results.............................73 
 
7.2.6. 
Follow-up....................................................................................................................73 
 
7.3. 
Evaluation of Severity and Causality .........................................................................73 
 
7.3.1. 
Evaluation of Severity ................................................................................................73 
 
7.3.2. 
Evaluation of Causality...............................................................................................74 
 
7.4. 
Safety Monitoring .......................................................................................................74 


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7.5. 
Investigator Alert Notification....................................................................................74 
 
8. 
STUDY VARIABLES................................................................................................75 
 
8.1. 
Demographic and Baseline Characteristics ................................................................75 
 
8.2. 
Primary and Secondary Endpoints..............................................................................75 
 
8.2.1. 
Primary Endpoint ........................................................................................................75 
 
8.2.2. 
Secondary Endpoints ..................................................................................................75 
 
8.2.3. 
Other Endpoints and Assessments..............................................................................76 
 
8.3. 
Pharmacokinetic Variables .........................................................................................76 
 
8.4. 
Anti-Drug Antibody Variables ...................................................................................76 
 
9. 
STATISTICAL PLAN................................................................................................77 
 
9.1. 
Statistical Hypothesis..................................................................................................77 
 
9.2. 
Justification of Sample Size........................................................................................77 
 
9.3. 
Analysis Sets...............................................................................................................79 
 
9.3.1. 
Efficacy Analysis Sets ................................................................................................79 
 
9.3.2. 
Safety Analysis Set .....................................................................................................79 
 
9.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................79 
 
9.3.4. 
Analysis Set for Anti-Drug Antibody Data ................................................................79 
 
9.4. 
Patient Disposition......................................................................................................79 
 
9.5. 
Statistical Methods......................................................................................................80 
 
9.5.1. 
Demography and Baseline Characteristics .................................................................80 
 
9.5.2. 
Efficacy Analyses .......................................................................................................80 
 
9.5.2.1. 
Primary Efficacy Analysis ..........................................................................................80 
 
9.5.2.2. 
Secondary Efficacy Analysis ......................................................................................81 
 
9.5.2.3. 
Multiplicity Considerations ........................................................................................81 
 
9.5.2.4. 
First-Step Analysis......................................................................................................83 
 
9.5.3. 
Safety Analysis ...........................................................................................................83 
 
9.5.3.1. 
Adverse Events ...........................................................................................................83 
 
9.5.3.2. 
Other Safety ................................................................................................................84 
 
9.5.3.3. 
Treatment Exposure ....................................................................................................84 
 
9.5.3.4. 
Treatment Compliance................................................................................................84 
 
9.5.4. 
Analysis of Drug Concentration Data.........................................................................85 
 
9.5.5. 
Analysis of Anti-Drug Antibody Data........................................................................85 


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9.5.6. 
Analysis of Biomarker Data .......................................................................................85 
 
9.6. 
Additional Statistical Data Handling Conventions .....................................................85 
 
9.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........86 
 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS.....................................86 
 
10.1. 
Data Management .......................................................................................................86 
 
10.2. 
Electronic Systems......................................................................................................86 
 
11. 
STUDY MONITORING ............................................................................................86 
 
11.1. 
Monitoring of Study Sites...........................................................................................86 
 
11.2. 
Source Document Requirements ................................................................................87 
 
11.3. 
Case Report Form Requirements ................................................................................87 
 
12. 
AUDITS AND INSPECTIONS .................................................................................87 
 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................88 
 
13.1. 
Good Clinical Practice Statement ...............................................................................88 
 
13.2. 
Informed Consent .......................................................................................................88 
 
13.3. 
Patient Confidentiality and Data Protection ...............................................................89 
 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................89 
 
14. 
PROTOCOL AMENDMENTS ..................................................................................89 
 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................89 
 
15.1. 
Premature Termination of the Study...........................................................................89 
 
15.2. 
Close-out of a Site ......................................................................................................90 
 
16. 
STUDY DOCUMENTATION ...................................................................................90 
 
16.1. 
Certification of Accuracy of Data...............................................................................90 
 
16.2. 
Retention of Records ..................................................................................................90 
 
17. 
CONFIDENTIALITY ................................................................................................91 
 
18. 
FINANCING AND INSURANCE.............................................................................91 
 
19. 
PUBLICATION POLICY ..........................................................................................91 
 
20. 
REFERENCES ...........................................................................................................92 
 
21. 
INVESTIGATOR’S AGREEMENT..........................................................................95 
 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................99 


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LIST OF TABLES 
 
Table 1: 
Schedule of Events (Screening, Baseline, and Treatment Period) .............................55 
 
Table 2: 
Schedule of Events (Treatment Period cont, Follow-Up Period, Unscheduled 
Visits, and Early Termination) ...................................................................................59 
 
Table 3: 
Statistical Hierarchy for Multiplicity Control.............................................................82 
 
 
 
LIST OF FIGURES 
 
Figure 1: 
Study Flow Diagram...................................................................................................40 
 
 
 
LIST OF APPENDICES 
 
APPENDIX 1:   FACTORS TO CONSIDER IN ASSESSING THE RELATIONSHIP 
OF ADVERSE EVENTS TO STUDY DRUG...................................................96 
 
APPENDIX 2: IGA SCALE .......................................................................................................97 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ACQ 
Asthma Control Questionnaire 
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 
CMH 
Cochran-Mantel-Haenszel 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CYP 
Cytochrome P450 
EASI 
Eczema Area and Severity Index 
EC 
Ethics Committee ECG
 
Electrocardiogram 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GISS 
Global Individual Signs Score 
HADS 
Hospital Anxiety and Depression Scale 
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 Harmonisation 
IDMC 
Independent Data Monitoring Committee 


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IGA                          Investigator’s Global Assessment 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IL-4Rα                     IL-4 receptor alpha subunit 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS                        Interactive voice response system 
IWRS                       Interactive web responses system 
LDH                         Lactate dehydrogenase 
LOCF                       Last observation carried forward 
MedDRA                  Medical Dictionary for Regulatory Activities 
MI                             Multiple imputation 
MMRM                    Mixed-effect model with repeated measures 
NAb 
Neutralizing antibody 
NRS 
Numerical Rating Scale 
OLE 
Open-label extension 
PCSV                       Potentially clinically significant value 
PD                            Pharmacodynamics 
PK                            Pharmacokinetic 
POEM                      Patient Oriented Eczema Measure 
PPS 
Per protocol set 
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 Software 
SC                             Subcutaneous 
SCORAD                 SCORing Atopic Dermatitis 
SOC                          System organ class 
TARC                       Thymus and activation-regulated chemokine 
TCI                           Topical calcineurin inhibitors 


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TCS 
Topical corticosteroids 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
TNSS 
ULN 
Total Nasal Symptom Score 
Upper limit of normal 
VAS 
Visual Analogue Scale 
WBC 
White blood cell 


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1. 
INTRODUCTION AND RATIONALE 
 
1.1. 
Introduction 
 
Atopic dermatitis (AD), also known as atopic eczema, is a pruritic skin condition characterized 
by a chronic, relapsing form of skin inflammation, a disturbance of the epidermal-barrier 
function associated with immune changes in the skin, and a high prevalence of 
immunoglobulin E (IgE)-mediated sensitization to food and environmental allergens 
(Bieber 2008). 
 
Atopic dermatitis is the most common inflammatory skin disease in childhood (Illi 2004). The 
disease usually presents during early infancy and childhood, but it can persist into or start in 
adulthood (Kay 1994). The disease affects 15% to 30% of children and 2% to 10% of adults in 
industrialized countries (Bieber 2008). Phase 1 of the International Study of Asthma and 
Allergies in Childhood showed a 1-year period prevalence rate as high as 20% in Australia, 
England, and Scandinavia (Williams 1999). Often, AD constitutes the first step of the “atopic 
march” (progression from one atopic disease to another). Up to 60% of AD patients have 
concomitant asthma, allergic rhinitis, or food allergy (Hong 2012). 
 
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 are less likely to have 
the exudative lesions of infancy, and instead exhibit more lichenified papules and plaques 
representing the more chronic disease involving the hands, feet, wrists, ankles, and antecubital 
and popliteal regions. The adult phase of AD begins at puberty and frequently continues into 
adulthood. 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 patients, 
greater than that seen in other common skin disorders like psoriasis and acne 
(Lewis-Jones 1995). 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). In addition to causing discomfort, sleep loss, and psychosocial challenges, 
AD can impose major financial burdens on families for direct medical care, household 
accommodations, and missed work (Su 1997, Verboom 2002, Williams 2005). 
 
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 


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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 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). Topical corticosteroids reduce inflammation and pruritus, and are useful in controlling 
acute flares. 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 many times as 
an alternative to or in combination with TCS. However, 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). 
 
To date, the only systemic agents approved for the treatment of AD in children are systemic 
corticosteroids. Other systemic agents are used off label (cyclosporine, methotrexate, 
azathioprine, and mycophenolate mofetil) and lack robust evidence for the basis of use. All of 
these systemic agents have significant side effects, including stunted growth, diabetes, 
hypertension, osteoporosis (corticosteroids), myelosuppression and hepatotoxicity 
(methotrexate), nephrotoxicity and hypertension (cyclosporine), and gastrointestinal disturbances 
and leucopenia (azathioprine). Moreover, a high proportion of patients in which disease is initially 
controlled by systemic agents suffer from relapse soon after therapy is discontinued (Granlund 
1995, Schmitt 2009). 
 
As a biologic product that selectively targets the Th2 inflammatory pathway, dupilumab is being 
developed to provide a safe and efficacious alternative treatment for AD patients, including 
children. Dupilumab is a human monoclonal antibody that targets the IL-4 receptor alpha subunit 
(IL-4Rα), a component of IL-4 receptors Type I and Type II, as well as the IL-13 Type II 
receptor system. The binding of dupilumab to IL-4Rα results in the blockade of both IL-4 and 
IL-13 signal transduction. Because up-regulation of IL-4 and IL-13 has been implicated as an 
important inflammatory component of AD disease progression, dupilumab may be an efficacious 
alternative AD treatment. 
 
Dupilumab, given subcutaneously (SC), is currently in clinical trials for multiple indications, 
including treatment of moderate-to-severe AD in patients intolerant of, or not adequately 
controlled with, topical treatments. As of 30 September 2016, 7408 subjects have been enrolled 


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into the dupilumab development program (completed and ongoing studies). This includes 
222 healthy volunteers, 4182 patients with AD, 2909 patients with asthma, 60 patients with nasal 
polyps, 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 polyps. Taking into account the number of 
patients exposed to dupilumab in blinded studies, the total number of patients exposed to 
dupilumab is over 5000. Further, 1 clinical study with dupilumab in the pediatric population has 
been completed at the time of this protocol development; a phase 2a study (R668-AD-1412) 
investigating the safety, pharmacokinetics (PK), immunogenicity, and exploratory efficacy of 
dupilumab in patients aged ≥6 to <18 years with AD. 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 from this completed study is summarized in section 1.2.3. An 
open-label extension study to assess the long-term safety and efficacy of dupilumab in patients 
aged ≥6 to<18 years with AD (R668-AD-1434) is currently ongoing. 
 
There is a paucity of clinical studies comparing adults and children, with respect to the cellular 
and molecular mechanisms of disease in AD. Based on similar clinical presentation and response 
to treatment, it has been postulated that these mechanisms are similar in adults and children. On 
this basis, some AD medications (eg, pimecrolimus) were granted regulatory approval in adults 
even though the pivotal clinical trials were largely conducted in pediatric patients. It is expected 
that the pharmacological activity of dupilumab will be similar in children and adults. 
 
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. 
 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
 
1.2. 
Rationale 
 
1.2.1. 
Rationale for Study Design 
 
This study is part of the pediatric clinical development plan for dupilumab in AD. The primary 
purpose of the study is to provide data on the use of dupilumab monotherapy to support 
registration and labeling for the use of dupilumab in adolescents with moderate-to-severe AD. 
 
The 16-week treatment duration is the same duration as in 2 of the adult pivotal trials 
(R668-AD-1416 and R668-AD-1334). This duration has been chosen because the maximum 
therapeutic effect for dupilumab is expected to be achieved by this time. Moreover, the selected 
dupilumab dose regimens will have achieved steady-state concentration before the end of this 
period. Based on PK simulations, in the absence of a loading dose, the time to steady-state is 
expected to be 12 weeks for 300 mg every 2 weeks (Q2W), and 4 weeks for 300 mg every 
4 weeks (Q4W). The use of a loading dose in this study will reduce the time to steady-state for 
the Q2W regimen, as has been observed in adults, enabling steady-state to be essentially 


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achieved after 3 doses. 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 Investigator’s 
Global Assessment [IGA] 0 or 1 and proportion of patients with ≥75% reduction in Eczema Area 
and Severity Index [EASI] from baseline [EASI-75] at week 16) are similar to 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 (Food and Drug 
Administration [FDA] is expected to request IGA 0/1 as the primary endpoint while EMA is 
expected to request 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 12 to 
17 years old in a prior study (Barbier 2004). 
 
1.2.2. 
Rationale for Dose Selection 
 
The dose justification for adolescent pediatric patients aged ≥12 to <18 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), and the modeling 
performed on the PK data obtained from this pediatric study. 
 
The adult dose-ranging study evaluated dupilumab dose regimens of 300 mg QW, 300 mg Q2W, 
300 mg Q4W, 200 mg Q2W, and 100 mg Q4W versus placebo, administered for 16 weeks. All 
5 dose regimens were efficacious. Efficacy data suggested a dose-response pattern for most 
efficacy outcome measures, including EASI, IGA, and pruritus scores, for which the 
corresponding endpoints at week 16 were 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. 
 
The dose regimens of 300 mg QW and 300 mg Q2W provided the most consistent clinical 
benefit and both had an acceptable safety profile. However, 300 mg QW and 300 mg Q2W 
dosing did not show clear differentiation in EASI and IGA changes from baseline in study 
R668-AD-1021. More recently, the lack of clear differentiation between 300 mg QW and 
300 mg Q2W dosing was further confirmed in 2 pivotal studies (R668-AD-1334 and 
R668-AD-1416) in adults based on EASI and IGA data. As PK modeling for dupilumab has 
shown weight to be the most important covariate influencing exposure, the use of the 300 mg 
QW regimen in adolescents with low body weight may lead to systemic exposure greater than 


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the maximum exposure that has been tested in adults. Therefore, 300 mg QW is not considered 
appropriate for adolescents. With the 300 mg Q2W regimen in adolescents ≥60 kg, the simulated 
exposure in adolescents substantially overlaps with the range of exposure in individual patients 
in studies R668-AD-1021 (300 mg Q2W and 300 mg QW) and DRI12544 (300 mg Q2W), 
where no significant safety risk was identified. Hence, the proposed 300 mg Q2W dosing 
regimen for adolescent patients weighing ≥60 kg is expected to have a significant clinical benefit 
with an appropriate safety profile. A similar exposure response to dupilumab treatment is 
anticipated between adolescent and adult AD patients, supporting dose selection by matching PK 
exposure with adults, for a clinical efficacy study in adolescent patients. 
 
Data from R668-AD-1021 also showed that a dose regimen of 200 mg Q2W was significantly 
superior to placebo on key efficacy endpoints. The use of 200 mg Q2W is expected to provide 
mean exposure in adolescents <60 kg similar to that with 300 mg Q2W in adolescents ≥60 kg 
supporting the use of this regimen in the lower weight cohort. Moreover, the 200 mg dose can be 
delivered using a 1 mL volume of injection. Since volume of injection has been shown to be an 
important factor impacting the tolerability of SC injections (Heise 2014), a 200 mg injection is 
expected to be less painful than a 300 mg injection. This might impact compliance and ultimately 
the therapeutic profile of the drug, especially in a pediatric population. Also, a 1 mL autoinjector 
device has already been commercialized for other monoclonal anitbodies. 
 
Study R668-AD-1021 demonstrated that efficacy for the 300 mg Q4W regimen was statistically 
superior to placebo and numerically similar to the 300 mg Q2W and 200 mg Q2W dose 
regimens. Pharmacokinetic simulation has shown that although this dose regimen is expected to 
provide lower exposure to the other 2 dupilumab dose regimens being studied, it should still have 
sufficient exposure to provide significant clinical benefit in adolescents. Data gathered from this 
dose regimen will also enable further PK modeling to better characterize exposure response 
relationship in pediatric patients. A less frequent dosing regimen is expected to enhance 
compliance, especially in a pediatric population. 
 
In study R668-AD-1412, weekly doses of up to 4 mg/kg SC were shown to be generally well 
tolerated in pediatric patients aged 6 to17 years old. The exposure for all proposed doses in the 
current study is expected to be lower in most patients than what was seen with use of repeated 
weekly doses of 4 mg/kg in the previous study. 
 
An advantage of fixed weight-based dosing compared to variable weight-based dosing is to 
allow self-administration using a prefilled syringe. 
 
The administration of the loading dose of dupilumab will allow systemic concentrations to reach 
steady-state faster, and potentially reduce the time to onset of clinical effect. 
 
1.2.3. 
Safety Considerations 
 
The safety profile of dupilumab is not expected to be different between adults and adolescents. 
Data gathered from the completed R668-AD-1412 study support this view. 
 
R668-AD-1412 was a phase 2a 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 in both 
pediatric age groups included in this study. There was a higher incidence of treatment-emergent 


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adverse events (TEAEs) after administration of the single dose 4 mg/kg dupilumab in both age- 
groups. Similarly, there was a higher incidence of TEAEs after administration of repeated 
weekly doses of 4 mg/kg in both age-groups. However, most of the AEs were mild in intensity, 
transient in nature, and not related to study drug. There were no new safety signals detected with 
dupilumab in this pediatric population. The most common AEs reported after both single doses 
and repeated weekly doses were Nasopharyngitis and Exacerbation of AD. 
 
Standard safety monitoring used in previous trials with dupilumab is planned to be conducted 
during this study. An 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. 
 
 
2. 
STUDY OBJECTIVES 
 
2.1. 
Primary Objective 
 
The primary objective of the study is to demonstrate the efficacy of dupilumab as a monotherapy 
in patients ≥12 years to <18 years of age with moderate-to-severe AD. 
 
2.2. 
Secondary Objective 
 
The secondary objective of the study is to assess the safety of dupilumab as a monotherapy in 
patients ≥12 years to <18 years of age with moderate-to-severe AD. 
 
 
3. 
STUDY DESIGN 
 
3.1. 
Study Description and Duration 
 
This is a randomized, double-blind, placebo-controlled, parallel-group study to investigate the 
efficacy and safety of dupilumab monotherapy in pediatric patients with moderate-to-severe AD. 
The study population will include patients ≥12 years to <18 years of age with moderate-to-severe 
AD whose disease cannot be adequately controlled with topical medications or for whom topical 
treatment is medically inadvisable (eg, intolerance, other important side effects or safety risks). 
Approximately 240 study patients are planned to be randomized to 1 of the following treatment 
groups: 
 
• Dupilumab Q2W treatment group: 200 mg Q2W for patients <60 kg or 300 mg Q2W 
for patients ≥60 kg 
 
• Dupilumab Q4W treatment group: 300 mg Q4W, irrespective of weight 
 
• Placebo group 
 
The study will consist of the following 3 periods: screening of up to 5 weeks, treatment period of 
16 weeks, and follow-up of 12 weeks (Figure 1). 
 
After the parents or legal guardians/patients provide informed consent and informed assent (as 
appropriate), the patients will be assessed for study eligibility at the screening visit. During the 
screening period, systemic and topical treatments for AD will be washed out, as applicable, 


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according to the eligibility requirements. Patients may be rescreened once if they fail the 
screening evaluation for reasons related to incidental transitory conditions, unless the reason for 
the screen failure is related to failing the disease severity inclusion criteria. Patients will be 
required to apply moisturizers twice daily for at least 7 days before randomization and continue 
throughout the study. 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. 
 
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 weight group (<60 kg 
and ≥60kg; each weight stratum will enroll approximately 120 patients) and baseline disease 
severity (moderate [IGA=3] vs. severe [IGA=4] AD) as follows: 
 
• Dupilumab Q2W treatment group: Patients with baseline weight <60 kg will receive 
Q2W SC injections of 200 mg dupilumab following a loading dose of 400 mg on 
day 1. Patients with baseline weight ≥60 kg will receive Q2W SC injections of 
300 mg dupilumab following a loading dose of 600 mg on day 1. 
 
• Dupilumab Q4W treatment group: Patients 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 placebo matching dupilumab Q2W 
(including doubling the amount of placebo on day 1 to match the loading dose). In 
order to maintain blinding for the study, patients in the <60 kg weight stratum will 
receive, in a 1:1 ratio, either placebo matching 200 mg dupilumab (including 
doubling the amount of placebo on day 1 to match the loading dose) or placebo 
matching 300 mg dupilumab (including doubling the amount of placebo on day 1 to 
match the loading dose). In the ≥60 kg weight stratum, the patients randomized to the 
placebo group will receive placebo matching 300 mg dupilumab (including doubling 
the amount of placebo on day 1 to match the loading dose). 
 
In order to maintain blinding, all patients will receive an injection Q2W from day 1 to week 14. 
Patients will receive placebo injection at the weeks dupilumab is not given. 
 
During the treatment period, patients will have weekly in-clinic visits through week 4, and then 
in-clinic visits every 4 weeks through week 16 with weekly telephone visits in between the 
in-clinic visits. Patients and/or parents/caregivers (as deemed appropriate based on age of 
patient) will be trained on injecting study drug during in-clinic visit 2 (day 1) to visit 6 (week 4). 
During weeks in which no in-clinic visit is scheduled, patients will either self-inject study drug 
or the parent/caregiver will administer study drug to the patient. In case patients do not want to 
self-inject and the parent/caregiver do not want to administer study drug to patient, patients 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. 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. 


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Patients who participate in the study may subsequently be eligible to participate in an open-label 
extension study. 
 
Patients who decline to enroll in the open-label extension study will be followed up for 
12 weeks. For these patients, after week 16, follow-up visits will occur every 4 weeks from 
week 20 through week 28. During the follow-up period, patients will be monitored for safety and 
tolerability and have laboratory and clinical assessments per schedule as noted in Table 2. 
 
Figure 1: 
Study Flow Diagram 
 
 
 
D = study day; W = study week 
 
3.1.1. 
End of Study Definition 
 
The end of study definition is defined as the last visit for the last patient. 
 
3.2. 
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 9.5.2.4. 
 
3.3. 
Study Committees 
 
3.3.1. 
Independent Data Monitoring Committee 
 
An IDMC, composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety 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 


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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. 
 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
 
4.1. 
Number of Patients Planned 
 
Approximately 240 patients are planned to be enrolled into 3 groups (80 per group): dupilumab 
Q2W treatment groups (200 mg Q2W or 300 mg Q2W), dupilumab Q4W treatment group 
(300 mg Q4W), or placebo group.  The study will be conducted at multiple sites in North 
America; other regions may be included. 
 
4.2. 
Study Population 
 
The study population includes pediatric patients (aged ≥12 to <18 years at the time of baseline) 
who have moderate-to-severe AD that cannot be adequately controlled with topical AD 
medications or for whom topical treatment is medically inadvisable (eg, intolerance, other 
important side effects or safety risks). 
 
4.2.1. 
Inclusion Criteria 
 
A patient must meet the following criteria to be eligible for inclusion in the study: 
 
1.   Male or female ≥12 to <18 years of age at time of screening visit 
 
2.   Diagnosis of AD according to the American Academy of Dermatology consensus criteria 
(Eichenfield 2014) at screening visit 
 
3.   Chronic AD diagnosed at least 1 year prior to the screening visit 
 
4.   IGA ≥3 at screening and baseline visits 
 
5.   EASI ≥16 at the screening and baseline visits 
 
6.   Baseline Pruritus Numerical Rating Scale (NRS) average score for maximum itch 
intensity ≥4 
 
NOTE: Baseline Pruritus NRS average score for maximum itch intensity will be 
determined based on the average of daily NRS 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. 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 35-day maximum 
duration for screening. 
 
7.   ≥10% body surface area (BSA) of AD involvement at the screening and baseline visits 


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8.   With documented recent history (within 6 months before the screening visit) of 
inadequate response to topical AD medication(s) or for whom topical treatments is 
medically inadvisable (eg, intolerance, because of important side effects or safety risks). 
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 higher potency (±TCI as appropriate), applied for 
at least 28 days or for the maximum duration recommended by the product 
prescribing information (eg, 14 days for super-potent TCS), whichever is shorter. 
 
• Patients with documented systemic treatment (systemic immunosuppressant drugs 
like cyclosporine, methotrexate, corticosteroids etc.) 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. 
 
• Important side effects or safety risks are those that outweigh the potential treatment 
benefits and include intolerance to treatment, hypersensitivity reactions, significant 
skin atrophy, and systemic effects, as assessed by the investigator or by the patient’s 
treating physician. 
 
• 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 or higher potency (±TCI as appropriate), applied for at 
least 28 days during the screening period, or for the maximum duration recommended 
by the product prescribing information, whichever is shorter. Patients who demonstrate 
inadequate response during this period, as defined above, will be eligible for inclusion 
in the study following appropriate washout. 
 
9.   Has applied a stable dose of topical emollient (moisturizer) twice daily for at least the 
7 consecutive days immediately before the baseline visit (see exclusion criterion 9 
regarding restrictions on the kind of emollients permitted during the study) 
 
10. Willing and able to comply with all clinic visits and study-related procedures 
 
11. 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) 


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4.2.2. 
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 
 
3.   Treatment with a topical investigational agent within 4 weeks or within 5 half-lives (if 
known), whichever is longer, before the baseline visit 
 
4.   Treatment with TCS or TCI within 2 weeks before the baseline visit (patients may be 
rescreened) 
 
5.   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 
 
6.   Treatment with biologics, as follows: 
 
a.   Any cell-depleting agents including but not limited to rituximab: within 6 months 
before the baseline visit, or until lymphocyte and CD 19+ lymphocyte count returns 
to normal, whichever is longer 
 
b.   Other biologics: within 5 half-lives (if known) or 16 weeks before the baseline visit, 
whichever is longer 
 
7.   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. 
 
8.   Planned or anticipated use of any prohibited medications and procedures during study 
treatment 
 
9.   Treatment with crisaborole within 2 weeks prior to the baseline visit. 
 
10. Body weight <30 kg at baseline 


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11. 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) 
 
12. Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the 
baseline visit 
 
13. 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 
 
14. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent 
infections of abnormal frequency or prolonged duration suggesting an 
immune-compromised status, as judged by the investigator 
 
15. Known history of human immunodeficiency virus (HIV) infection or HIV seropositivity 
at the screening visit 
 
16. 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. These patients will be allowed 
to enroll into the study, but will be followed using routine clinical and liver function tests. 
 
17. 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 
 
18. On current treatment for hepatic disease including but not limited to acute or chronic 
hepatitis, cirrhosis, or hepatic failure, or has evidence of liver disease as indicated by 
persistent (confirmed by repeated tests ≥2 weeks apart) elevated transaminases (alanine 
aminotransferase [ALT] and/or aspartate aminotransferase [AST]) more than 3 times the 
upper limit of normal (ULN) during the screening period 
 
19. Presence of any 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. 


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20. Presence of skin comorbidities that may interfere with study assessments 
 
21. History of malignancy before the baseline visit 
 
22. Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic 
infection, unless clinical and (if necessary) laboratory assessment have ruled out active 
infection before randomization 
 
23. History of alcohol or drug abuse within 2 years before the screening visit, or evidence of 
such abuse as documented by a positive result in a laboratory test for alcohol and/or drug 
panel conducted at the screening visit 
 
Note: If a patient has a positive drug test for a prescription drug being used for medical 
reasons, the patient would still be eligible for enrollment. In such cases, the site would 
need to confirm the medical reason for use with the treating physician. 
 
24. 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). 
 
25. 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). 
 
26. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities will be excluded from this study. 
 
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 


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30. Patient is female of childbearing potential* and sexually active, who is unwilling to use 
adequate methods of contraception** throughout the duration of the study and for 
120 days after the last dose of study drug 
 
* 
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. 
 
** 
Adequate methods of contraception include: female sterilization (with documented 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation), hormonal 
contraceptives, intrauterine device, or condom + diaphragm***, or single male 
partner with documented vasectomy. Additional requirements for acceptable 
contraception may apply in certain countries, based on local regulations. Investigators 
in these countries will be notified accordingly in a Protocol Clarification Letter***. 
 
***   The study may enroll patients from sites in the UK. Double barrier methods (eg, 
condom + diaphragm) would not be considered adequate methods of contraception 
for patients enrolled in the UK for the purpose of this study. 
 
4.3. 
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 6.1. 
 
4.4. 
Replacement of Patients 
 
Patients prematurely discontinued from the study or study treatment will not be replaced. 
 
 
5. 
STUDY TREATMENTS 
 
5.1. 
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) 


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Placebo matching dupilumab is prepared in the same formulation without the addition of protein 
(ie, active substance, anti-IL-4Rα monoclonal antibody). 
 
Patients will be randomized to receive 1 of the following treatment regimens: 
 
• Dupilumab Q2W treatment: 
 
 Patients <60 kg in baseline body weight: SC injections of dupilumab, 400 mg 
loading dose on day 1, then 200 mg Q2W from week 2 to week 14, or 
 
 Patients ≥60 kg in baseline body weight: SC injections of dupilumab, 600 mg 
loading dose on day 1, then 300 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; in order to maintain the blind, 
there will be an SC injection of placebo in between dupilumab doses during the 
week 2 to week 14 dosing period so the injection frequency will match the other 
2 groups. 
 
• Placebo: SC injections of placebo matching dupilumab Q2W (including doubling the 
amount of placebo on day 1 to match the loading dose). In order to maintain blinding 
for the study, patients in the <60 kg weight stratum who are randomized to the placebo 
group will receive, in a 1:1 ratio, either placebo matching 200 mg dupilumab 
(including doubling the amount of placebo on day 1 to match the loading dose) or 
placebo matching 300 mg dupilumab (including doubling the amount of placebo on 
day 1 to match the loading dose). In the ≥60 kg weight stratum, the patients 
randomized to the placebo group will receive placebo matching 300 mg dupilumab. 
 
In order to maintain blinding, all patients will receive an injection Q2W from day 1 to week 14. 
Patients will receive placebo injection at the weeks dupilumab is not given. 
 
Study drug will be administered per the scheduled described in section 6.1. 
 
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 weeks. To allow for adequate assessment of possible 
injection site reactions, study drug should be administered only into areas of normal-looking 
skin. Instructions for recording and reporting injection site reactions will be provided in the study 
reference manual. 
 
Patients will have the option to administer study drug (or have a caregiver administer study drug) 
outside the study site during weeks in which no in-clinic visit is scheduled. The study staff will 
train the patient/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 patient/caregiver will 
administer the second injection required for the loading dose under the supervision of the clinic 
staff. The patient/caregiver will administer study drug under the supervision of the clinic staff at 
visits 4 and 6 (weeks 2 and 4, respectively) and at other in-clinic visits. Patients will be 
monitored at the study site for a minimum of 30 minutes after the first 3 doses of study drug 
(visits 2 [day 1], 4 [week 2], and 6 [week 4]); vital signs (sitting blood pressure, heart rate, and 
respiratory rate) and AE assessments will be done at 30 minutes (±10 minutes) post dose. The 


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patient (or caregiver) will administer study drug outside of the clinic during weeks in which no 
clinic visit is scheduled. 
 
Patients (or caregivers) who prefer to have the clinic staff administer study drug may choose to 
have injections administered in the clinic. 
 
5.2. 
Background Treatment 
 
All patients are required to 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 or moisturizers containing additives during the 
screening period or during the study. Patients may continue using stable doses of such 
moisturizers if initiated before the screening visit. 
 
5.3. 
Rescue Treatment 
 
If medically necessary (ie, to control intolerable AD symptoms), rescue treatment for AD may be 
provided to study patients at the discretion of the investigator. If possible, investigators are 
encouraged to consider rescue initially with topical treatment (eg, medium/high potency TCS) 
and to escalate to systemic medications only for patients who do not respond adequately after at 
least 7 days of topical treatment. Topical calcineurin inhibitors may be used for rescue, alone or 
in combination with TCS, but the use of TCIs should be reserved for problem areas only (eg, 
face, neck, intertriginous and genital areas, etc.). Investigators may also consider rescue with 
crisaborole. Rescue treatment for these topical therapies should be used as per prescribing 
information and local guidelines. Patients may continue study treatment if rescue consists of 
topical medications. 
 
Patients who receive systemic corticosteroids or systemic nonsteroidal 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. 
 
5.4. 
Dose Modification and Study Drug Discontinuation Rules 
 
5.4.1. 
Dose Modification 
 
Dose modification for an individual patient is not allowed. 


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5.4.2. 
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 6.1. 
 
5.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
 
Study drug dosing will be permanently discontinued in the event of: 
 
• Anaphylactic reaction or other severe systemic reaction to study drug 
 
• Repeated (2 or more during the course of the study) severe injection site reactions that are 
deemed to be immune mediated* 
 
* This is based on investigator’s assessment. A consultation with the medical monitor can 
be sought to determine the exact etiology of an injection site reaction. 
 
• 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: 
 
 Neutrophil count ≤0.5× 103/μL 
 
 Platelet count ≤50× 103/μL 
 
 ALT and/or AST values greater than 3× ULN with total bilirubin >2× ULN 
(unless elevated bilirubin is related to confirmed Gilbert’s Syndrome) 
 
 Confirmed AST and/or ALT >5× ULN (for more than 2 weeks) 
 
NOTE: If the laboratory abnormality is considered causally related to study drug, study 
treatment will be permanently discontinued. In cases in which a causal relationship to 
study drug can be reasonably excluded, (ie, an alternative cause is evident), study 
treatment will be discontinued but it may be resumed when the laboratory abnormality is 
sufficiently normalized. A decision to resume study treatment will be made jointly by the 
investigator and medical monitor (medical monitor’s written approval is required). 
 
• Treatment with any prohibited concomitant medication or procedure (section 5.7.1) 
 
NOTE: The use of TCS, TCI and crisaborole is prohibited during the study. 
However, these drugs may be used as rescue. In that case, the study drug will be 
continued. 


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5.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
 
Study drug dosing may be temporarily discontinued in the event of: 
 
•
Clinic

ally important laboratory abnormalities, such as: 
ALT or AST 3× 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 
• 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. 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. 
 
5.5. 
Method of Treatment Assignment 
 
Approximately 240 patients will be randomized by weight group (<60 kg or ≥60 kg [with 
approximately 120 patients to each weight group]) and by baseline disease severity (moderate 
[IGA=3] vs. severe [IGA=4] AD) to 1 of the following treatment groups 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): 
 
• Dupilumab Q2W treatment groups: Patients whose baseline weight <60 kg will 
receive Q2W SC injections of 200 mg dupilumab following a loading dose of 400 mg 
on day 1. Patients whose baseline weight ≥60 kg will receive Q2W SC injections of 
300 mg dupilumab following a loading dose of 600 mg on day 1. 
 
• Dupilumab Q4W treatment group: Patients 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 placebo matching dupilumab Q2W 
(including doubling the amount of placebo on day 1 to match the loading dose).  In 
the <60 kg weight stratum, since the dose level (ie, 300 mg or 200 mg) won’t be 
blinded, in order to maintain blinding for the study, the patients in the <60 kg weight 
stratum who are randomized to the placebo group will receive, in a 1:1 ratio, either 
placebo matching 200 mg dupilumab (including doubling the amount of placebo on 
day 1 to match the loading dose) or placebo matching 300 mg dupilumab (including 


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doubling the amount of placebo on day 1 to match the loading dose).  In the ≥60 kg 
weight stratum, the patients randomized to the placebo group will receive placebo 
matching 300 mg dupilumab. 
 
5.5.1. 
Blinding 
 
With the exception of the IDMC members and the provisions in section 5.5.2, 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. To maintain the blind, all patients will receive Q2W 
injections of dupilumab or placebo starting at day 1. During weeks in which dupilumab is not 
administered in the Q4W dosing regimen, patients will receive placebo. 
 
Anti-drug antibody (ADA) and drug concentration results will not be communicated to the sites, 
and the sponsor’s operational team will not have access to results associated with patient 
identification until after the final database lock. 
 
5.5.2. 
Emergency Unblinding 
 
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. 
 
5.6. 
Treatment Logistics and Accountability 
 
5.6.1. 
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. 
 
5.6.2. 
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 


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(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. 
 
5.6.3. 
Treatment Accountability 
 
All drug accountability records must be kept current. 
 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication. 
 
• dispensed to each patient, 
 
• returned from each patient (if applicable), and 
 
• disposed of at the site or returned to the sponsor or designee. 
 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
 
5.6.4. 
Treatment Compliance 
 
All drug compliance records must be kept current and must be made available for inspection by 
the sponsor and regulatory agency inspectors. 
 
5.7. 
Concomitant Medications and Procedures 
 
Any treatment administered from the time of the first dose of study drug to the final study visit 
will be considered concomitant medication. This includes medications that were started before 
the study and are ongoing during the study. 
 
5.7.1. 
Prohibited Medications and Procedures 
 
Treatment with the following concomitant medications is prohibited during the study. Study drug 
will be immediately discontinued if any of the following are used during the study: 
 
• Treatment with a live (attenuated) vaccine; below is a list of examples of such 
vaccines; refer to 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) 


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• Treatment with an investigational drug (other than dupilumab) 
 
• Treatment with immunomodulating biologics 
 
• Treatment with systemic nonsteroid immunosuppressant (may be used as rescue, see 
section 5.3 for details) 
 
• Treatment with systemic corticosteroids (may be used as rescue, see section 5.3 for 
details) 
 
 Treatment with TCS or TCI (may be used as rescue, see section 5.3 for details) 
 
• Treatment with crisaborole (may be used as rescue, see section 5.3 for details) 
 
• 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) 
 
5.7.2. 
Permitted Medications and Procedures 
 
Other than the prohibited medications listed in section 5.7.1, 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. 
 
5.8. 
Continuation of Dupilumab Treatment in an Open-Label Extension 
Study 
 
Patients who complete the treatment period (week 16) will be offered an opportunity to screen for 
the open-label extension (OLE) at end of treatment visit. These patients should complete the 
end-of-treatment [EOT] visit (as per Table 2) before screening for the OLE. Patients who 
discontinued prematurely (ie patients who did not complete the protocol-defined end-of- 
treatment [EOT] visit) cannot screen for the OLE study before the date when the EOT visit (week 
16) would have normally occurred. Patients who decline to participate in the OLE study will 
have a 12-week follow-up period. 
 
NOTE: Patients who turned 18 years of age during this study will not be eligible to enroll into 
the pediatric open-label extension study (R668-AD-1434). In case the drug is not 
commercially available for patients aged ≥18 years at the time the patient completes this 
study, these patients may be eligible for, and might have the opportunity to, enroll into 
the adult open-label extension study (R668-AD-1225), if the study is still ongoing. 


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6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
 
6.1. 
Schedule of Events 
 
Study assessments and procedures are presented by study period and visit in Table 1 (Screening, 
Baseline, and Treatment Period) and in Table 2 (Treatment Period cont, Follow-up Period, 
Unscheduled Visits, and Early Termination). 


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Table 1: 
Schedule of Events (Screening, Baseline, and Treatment Period) 
 
Screening 
Treatment Period 
BL 
In-clinic Visit (V) or Phone 
Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
PV7a 
PV8a 
PV9a 
V10 
PV11a 
PV12a 
PV13a 
V14 
Week (W) 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
Study Day (D) 
D-35 to 
D-1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
Window in days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/Baseline: 
Informed consent/assent 
X 
X 
Medical history 
X 
Demographics 
X 
Inclusion/exclusion criteria 
X 
X 
Randomization 
X 
Patient ediary training for 
pruritus assessments, TNSS 
assessment, and emollient use 
c 
X 
X 
Treatment:d 
Injection training/observation 
e 
X 
X 
X 
X 
X 
Study drug administration 
Xf 
Xf 
Xf 
X 
X 
X 
X 
Patient/parent(s) or caregiver 
paper diary training for 
dosing 
X 
Patient dosing diary 
completion 
X 
X 
Study drug dispensationg 
X 
X 
X 
Study drug accountability g 
X 
X 
Review home ediary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening 
Treatment Period 
BL 
In-clinic Visit (V) or Phone 
Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
PV7a 
PV8a 
PV9a 
V10 
PV11a 
PV12a 
PV13a 
V14 
Week (W) 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
Study Day (D) 
D-35 to 
D-1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
Window in days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Efficacy:d 
Patient assessment of pruritus 
intensity using NRS via diary 
(daily) h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient assessment of pruritus 
intensity using PCS via diary 
(daily) h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient global assessment of 
disease h 
X 
X 
X 
X 
X 
X 
Patient global assessment of 
treatment h 
X 
X 
X 
X 
h Patient-reported CDLQIi, 
POEMi, HADSi 
X 
X 
X 
X 
X 
X 
h Patient-reported ACQ-5i, j 
X 
X 
Patient-reported TNSSh, i, k 
X 
X 
Patient assessment of 
injection pain using VASh 
X 
X 
X 
X 
X 
IGA, EASI, GISS, SCORAD, 
BSA 
X 
X 
X 
X 
X 
X 
X 
X 
Assess missed school days 
X 
X 
X 
X 
Photograph AD areas 
(select sites) 
X 
Safety: d 
Weight 
X 
X 
Height 
X 
Vital signs 
X 
Xf 
X 
Xf 
X 
Xf 
X 
X 
Physical examination 
X 
ECG 
X 
Adverse events 
X 
Xf 
X 
Xf 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 


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In-clinic Visit (V) or Phone 
Visit (PV) 
Screening 
Treatment Period 
BL 
V1 
V2 
V3 
V4 
V5 
V6 
PV7a 
PV8a 
PV9a 
V10 
PV11a 
PV12a 
PV13a 
V14 
Week (W) 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
Study Day (D) 
D-35 to 
D-1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
Window in days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Laboratory Testing: d 
Hematology                                         X                   X                                               X                                                     X 
Chemistrym                                                                X                   X                                               X                                                     X 
Urinalysism                                                                 X                   X                                               X 
Alcohol & drug screen test                 X 
Pregnancy test, WOCBP only         Serum               Ur            Ur       Ur      Ur       Ur                                                    Ur                                                          Ur 
HIV, HBsAg, HBsAb, 
HBcAb, Hep C Ab, TBl                                X 
Biomarker: d 
TARC 
X 
X 
X 
X 
X 
X 
Total serum IgE, 
immunoglobulin profiling, 
antigen specific IgE 
X 
X 
X 
X 
X 
Biomarker samples (serum) 
X 
X 
X 
 
 
X 
 
Drug Concentration and 
ADA: d 
Functional dupilumab 
concentration sample 
X 
X 
X 
X 
X 
ADA sample 
X 
X 
BL = baseline; Ur = urine; WOCBP = women of childbearing potential; TB = tuberculosis 
a  The site will contact the patient/caregiver by telephone to conduct these visits. The patient/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. 


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c  Training of patients regarding completion of diary to record (1) completion of assessment of Pruritus NRS scale, (2) completion of assessment of Pruritus 
Categorical Scale, (3) completion of assessment of Total Nasal Symptoms Score (TNSS), and (4) emollient usage. 
d  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, and optional DNA and RNA), and  administration of 
study drug. 
e  Patients or parents/caregivers will be trained on how to administer study drug. This will enable administration at home in between clinic visits. 
f  Patients will be monitored at the study site at visits 2, 4, and 6 for a minimum of 30 minutes after study drug administration. Vital signs (sitting blood pressure, 
heart rate, and respiratory rate) and AEs will be assessed at 30 minutes (±10 minutes) post-injection. 
g  Starting at visit 6, study drug will be dispensed to the patients or parents/caregivers for the dose that will be administered before the next clinic visit. Patients or 
parents/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 patients or parents/caregivers have returned to the site. 
h  Patient-reported assessments are to be completed only by the patient. 
i   The questionnaires will be administered only to the subset of patients who speak fluently the language in which the questionnaire is presented (based on 
availability of validated translations in participating countries). 
j   ACQ-5 will be administered only to patients with ongoing asthma. 
k  TNSS will be administered only to patients with medical history of allergic rhinitis throughout the screening period (at least 7 days before baseline/day 1) and 
only for 7 days preceding visit 6. 
l   Tuberculosis testing will be performed on a country-by-country basis, according to local guidelines if required by regulatory authorities or ethics boards. 
m If baseline/day 1 visit occurs within 14 days of screening, hematology and serum chemistry do not need to be repeated at the baseline/day 1 visit as long as 
these assessments were performed at the screening visit 


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Table 2: 
Schedule of Events (Treatment Period cont, Follow-Up Period, Unscheduled Visits, and Early Termination) 
 
Study Procedure 
Treatment Period 
Follow-Up Periodi 
Unscheduled 
Visitb 
Early 
Termination Visit 
EOTi 
EOS 
In-clinic Visit (V) 
PV15a 
PV16a 
PV17a 
V18 
V19 
V20 
V21 
Week (W) 
W13 
W14 
W15 
W16 
W20 
W24 
W28 
Study Day (D) 
D92 
D99 
D106 
D113 
D141 
D169 
D197 
Window in days 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
Treatment:c 
Study drug administration 
X 
Patient dosing paper diary completion 
X 
Study drug accountability d 
X 
X 
X 
Review home ediary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:c 
Patient assessment of pruritus intensity using 
NRS via diary (daily) e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient assessment of pruritus intensity using 
PCS via diary (daily) e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient global assessment of disease e 
X 
X 
X 
X 
X 
X 
Patient global assessment of treatment e 
X 
X 
X 
X 
X 
X 
e Patient-reported CDLQIf, POEMf, HADSf 
X 
X 
X 
X 
X 
X 
e Patient-reported ACQ-5 g 
X 
X 
X 
Patient-reported TNSS e, f, h 
X 
X 
Patient assessment of injection pain using 
VASh 
IGA, EASI, GISS, SCORAD, BSA 
X 
X 
X 
X 
X 
X 
Assess missed school days 
X 
X 
X 
X 
X 
X 
Photograph AD areas (select sites) 
X 
X 
X 
Safety:c 
Weight 
X 
X 
X 
Height 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Procedure 
Treatment Period 
Follow-Up Periodi 
Unscheduled 
Visitb 
Early 
Termination Visit 
EOTi 
EOS 
In-clinic Visit (V) 
PV15a 
PV16a 
PV17a 
V18 
V19 
V20 
V21 
Week (W) 
W13 
W14 
W15 
W16 
W20 
W24 
W28 
Study Day (D) 
D92 
D99 
D106 
D113 
D141 
D169 
D197 
Window in days 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
Laboratory Testing:c 
Hematology 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Pregnancy test, WOCBP only 
Urine 
Urine 
Urine 
Urine 
Biomarker: c 
TARC 
X 
X 
X 
X 
Total Serum IgE, immunoglobulin profiling, 
antigen specific IgE 
X 
X 
X 
X 
Biomarker samples (serum) 
X 
Drug Concentration and ADA Samples: c 
Functional dupilumab concentration sample 
X 
X 
X 
X 
ADA sample 
X 
X 
X 
X 
EOT = End of Treatment; EOS = End of Study 
a  The site will contact the patient/caregiver by telephone to conduct these visits. The patient/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. 
b Unscheduled visits may be necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any other reason (eg, before a rescue 
medication/procedure is used), as warranted. 
c  Assessments/procedures should be conducted in the following order: patient reported outcomes(other than patient assessment of injection pain), investigator 
assessments, and safety and laboratory assessments (including sample collection for ADA, PK, and biomarkers). Samples positive in the ADA assay will be 
analyzed in the neutralizing antibody (NAb) assay. 
d  Patients or parents/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 patients or parents/caregivers have returned to the site. 
e  Patient-reported assessments are to be completed only by the patient. 
f   The questionnaires will be administered only to the subset of patients who speak fluently the language in which the questionnaire is presented (based on 
availability of validated translations in participating countries). 
g  ACQ-5 will be administered only to patients with ongoing asthma. 
h  Total Nasal Symptoms Score will be administered only to patients with medical history of allergic rhinitis for 7 days preceding visit 18 and visit 21. 
i   The follow-up period will be for those patients who decline to enter the open-label extension study. 


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6.2. 
Study Procedures 
 
Assessments/procedures at the clinic visit should be performed in the following order: 
 
1.   Patient Reported Outcomes (other than patient assessment of injection pain) 
 
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 (including sample collection for ADA, PK, biomarker, 
and optional DNA and RNA). 
 
4.   Administration of study drug 
 
6.2.1. 
Procedures Performed only at the Screening/Baseline Visit 
 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population: medical history and demographics. 
 
6.2.2. 
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 Pruritus NRS, patient global assessment of disease, patient global 
assessment of treatment, Children’s Dermatology Life Quality Index [CDLQI], Patient Oriented 
Eczema Measure [POEM], and Hospital Anxiety and Depression Scale [HADS]). 
 
6.2.2.1. 
Patient Assessment of Pruritus Using Numerical Rating Scale 
 
The Pruritus NRS is a simple assessment tool that patients will use to report the intensity of their 
pruritus (itch) during a 24-hour recall period. Patients will be asked the following question: 
 
For maximum itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being 
the ‘worst itch imaginable’, how would you rate your itch at the worst moment during the 
previous 24 hours?” 
 
Patients will be instructed on using the patient diary to record their Pruritus NRS score at the 
screening and baseline visits. Patients will complete the rating scale DAILY throughout the 
entire study (screening period, treatment period, and follow-up period; see time point in 
section 6.1). Clinical sites will check and remind patient to complete the diary at each visit. 


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6.2.2.2. 
Patient Assessment of Pruritus Using Pruritus Categorical Scale 
 
The pruritus categorical scale is a 4-point scale used to assess symptoms that has been used in 
previous clinical studies of AD, and there is less of a tendency for patients to provide an 
“average” response than there might be with a 5-point scale (Kaufmann 2006). The scale is rated 
as follows: 0 = absence of pruritus; 1 = mild pruritus (occasional slight itching/scratching); 
2 = moderate pruritus (constant or intermittent itching/scratching that does not disturb sleep); and 
3 = severe pruritus (bothersome itching/scratching that disturbs sleep). Patients will be instructed 
on using the patient diary to record their pruritus categorical scale score at the screening and 
baseline visits. Patients will complete the rating scale DAILY throughout the entire study 
(screening period, treatment period, and follow-up period; see time point in section 6.1). Clinical 
sites will check and remind patient to complete the diary at each visit. 
 
6.2.2.3. 
Patient Global Assessment of Disease 
 
Patients will rate their disease based on the 5-level scale as follows: 
Overall, how would you rate your eczema symptoms right now? 
• No symptoms 
 
• Mild symptoms 
 
• Moderate symptoms 
 
• Severe symptoms 
 
• Very severe symptoms 
 
Patients will undergo this assessment at time points according to section 6.1. 
The assessment tool is provided in the study reference manual. 
 
6.2.2.4. 
Patient Global Assessment of Treatment 
 
Patients will respond to the following question based on the 5-level scale as follows: 
 
Compared to before you started the study, how would you rate your eczema symptoms 
now? 
 
• Much better 
 
• A little better 
 
• No difference 
 
• A little worse 
 
• Much worse 
 
Patients will undergo this assessment at time points according to section 6.1. 
The assessment tool is provided in the study reference manual. 


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6.2.2.5. 
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. 
 
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 6.1. 
The CDLQI is provided in the study reference manual. 
 
6.2.2.6. 
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 6.1. 
 
6.2.2.7. 
Patient-Assessed Hospital Anxiety and Depression Scale 
 
The HADS is an instrument for screening anxiety and depression in non-psychiatric populations; 
repeated administration also provides information about changes to a patient’s emotional state 
(Zigmond 1983, Herrmann 1997). The HADS consists of 14 items, 7 each for anxiety and 
depression symptoms; possible scores range from 0 to 21 for each subscale. The following 
cut-off scores are recommended for both subscales: 7 to 8 for possible presence, 10 to 11 for 
probable presence, and 14 to 15 for severe anxiety or depression. The questionnaire will be 
administered only to the subset of patients who fluently speak a language in which the 


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questionnaire is presented (based on availability of validated translations in participating 
countries), at time points according to section 6.1. 
 
The HADS is provided in the study reference manual. 
 
6.2.2.8. 
Juniper Asthma Control Questionnaire – 5 
 
The 5-question version of the Juniper Asthma Control Questionnaire (ACQ) is a validated 
questionnaire to evaluate asthma control. The questionnaire will be administered only to the 
subset of patients with ongoing asthma and who fluently speak a language in which the 
questionnaire is presented (based on availability of validated translations in participating 
countries), at time points according to section 6.1. 
 
The assessment tool is provided in the study reference manual. 
 
6.2.2.9. 
Total Nasal Symptom Score 
 
The Total Nasal Symptom Score (TNSS) will be used to assess the effect of study drug on 
symptoms of allergic rhinitis. The summed score will include the following 5 symptoms: 
rhinorrhea, nasal congestion, nasal itching, sneezing, and difficulty in sleeping, each rated on a 0 
to 3 scale of severity. This instrument has been extensively used in previous trials conducted in 
patients with allergic rhinitis (Berger 2015, Benninger 2010). The questionnaire will be 
administered only to the subset of patients with a medical history of allergic rhinitis who fluently 
speak a language in which the questionnaire is presented (based on availability of translations in 
participating countries). Patients will be instructed on using the patient diary to record their 
TNSS throughout the screening period (at least 7 days before baseline/day 1) and only for 7 days 
preceding visit 6, visit 18, and visit 21. 
 
The assessment tool is provided in the study reference manual. 
 
6.2.2.10. Injection Site Pain Visual Analogue Scale 
 
Patients will be asked to provide an assessment of pain experienced during injection of study 
drug using a Visual Analogue Scale (VAS). This assessment will be performed after injection of 
the study drug at certain in-clinic visits according to section 6.1. 
 
The assessment tool is provided in the study reference manual. 
 
6.2.2.11. 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 6.1. 
 
The IGA is provided in the study reference manual and in Appendix 2. 


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6.2.2.12. Eczema Area and Severity Index 
 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin 2001). The EASI is a composite index with scores ranging from 0 to 
72. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], 
scratching [excoriation], and lichenification) will each be assessed for severity by the 
investigator or designee on a scale of “0” (absent) through “3” (severe). In addition, the area of 
AD involvement will be assessed as a percentage by body area of head, trunk, upper limbs, and 
lower limbs, and converted to a score of 0 to 6. In each body region, the area is expressed as 0, 
1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 
100%). The EASI will be collected at time points according to section 6.1. 
The EASI assessment tool is provided in the study reference manual. 
 
6.2.2.13. 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 6.2.2.12). The Global Individual Signs Score (GISS) will be assessed at time points 
according to section 6.1. 
 
The GISS assessment tool is provided in the study reference manual. 
 
6.2.2.14. 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 6.2.2.15) 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 6.1. 
 
The SCORAD assessment tool is provided in the study reference manual. 


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6.2.2.15. 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 6.1. 
 
The BSA assessment tool is provided in the study reference manual. 
 
6.2.2.16. 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 6.1. 
 
The assessment tool is provided in the study reference manual. 
 
6.2.2.17. 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 6.1. 
 
Instructions for taking the photographs are provided in the photography reference manual. 
 
6.2.3. 
Safety Procedures 
 
6.2.3.1. 
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), sitting blood pressure, heart rate, and respiratory rate will also be assessed 
at 30 (±10) minutes postdose. See section 6.1 for assessment time points. 
 
6.2.3.2. 
Body Weight and Height 
 
Body weight and height will be measured at time points according to section 6.1. 
 
6.2.3.3. 
Physical Examination 
 
A thorough and complete physical examination will be performed at visits according to 
section 6.1. Care should be taken to examine and assess any abnormalities that may be present, 
as indicated by the patient’s medical history. 
 
6.2.3.4. 
Electrocardiogram 
 
Electrocardiograms should be performed before blood is drawn during visits requiring blood 
draws. A standard 12-lead electrocardiogram (ECG) will be performed at time points according 
to section 6.1. 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. 


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6.2.3.5. 
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 6.1. Tests will 
include: 
 
Serum Chemistry 
 
Sodium 
Potassium 
Total protein, serum 
Creatinine 
Total bilirubin1 
Total cholesterol2 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Calcium 
AST 
ALT 
Uric acid 
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 
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 6.1. 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), and alcohol and drug screen test. 


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Abnormal Laboratory Values and Laboratory Adverse Events 
 
• All laboratory values must be reviewed by the investigator or authorized designee. 
 
• Significantly abnormal tests must be repeated to confirm the nature and degree of the 
abnormality. When necessary, appropriate ancillary investigations should be initiated. 
If the abnormality fails to resolve or cannot be explained by events or conditions 
unrelated to the study medication or its administration, the medical monitor must be 
consulted. 
 
• The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
 
Criteria for reporting laboratory values as an AE are provided in section 7.2.5. 
 
6.2.4. 
Pharmacokinetic and Antibody Procedures 
 
6.2.4.1. 
Drug Concentration Measurements and Samples 
 
Serum samples for measuring functional dupilumab concentrations will be collected at time 
points listed in section 6.1. 
 
6.2.4.2. 
Anti-Drug Antibody Measurements and Samples 
 
Serum samples for ADA assessment will be collected at time points listed in section 6.1. 
 
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. 
 
6.2.5. 
Biomarker Procedures 
 
Thymus and activation-regulated chemokine and total serum IgE are markers of Th2 activity as 
downstream mediators in the IL-4/IL-13 signaling pathway (Wirnsberger 2006, Takeda 1997). 
These analytes will be assessed as measures of Th2 activity and PD effect of dupilumab. The 
results may be used for modeling dupilumab activity with drug levels in the comparison of 
dosing regimens. Thymus and activation-regulated chemokine levels have also been closely 
associated with AD disease activity and severity (Beck 2014), and will be evaluated as an 
exploratory marker of efficacy. These markers may also be assessed for their potential value in 
predicting treatment response. 
 
Lactate dehydrogenase levels have also been shown to correlate with disease severity and 
activity in patients with AD (Mukai 1990). 
 
Patients with total serum IgE levels in the normal range may still have antigen-specific IgE in 
circulation, indicating they are atopic. To further understand atopy in this patient population, 
region-specific, allergen-specific IgE panels will be performed. These markers may be used to 
understand PD activity, efficacy, and may be also tested for predictive utility. 


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Serum samples for measurements of biomarkers (including TARC, total IgE, immunoglobulin 
profiling, allergen-specific IgE, and LDH [which will be measured as part of the blood 
chemistry]) to study the PD activity of dupilumab in pediatric AD patients will be collected at 
time points according to section 6.1. 
 
Additional biomarker serum samples will be collected to study exploratory biomarkers of 
dupilumab activity and AD. 
 
6.2.6. 
Future Biomedical Research 
 
Biomarker samples will be collected at time points specified in section 6.1. 
 
The biomarker samples unused for study-related research, as well as unused PK and ADA 
samples, will be stored for up to 15 years after the final date of the database lock. The unused 
samples may be utilized for future biomedical research of AD and other diseases. No additional 
samples will be collected for future biomedical research. After 15 years, any residual samples 
will be destroyed. 


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7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
 
7.1. 
Definitions 
 
7.1.1. 
Adverse Event 
 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of the study drug. 
 
7.1.2. 
Serious Adverse Event 
 
An SAE is any untoward medical occurrence that at any dose: 
 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
In-patient hospitalization is defined as 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 7.2 for more 
information on recording and reporting SAEs. 


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7.2. 
Recording and Reporting Adverse Events 
 
7.2.1. 
Adverse Events 
 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study. Refer to the study reference manual for the procedures to be 
followed. 
 
Information on follow-up for AEs is provided in section 7.2.6. Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in section 7.2.5. 
 
7.2.2. 
Serious Adverse Events 
 
All SAEs, regardless of assessment of causal relationship to study drug must be reported to the 
sponsor (or designee) within 24 hours. Refer to the 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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7.2.3. 
Other Events that Require Accelerated Reporting 
 
The following events also require reporting to the sponsor (or designee) within 24 hours of 
learning of the event: 
 
Symptomatic Overdose of Study Drug: Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE, 
 
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 or female partner of a 
male patient, during the study or within 120 days of the last dose of study drug. 
Any complication of pregnancy affecting a female study patient or female partner 
of a male study patient, and/or fetus and/or newborn must be reported as an SAE. 
 
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: 
 
• Anaphylactic reactions 
 
• Systemic or severe hypersensitivity reactions 
 
• Malignancy (except in situ carcinoma of the cervix, non-metastatic squamous 
or basal cell carcinoma of the skin) 
 
• Helminthic infections 
 
• Suicide-related events 
 
• Any type of conjunctivitis or blepharitis (severe or serious or lasting 
≥ 4 weeks) 
 
• Keratitis 
 
Refer to the study reference manual for the procedures to be followed. 
 
7.2.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
 
Refer to the study reference manual for the procedures to be followed. 


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7.2.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 
• the test result is associated with accompanying symptoms, and/or 
 
• the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 
• the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
 
Contact the medical monitor in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in section 7.3.1. 
 
7.2.6. 
Follow-up 
 
Adverse event information will be collected until the patient’s last study visit. 
 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
 
7.3. 
Evaluation of Severity and Causality 
 
7.3.1. 
Evaluation of Severity 
 
The severity of AEs will be graded according to the following scale: 
 
• Mild: 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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7.3.2. 
Evaluation of Causality 
 
The relationship of AEs to study drug will be assessed by the investigator, and will be a clinical 
decision based on all available information. The following question will be addressed: 
 
Is there a reasonable possibility that the 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 investigator will also assess whether the AEs are related to any study procedures (as listed in 
Table 1 and Table 2). 
 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
 
7.4. 
Safety Monitoring 
 
The investigator will monitor the safety of study patients at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The medical monitor will have primary responsibility for 
the emerging safety profile of the compound. The 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. 
 
7.5. 
Investigator Alert Notification 
 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the 
Investigator’s Brochure, and has a reasonable suspected causal relationship to the medicinal/study 
drug). 


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8. 
STUDY VARIABLES 
 
8.1. 
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. 
 
8.2. 
Primary and Secondary Endpoints 
 
8.2.1. 
Primary Endpoint 
 
The primary endpoint in the study is: 
 
• Proportion of patients with IGA 0 to 1 (on a 5-point scale) at week 16 
 
For the ex-US countries, the co-primary endpoints are: 
 
• Proportion of patients with EASI-75 (≥75% improvement from baseline) at week 16 
 
• Proportion of patients with IGA 0 to 1 (on a 5-point scale) at week 16 
 
8.2.2. 
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 peak Pruritus 
NRS 
 
• Proportion of patients with improvement (reduction) of weekly average of daily peak 
Pruritus NRS ≥3 from baseline to week 16 
 
• Proportion of patients with improvement (reduction) of weekly average of daily peak 
Pruritus NRS ≥4 from baseline to week 16 
 
Other secondary endpoints are: 
 
• Proportion of patients with EASI-50 at week 16 
 
• Proportion of patients with EASI-90 at week 16 
 
• Time to onset of effect on pruritus during the 16-week treatment period (≥3 point 
reduction of weekly average of peak Pruritus NRS from baseline 
 
• Time to onset of effect on pruritus during the 16-week treatment period (≥4 point 
reduction of weekly average of peak Pruritus NRS from baseline 
 
• Change from baseline to week 16 in percent BSA affected by AD 
 
• Percent change from baseline to week 16 in SCORAD 


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•
•
•
•
Change from baseline to week 16 in CDLQI 
Change from baseline to week 16 in POEM 
Change from baseline to week 16 in weekly average of daily peak Pruritus NRS 
Percent change from baseline to week 4 in weekly average of daily peak Pruritus 
NRS 
•Change from baseline to week 16 in HADS 
•Proportion of patients with improvement (reduction) of weekly average of daily peak 
Pruritus NRS ≥4 from baseline to week 4 
•Incidence of skin-infection TEAEs (excluding herpetic infections) through week 16 
•Incidence of serious TEAEs through week 16 
8.2.3. 
Other Endpoints and Assessments 
Other endpoints and assessments, as applicable, will be specified in the statistical analysis plan 
(SAP). 
 
8.3. 
Pharmacokinetic Variables 
 
Concentration of functional dupilumab in serum at each time point will be considered to be 
trough values (Ctrough.timepoint). 
 
8.4. 
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 postbaseline ADA results 
negative, or a positive response at baseline with all postbaseline ADA titer <4-fold 
over baseline titer level 
 
• Total patients with 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 into the following 
categories: 
 
 Persistent ADA response – a treatment-emergent ADA positive response with 
2 or more consecutive ADA positive sampling time points, separated by >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 


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 Indeterminate ADA response – a treatment-emergent ADA positive response with 
only the last collected sample positive in the ADA assay 
 
• Total patients with 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 
 
• 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 patients positive in the NAb assay at the time points analyzed 
 
 
9. 
STATISTICAL PLAN 
 
This section provides the basis for the SAP for the study. The SAP may be revised during the 
study to accommodate amendments to the clinical study protocol and to make changes to adapt 
to unexpected issues in study execution and data that may affect the planned analyses. The final 
SAP will be issued before the database is locked. 
 
Analysis variables are listed in section 8. 
 
9.1. 
Statistical Hypothesis 
 
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 (<60 kg and ≥60kg) and disease severity (moderate [IGA=3] vs. severe 
[IGA=4] AD) will be the 2 stratification factors for patient randomization and will be accounted 
for in the statistical modeling for efficacy. 
 
9.2. 
Justification of Sample Size 
 
It is estimated that with 80 patients per group, at the 2-sided 5% significance level, the study will 
have: 
 
• 98% power to detect a difference of 28% between dupilumab Q2W treatment and 
placebo treatment in the percentage of patients who achieve an IGA score 0 to 1 at 
week 16, assuming that the percentages are 37% and 9% for dupilumab Q2W and 
placebo, respectively. 
 
• 88% power to detect a difference of 20% between dupilumab Q4W treatment and 
placebo treatment in the percentage of patients who achieve an IGA score 0 to 1 at 


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week 16, assuming that the percentages are 29% and 9% for dupilumab Q4W and 
placebo, respectively. 
 
• 99% power to detect a difference of 35% between dupilumab Q2W treatment and 
placebo treatment in the percentages of patients achieving EASI-75 response at week 
16, assuming that the percentages are 48% and 13% for dupilumab Q2W and placebo, 
respectively. 
 
• 99% power to detect a difference of 32% between dupilumab Q4W treatment and 
placebo treatment in percentages of patients achieving EASI-75 response at week 16, 
assuming that the percentages are 45% and 13% for dupilumab Q4W and placebo, 
respectively. 
 
Additional power calculation based on the key secondary endpoint “proportion of patients with 
improvement (reduction) of Pruritus NRS ≥4 from baseline to week 16”, with 80 patients per 
group, the study will provide: 
 
• 97% power at a 0.05 level to detect a difference of 27% in the percentages of patients 
achieving Pruritus NRS reduction ≥4 at week 16, assuming that the percentages are 
38% and 11% for dupilumab Q2W and placebo, respectively. 
 
• 95% power at a 0.05 level to detect a difference of 25% in the percentages of patients 
achieving weekly average of daily peak Pruritus NRS reduction ≥4 at week 16, 
assuming that the percentages are 36% and 11% for dupilumab Q4W and placebo, 
respectively. 
 
The assumptions used for the power calculations were estimated based on results from the R668-
AD-1334 and R668-AD-1416 studies (phase 3 studies for adult AD patients), and the R668-AD-
1021 study (a phase 2b dose-ranging study in adults with AD). Based on the result from the 
R668-AD-1021 study, the efficacy profile of 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-1334, R668-AD-1416, 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). 


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9.3. 
Analysis Sets 
 
9.3.1. 
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). 
 
The per protocol set (PPS) includes all patients in the FAS except for those who are excluded 
because of major efficacy-related protocol violations. A major protocol violation is one that may 
affect the interpretation of study results. 
 
All efficacy variables will be evaluated on the FAS; the primary endpoint will also be evaluated 
on the PPS. Analysis on the FAS will be considered to be primary. 
 
9.3.2. 
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. 
 
9.3.3. 
Pharmacokinetic Analysis Sets 
 
The PK analysis set includes all randomized patients who received any study drug and who had 
at least 1 qualified PK sample result following the first dose of study drug. 
 
9.3.4. 
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 reportable ADA result (either “ADA negative” or “ADA positive”) after the 
first dose of study drug. 
 
9.4. 
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 
 
• 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 


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9.5. 
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. 
 
9.5.1. 
Demography and Baseline Characteristics 
 
Demographic and baseline characteristics will be summarized descriptively by treatment group. 
 
9.5.2. 
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. 
 
9.5.2.1. 
Primary Efficacy Analysis 
 
The Cochran-Mantel-Haenszel test adjusted by randomization strata (baseline disease severity 
and weight group) 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. 
 
All efficacy data, regardless of the patient being 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 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 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 5.3), 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. 
 
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. 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 nonresponder. Other sensitivity analyses may be conducted. 


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9.5.2.2. 
Secondary Efficacy Analysis 
 
For binary endpoints, the secondary efficacy analysis will use the same approach as that used for 
the primary 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 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. 
 
 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 (disease severity, 
weight group), 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 
(disease severity, 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 the 40 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 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. 
 
9.5.2.3. 
Multiplicity Considerations 
 
For multiplicity adjustment, 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 following is the preliminary plan for order of testing (Table 3).  The final hierarchy will be 
provided in the SAP that will be finalized prior to database lock. 


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Table 3: 
Statistical Hierarchy for Multiplicity Control 
 
 
 
Endpoints 
 
Primary endpoint 
Proportion of patients with IGA 0 to 1 (on a 5-point 
scale) at week 16 
Dupilumab 
 
q4w group 
q2w group 
10 
1 
 
Co-primary 
endpoint for ex- 
US countries, key 
secondary for US 
 
 
Proportion of patients with EASI-75 (≥75% 
9 
2 
improvement from baseline) at week 16 
Percent change in EASI score from baseline to week 16 
11 
3 
 
 
 
 
Key Secondary 
endpoints 
Percent change from baseline to week 16 in weekly 
average of daily peak Pruritus NRS 
Proportion of patients with improvement (reduction) of 
weekly average of daily peak Pruritus NRS ≥3 from 
baseline to week 16 
Proportion of patients with improvement (reduction) of 
weekly average of daily peak Pruritus NRS ≥4 from 
baseline to week 16 
12 
4 
 
 
13 
5 
 
 
 
14 
6 
Secondary 
endpoints 
Proportion of patients with EASI-50 at week 16 
15 
7 
 
Proportion of patients with EASI-90 at week 16 
16 
8 
 
Time to onset of effect on pruritus during the 16-week 
treatment period (≥3 point reduction of weekly average 
of peak Pruritus NRS from baseline) 
 
Time to onset of effect on pruritus during the 16-week 
treatment period (≥4 point reduction of weekly average 
of peak Pruritus NRS from baseline) 
 
Change from baseline to week 16 in percent BSA 
affected by AD 
 
25 
17 
 
 
 
26 
18 
 
 
 
27 
19 
 
Percent change from baseline to week 16 in SCORAD 
28 
20 
 
Change from baseline to week 16 in CDLQI 
29 
21 
 
Change from baseline to week 16 in POEM 
30 
22 
 
Change from baseline to week 16 in weekly average of 
daily peak Pruritus NRS 
 
Percent change from baseline to week 4 in weekly 
average of daily peak Pruritus 
 
31 
23 
 
 
32 
24 
 
Change from baseline to week 16 in HADS 
35 
33 
 
Proportion of patients with improvement (reduction) of 
weekly average of daily peak Pruritus NRS ≥4 from 
baseline to week 4 
 
Incidence of skin-infection TEAEs (excluding herpetic 
infections) through week 16 
 
36 
34 
 
 
 
39 
37 
 
Incidence of serious TEAEs through week 16 
40 
38 


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9.5.2.4. 
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 8.2.1 and section 8.2.2 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. 
 
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. 
 
9.5.3. 
Safety Analysis 
 
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). 
 
9.5.3.1. 
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. 
 
Treatment-emergent adverse events are defined as those that are not present at baseline or 
represent the exacerbation of a preexisting condition during the treatment-emergent 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 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 7.3.1), 
presented by SOC and PT 
 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
Deaths and other SAEs will be listed and summarized by treatment group. 


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Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
 
9.5.3.2. 
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. 
 
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. 
 
9.5.3.3. 
Treatment Exposure 
 
The duration of exposure during the study will be presented by treatment group and calculated 
as: 
 
(Date of last study drug injection – date of first study drug injection) + 14 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, medians, and maximums. 
 
A summary of the number of doses by treatment group will be provided. 
 
9.5.3.4. 
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. 


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9.5.4. 
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 for analysis using population methods. 
Any population PK analysis will be reported separately. 
 
9.5.5. 
Analysis of Anti-Drug Antibody Data 
 
The ADA variables described in section 8.4 will be summarized using descriptive statistics by 
treatment groups. 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. 
 
9.5.6. 
Analysis of Biomarker Data 
 
All exploratory biomarker data analyses will be performed on the FAS and no multiplicity 
adjustment is planned. Analyses of exploratory endpoints will be provided in the SAP. 
 
9.6. 
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. 


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9.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in section 15.1. 
 
 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
 
10.1. 
Data Management 
 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting, releasing) will be maintained and stored at 
Regeneron. 
 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
 
The CRF data for this study will be collected with an electronic data capture (EDC) tool. 
 
10.2. 
Electronic Systems 
 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 
• 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 
 
• Argus – a pharmacovigilance and clinical safety software system (Regeneron) 
 
• AWARE, Business Objects XI – pharmacovigilance activities (Sanofi) 
 
 
11. 
STUDY MONITORING 
 
11.1. 
Monitoring of Study Sites 
 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study. In accordance 
with 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. 


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11.2. 
Source Document Requirements 
 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
 
11.3. 
Case Report Form Requirements 
 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs 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. 
 
 
12. 
AUDITS AND INSPECTIONS 
 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
 
• Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
 
• Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 
• Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
 
Documents subject to audit or inspection include but are not limited to all source documents, 
CRFs, medical records, correspondence, ICFs/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. 


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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
13.1. 
Good Clinical Practice Statement 
 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable 
regulatory requirements. 
 
13.2. 
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). 


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13.3. 
Patient Confidentiality and Data Protection 
 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by their 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. 
 
The patient's and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third 
party. 
 
13.4. 
Institutional Review Board/Ethics Committee 
 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 
• The protocol, ICF/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. 
 
 
14. 
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. 
 
15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
 
15.1. 
Premature Termination of the Study 
 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, 
safety, or futility, among others. Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 


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15.2. 
Close-out of a Site 
 
The sponsor and the investigator have the right to close-out a site prematurely. 
 
Investigator’s Decision 
 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at 
least 30 days’ notice. The final decision should be made through mutual agreement with the 
sponsor. Both parties will arrange the close-out procedures after review and consultation. 
 
Sponsor’s Decision 
 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. 
Reasons may include the following, among others: 
 
• The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines 
 
• The total number of patients required for the study are enrolled earlier than expected 
 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection 
of the patients’ interests. 
 
 
16. 
STUDY DOCUMENTATION 
 
16.1. 
Certification of Accuracy of Data 
 
A declaration assuring the accuracy and content of the data recorded on the CRFs must be signed 
by the investigator. This certification form accompanies each set of CRFs. The signed form will 
be provided to the sponsor with the final set of CRFs for each patient. 
 
16.2. 
Retention of Records 
 
The investigator must retain all essential study documents, including ICFs/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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17. 
CONFIDENTIALITY 
 
Confidentiality of information is provided as a separate agreement. 
 
 
18. 
FINANCING AND INSURANCE 
 
Financing and insurance information is provided as a separate agreement. 
 
 
19. 
PUBLICATION POLICY 
 
The publication policy is provided as a separate agreement. 


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20. 
REFERENCES 
 
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. 
 
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. 
 
Benninger M, Farrar JR, Blaiss M, Chipps B, Ferguson B, Krouse J, et al. Evaluating approved 
medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy 
for nasal symptoms by class. Ann Allergy Asthma Immunol. 2010 Jan;104(1):13-29. doi: 
10.1016/j.anai.2009.11.020. 
 
Berger WE, Meltzer EO. Intranasal spray medications for maintenance therapy of allergic 
rhinitis. Am J Rhinol Allergy. 2015 Jul-Aug;29(4):273-82. doi: 10.2500/ajra.2015.29.4215. Epub 
2015 Jun 29. 
 
Bieber T. Atopic dermatitis. The New England journal of medicine. 2008 Apr 
3;358(14):1483-94. PubMed PMID: 18385500. 
 
Czarnowicki T, Esaki H, Gonzalez J, Malajian D, Shemer A, Noda S, Talasila S, Berry A, Gray 
J, Becker L, Estrada Y, Xu H, Zheng X, Suárez-Fariñas M, Krueger JG, Paller AS, 
Guttman-Yassky E. 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 Aug 1. pii: S0091-6749(15)00866-0. doi: 
10.1016/j.jaci.2015.05.049. 
 
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. 
 
Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, et al. Guidelines 
of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic 
dermatitis. J Am Acad Dermatol. 2014 Feb;70(2):338-351. doi: 10.1016/j.jaad.2013.10.010. Epub 
2013 Nov 27. 
 
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. 
 
Granlund H, Erkko P, Sinisalo M, Reitamo S. Cyclosporin in atopic dermatitis: time to relapse 
and effect of intermittent therapy. The British journal of dermatology. 1995 Jan;132(1):106-12. 
PubMed PMID: 7756119. 


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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 
immunology. 2011a May;127(5):1110-8. PubMed PMID: 21388665. 
 
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 
clinical immunology. 2011b Jun;127(6):1420-32. PubMed PMID: 21419481. 
 
Hanifin JM, Thurston M, et al. The eczema area and severity index (EASI): assessment of 
reliability in atopic dermatitis. Exp Dermatol 2001; 10: 11-18. 
 
Heise T, Nosek L, Dellweg S, Zijlstra E, Præstmark KA, Kildegaard J, et al. Impact of injection 
speed and volume on perceived pain during subcutaneous injections into the abdomen and thigh: 
a single-centre, randomized controlled trial. Diabetes Obes Metab. 2014 Oct;16(10):971-6. doi: 
10.1111/dom.12304. Epub 2014 May 11. 
 
Herrmann C. International experiences with the hospital anxiety and depression scale – a review 
of validation data and clinical results. J Psychosom Res 1997;42(1):17-41. 
 
Hong S, Son DK, Lim WR, Kim SH, Kim H, Yum HY, et al. The prevalence of atopic 
dermatitis, asthma, and allergic rhinitis and the comorbidity of allergic diseases in children. 
Environmental health and toxicology. 2012;27:e2012006. PubMed PMID: 22359737. Pubmed 
Central PMCID: 3282234. 
 
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. 
 
Illi S, von Mutius E, Lau S, Nickel R, Gruber C, Niggemann B, et al. The natural course of 
atopic dermatitis from birth to age 7 years and the association with asthma. The Journal of 
allergy and clinical immunology. 2004 May;113(5):925-31. PubMed PMID: 15131576. 
 
Kay J, Gawkrodger DJ, Mortimer MJ, Jaron AG. The prevalence of childhood atopic eczema in 
a general population. Journal of the American Academy of Dermatology. 1994 Jan;30(1):35-9. 
PubMed PMID: 8277028. 
 
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. 
 
Kim DH, Li K, Seo SJ, Jo SJ, Yim HW, Kim CM, et al. Quality of life and disease severity are 
correlated in patients with atopic dermatitis. Journal of Korean medical science. 2012 
Nov;27(11):1327-32. PubMed PMID: 23166413. Pubmed Central PMCID: 3492666. 
 
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. 
 
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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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. 
 
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 
PMCID: 1717083. 
 
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. 
 
Verboom P, Hakkaart-Van L, Sturkenboom M, De Zeeuw R, Menke H, Rutten F. The cost of 
atopic dermatitis in the Netherlands: an international comparison. The British journal of 
dermatology. 2002 Oct;147(4):716-24. PubMed PMID: 12366418. 
 
Williams H, Robertson C, Stewart A, Ait-Khaled N, Anabwani G, Anderson R, et al. Worldwide 
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and Allergies in Childhood. The Journal of allergy and clinical immunology. 1999 Jan;103(1 Pt 
1):125-38. PubMed PMID: 9893196. 
 
Williams HC. Clinical practice. Atopic dermatitis. The New England journal of medicine. 2005 
Jun 2;352(22):2314-24. PubMed PMID: 15930422. 
 
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. 
 
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 
1983;67:361-370. 


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21. 
INVESTIGATOR’S AGREEMENT 
 
I have read the attached protocol: A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF 
DUPILUMAB MONOTHERAPY IN PATIENTS ≥12 TO <18 YEARS OF AGE, WITH 
MODERATE-TO-SEVERE ATOPIC DERMATITIS, Amendment 3, and agree to abide by all 
provisions set forth therein. 
 
I agree to comply with the current International Council for 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: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes: 
• 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 
 
 
 
• 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: 


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Score 
Investigator’s Global Assessment (IGA) 
Standard Definitions 
Investigator’s Global Assessment (IGA): 
Proposed Morphological Descriptors 
0 = Clear 
No inflammatory signs of atopic dermatitis 
No inflammatory signs of atopic dermatitis 
1 = Almost clear 
Just perceptible erythema, and just perceptible 
papulation/infiltration 
Barely perceptible erythema and/or minimal lesion elevation 
(papulation/infiltration) 
2 = Mild disease 
Mild erythema and mild papulation/infiltration 
Visibly detectable, light pink erythema and very slight 
elevation (papulation/infiltration) 
3 = Moderate disease 
Moderate erythema and moderate 
papulation/infiltration 
Dull red, clearly distinguishable erythema; clearly perceptible 
elevation (papulation/infiltration), but not extensive 
4 = Severe disease 
Severe erythema and severe papulation/infiltration Deep/dark red erythema; marked and extensive elevation 
(papulation/infiltration) 


VV-RIM-00038275-2.0 Approved - 23 Feb 2018 GMT-5:00 
 
 
Clinical Study Protocol 
R668-AD-1526 Amendment 3 
 
 
 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
 
(Medical/Study  Director,  Regulatory  Representative,  Clinical  Study  Team  Lead,  and 
Biostatistician) 
 
To the best of my knowledge, this report accurately describes the conduct of the study. 
 
Study Title:     A randomized, double-blind, placebo-controlled study to investigate the efficacy 
and safety of dupilumab monotherapy in patients ≥12 to <18 years of age, with moderate-to- 
severe Atopic Dermatitis 
 
Protocol Number:       R668-AD-1526 
 
Protocol Version:       R668-AD-1526 Amendment 3 
 
 
 
See appended electronic signature page 
 
Sponsor’s Responsible Medical/Study Director 
 
 
 
 
 
See appended electronic signature page 
 
Sponsor’s Responsible Regulatory Liaison 
 
 
 
 
 
See appended electronic signature page 
 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
 
 
 
See appended electronic signature page 
 
Sponsor’s Responsible Biostatistician 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regeneron Pharmaceuticals, Inc. 
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Signature Page for VV-RIM-00038275 v2.0 
 
 
Approval 
 
 
23-Feb-2018 17:09:56 GMT+0000 
 
 
Approval 
 
 
ement 
23-Feb-2018 17:13:48 GMT+0000 
 
 
Approval 
 
 
23-Feb-2018 17:25:15 GMT+0000 
 
 
Approval 
 
 
23-Feb-2018 18:53:42 GMT+0000 
 
Signature Page for VV-RIM-00038275 v2.0 Approved 

SAP_001.pdf: 
CONFIDENTIAL 
Page 1 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
NCT03054428 
 
Regeneron Pharmaceuticals, Inc. 
R668-AD-1526 
Statistical Analysis Plan 
 
 
Title:  A randomized, double-blind, placebo-controlled study to investigate the efficacy and 
safety of dupilumab monotherapy in patients ≥12 to <18 years of age, with moderate-to-severe 
Atopic Dermatitis 
 
 
Protocol: 
R668-AD-1526.03 
 
Investigational product: 
Dupilumab (REGN668) 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Statistician: 
Clinical Trial Manager: 
Study Medical Director: 


CONFIDENTIAL 
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Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
 
 
 
 
 
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) 
 
See appended electronic signature page 
 
 
 
 
 
Study Medical Director (Approver) 
 
See appended electronic signature page 
 
 
 
 
 
 
Head of BDM or designee (Approver) 
 
See appended electronic signature page 


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Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
 
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 ....................................................................................15 
 
3.1. 
Efficacy Analysis Sets ................................................................................................15 
 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................15 
 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................16 
 
3.4. 
The ADA Analysis Set (AAS)....................................................................................16 
 
4. 
ANALYSIS VARIABLES .........................................................................................17 
 
4.1. 
Demographic and Baseline Characteristics ................................................................17 
 
4.2. 
Medical History and Atopic Disease Medical History ...............................................17 
 
4.3. 
Pre-treatment/Concomitant Medications and Procedures ..........................................17 
 
4.4. 
Efficacy Variables ......................................................................................................19 
 
4.4.1. 
Primary Efficacy Variable ..........................................................................................19 
 
4.4.2. 
Secondary Efficacy Variables.....................................................................................20 
 
4.4.3. 
Other Efficacy Variables ............................................................................................24 
 
4.5. 
Safety Variables ..........................................................................................................27 
 
4.5.1. 
Adverse Events and Serious Adverse Events Variables .............................................27 
 
4.5.2. 
Laboratory Safety Variables .......................................................................................29 
 
4.5.3. 
Vital Sign Variables....................................................................................................30 
 
4.5.4. 
Body Weight and Height ............................................................................................30 
 
4.5.5. 
Physical Examination Variables .................................................................................30 
 
4.6. 
Pharmacokinetic (PK) Variables ................................................................................30 


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4.7. 
Antibody (ADA) Variable ..........................................................................................30 
 
4.8. 
Biomarkers Variables .................................................................................................31 
 
5. 
STATISTICAL METHODS.......................................................................................32 
 
5.1. 
Demographics and Baseline Characteristics...............................................................32 
 
5.2. 
Medical and AD History.............................................................................................32 
 
5.3. 
Pre-treatment/Concomitant Medications/Procedures .................................................32 
 
5.4. 
Subject Disposition .....................................................................................................33 
 
5.5. 
Dose administration ....................................................................................................33 
 
5.6. 
Treatment Exposure and Observation Period .............................................................34 
 
5.7. 
Analyses of Efficacy Variables ..................................................................................34 
 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................35 
 
5.7.2. 
Analyses of Secondary Efficacy Variables.................................................................36 
 
5.7.3. 
Subgroup Analysis ......................................................................................................39 
 
5.7.4. 
Analyses of Other Efficacy Variables ........................................................................39 
 
5.8. 
Analysis of Safety Data ..............................................................................................39 
 
5.8.1. 
Adverse Events ...........................................................................................................40 
 
5.8.2. 
Analysis of Clinical Laboratory Measurements .........................................................41 
 
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..............................................................................42 
 
5.10. 
Analysis of Immunogenicity Data ..............................................................................42 
 
5.10.1. 
Analysis of ADA Data ................................................................................................42 
 
5.10.2. 
Analysis of Neutralizing Antibodies (NAb) ...............................................................42 
 
5.11. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................42 
 
5.11.1. 
Immunogenicity and Exposure ...................................................................................42 
 
5.11.2. 
Immunogenicity and Safety and Efficacy...................................................................43 
 
5.12. 
Analysis of Biomarker Data .......................................................................................43 
 
6. 
DATA CONVENTIONS ............................................................................................45 
 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................45 
 
6.2. 
General Data Handling Conventions ..........................................................................45 
 
6.3. 
Data Handling Convention Missing Data ...................................................................45 


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6.4. 
Analysis Visit Window ...............................................................................................48 
 
7. 
INTERIM ANALYSIS ...............................................................................................49 
 
8. 
SOFTWARE ...............................................................................................................50 
 
9. 
REFERENCES ...........................................................................................................50 
 
10. 
APPENDIX.................................................................................................................51 
 
10.1. 
Summary of Statistical Analyses ................................................................................51 
 
10.2. 
Schedule of Events .....................................................................................................54 
 
10.3. 
Criteria for Treatment-Emergent Potentially Clinical Significant Value for 
Pediatric Patients ........................................................................................................60 
 
10.4. 
Search Criteria for TEAE of Special Interest/TEAE Syndrome1 ...............................65 
 
10.5. 
Algorithm for RESCUE TREATMENTS ..................................................................67 
 
 
 
LIST OF TABLES 
 
Table 1: 
Schedule of Events – Screening, Baseline and Treatment Periods ............................54 
 
Table 2: 
Schedule of Events (Treatment Period cont, Follow-Up Period, Unscheduled 
Visits, and Early Termination) ...................................................................................58 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACQ 
Asthma Control Questionnaire 
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 
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 
MMRM 
Mixed-effect model with repeated measures 
NAb 
Neutralizing Antibody 


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NRS 
Numerical rating scale 
PCS 
Pruritus Categorical Scale 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
POEM 
Patient Oriented Eczema Measure 
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-1526 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 the most common inflammatory skin disease in childhood.  The disease 
usually presents during early infancy and childhood, but it can persist into or start in adulthood. 
The disease affects 15% to 30% of children and 2% to 10% of adults in industrialized countries. 
Phase 1 of the International Study of Asthma and Allergies in Childhood showed a 1-year period 
prevalence rate as high as 20% in Australia, England, and Scandinavia.  Often, AD constitutes 
the first step of the “atopic march” (progression from one atopic disease to another). Up to 60% 
of AD patients have concomitant asthma, allergic rhinitis, or food allergy. 
 
There is currently a high unmet medical need for a safe and effective therapy for AD in 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 an important therapeutic role to help 
control mild disease and a supportive role 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).  Topical corticosteroids reduce 
inflammation and pruritus, and are useful in controlling acute flares.  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 many times as an alternative to or in 
combination with TCS. However, 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). 


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Systemic agents are used off label (cyclosporine, methotrexate, azathioprine, systemic steroids 
and mycophenolate mofetil) in the treatment of AD in children and lack robust evidence for the 
basis of use.  All of these systemic agents have significant side effects, including stunted growth, 
diabetes, hypertension, osteoporosis (corticosteroids), myelosuppression and hepatotoxicity 
(methotrexate), nephrotoxicity and hypertension (cyclosporine), and gastrointestinal disturbances 
and leucopenia (azathioprine). Moreover, a high proportion of patients in which disease is 
initially controlled by systemic agents suffer from relapse soon after therapy is discontinued. 
 
As a biologic product that selectively targets the Th2 inflammatory pathway, dupilumab is being 
developed to provide a safe and efficacious alternative treatment for AD patients, including 
children.  Dupilumab is a human monoclonal antibody that targets the IL-4 receptor alpha 
subunit (IL-4Rα), a component of IL-4 receptors Type I and Type II, as well as the IL-13 Type II 
receptor system.  The binding of dupilumab to IL-4Rα results in the blockade of both IL-4 and 
IL-13 signal transduction. Because up-regulation of IL-4 and IL-13 has been implicated as an 
important driver of AD, treatment with dupilumab may demonstrate efficacy in the treatment of 
this disease. 
 
1.2. 
Study Objectives 
 
1.2.1. 
Primary Objective 
 
The primary objective of the study is to demonstrate the efficacy of dupilumab as a monotherapy 
in patients ≥12 years to <18 years of age with moderate-to-severe AD. 
 
1.2.2. 
Secondary Objectives 
 
The secondary objective of the study is to assess the safety of dupilumab as a monotherapy in 
patients ≥12 years to <18 years of age with moderate-to-severe AD. 
 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
•Removed the “or lasting ≥ 4 weeks” condition from the AESI criteria for any type of 
conjunctivitis or blepharitis (i.e. Any type of conjunctivitis or blepharitis (only events 
that are severe or serious or lasting ≥ 4 weeks)) according to recent revision of list of 
AESIs across the dupilumab program in AD. 


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2. 
INVESTIGATIONAL PLAN 
 
2.1. 
Study Design and Randomization 
 
This is a randomized, double-blind, placebo-controlled, parallel-group study to investigate the 
efficacy and safety of dupilumab monotherapy in pediatric patients with moderate-to-severe AD. 
The study population will include patients ≥12 years to <18 years of age with moderate-to-severe 
AD whose disease cannot be adequately controlled with topical medications or for whom topical 
treatment is medically inadvisable (eg, intolerance, other important side effects or safety risks). 
 
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 weight group (<60 kg 
and ≥60kg; each weight stratum will enroll approximately 120 patients) and baseline disease 
severity (moderate [IGA=3] vs. severe [IGA=4] AD) as follows: 
 
• Dupilumab Q2W treatment group:  Patients with baseline weight <60 kg will receive 
Q2W subcutaneous (SC) injections of 200 mg dupilumab following a loading dose of 
400 mg on day 1.  Patients with baseline weight ≥60 kg will receive Q2W SC 
injections of 300 mg dupilumab following a loading dose of 600 mg on day 1. 
 
• Dupilumab Q4W treatment group:  Patients will receive Q4W SC injections of 
300 mg dupilumab following a loading dose of 600 mg on day 1, irrespective of 
weight. 
 
• Placebo treatment group:  Patients will receive placebo matching dupilumab Q2W 
(including doubling the amount of placebo on day 1 to match the loading dose).  In 
order to maintain blinding for the study, patients in the <60 kg weight stratum will 
receive, in a 1:1 ratio, either placebo matching 200 mg dupilumab (including 
doubling the amount of placebo on day 1 to match the loading dose) or placebo 
matching 300 mg dupilumab (including doubling the amount of placebo on day 1 to 
match the loading dose).  In the ≥60 kg weight stratum, the patients randomized to the 
placebo group will receive placebo matching 300 mg dupilumab (including doubling 
the amount of placebo on day 1 to match the loading dose). 
 
In order to maintain blinding, all patients will receive an injection Q2W from day 1 to week 14. 
Patients will receive placebo injection at the weeks dupilumab is not given. 
 
Below diagram shows the planned number of patients in each dose group. 


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2.2. 
Sample Size and Power Considerations 
 
Approximately 240 patients are planned to be randomized to 1 of the following treatment groups: 
 
• Dupilumab Q2W treatment group:  200 mg Q2W patients <60 kg or 300 mg Q2W patients 
≥60 kg 
 
• Dupilumab Q4W treatment group:  300 mg Q4W 
 
• Placebo group 
 
It is estimated that with 80 patients per group, at the 2-sided 5% significance level, the study will 
have: 
 
• 98% power to detect a difference of 28% between dupilumab Q2W treatment and placebo 
treatment in the percentage of patients who achieve an IGA score 0 to 1 at week 16, 
assuming that the percentages are 37% and 9% for dupilumab Q2W and placebo, 
respectively. 
 
• 88% power to detect a difference of 20% between dupilumab Q4W treatment and placebo 
treatment in the percentage of patients who achieve an IGA score 0 to 1 at week 16, 
assuming that the percentages are 29% and 9% for dupilumab Q4W and placebo, 
respectively. 
 
• 99% power to detect a difference of 35% between dupilumab Q2W treatment and placebo 
treatment in the percentages of patients achieving EASI-75 response at week 16, assuming 
that the percentages are 48% and 13% for dupilumab Q2W and placebo, respectively. 
 
• 99% power to detect a difference of 32% between dupilumab Q4W treatment and placebo 
treatment in percentages of patients achieving EASI-75 response at week 16, assuming that 
the percentages are 45% and 13% for dupilumab Q4W and placebo, respectively. 


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Additional power calculation based on the key secondary endpoint “proportion of patients with 
improvement (reduction) of Pruritus NRS ≥4 from baseline to week 16”, with 80 patients per 
group, the study will provide: 
 
• 97% power at a 0.05 level to detect a difference of 27% in the percentages of patients 
achieving Pruritus NRS reduction ≥4 at week 16, assuming that the percentages are 38% and 
11% for dupilumab Q2W and placebo, respectively. 
 
• 95% power at a 0.05 level to detect a difference of 25% in the percentages of patients 
achieving weekly average of daily peak Pruritus NRS reduction ≥4 at week 16, assuming that 
the percentages are 36% and 11% for dupilumab Q4W and placebo, respectively. 
 
In the absence for data of dupilumab in pediatric patients with AD, the data observed in the adult 
studies R668AD-1334 and R668-AD-1416 studies (phase 3 studies for adult AD patients), and 
the R668AD1021 study (a phase 2b dose-ranging study in adults with AD) are used to generate 
the assumptions for these sample size calculations.  Based on the result from the R668-AD-1021 
study, the efficacy profile of dupilumab 200 mg Q2W is similar to dupilumab 300 mg Q2W. 
 
2.3. 
Study Plan 
 
The study will consist of the following 3 periods: screening of up to 5 weeks, treatment period of 
16 weeks, and follow-up of 12 weeks as presented below: 
 
 
Note: D = study day; W = study week 
 
After the parents or legal guardians/patients provide an Informed Consent and Informed Assent 
(as appropriate), the patients will be assessed for study eligibility at the screening visit.  During 
the screening period, systemic and topical treatments for AD will be washed out, as applicable, 
according to the eligibility requirements.  Patients may be rescreened once if they fail the 
screening evaluation for reasons related to incidental transitory conditions, unless the reason for 
the screen failure is related to failing the disease severity inclusion criteria.  Patients will be 
required to apply moisturizers twice daily for at least 7 days before randomization and continue 
throughout the study.  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. 


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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 weight group (<60 kg 
and ≥60kg; each weight stratum will enroll approximately 120 patients) and baseline disease 
severity (moderate [IGA=3] vs. severe [IGA=4] AD) as follows: 
 
• Dupilumab Q2W treatment group:  Patients with baseline weight <60 kg will receive Q2W 
SC injections of 200 mg dupilumab following a loading dose of 400 mg on day 1. Patients 
with baseline weight ≥60 kg will receive Q2W SC injections of 300 mg dupilumab following 
a loading dose of 600 mg on day 1. 
 
• Dupilumab Q4W treatment group:  Patients 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 placebo matching dupilumab Q2W (including 
doubling the amount of placebo on day 1 to match the loading dose). In order to maintain 
blinding for the study, patients in the <60 kg weight stratum will receive, in a 1:1 ratio, either 
placebo matching 200 mg dupilumab (including doubling the amount of placebo on day 1 to 
match the loading dose) or placebo matching 300 mg dupilumab (including doubling the 
amount of placebo on day 1 to match the loading dose). In the ≥60 kg weight stratum, the 
patients randomized to the placebo group will receive placebo matching 300 mg dupilumab 
(including doubling the amount of placebo on day 1 to match the loading dose). 
 
In order to maintain blinding, all patients will receive an injection Q2W from day 1 to week 14. 
Patients will receive placebo injection at the weeks dupilumab is not given. 
 
During the treatment period, patients will have weekly in-clinic visits through week 4, and then 
in-clinic visits every 4 weeks through week 16 with weekly telephone visits in between the 
in-clinic visits.  Patients and/or parents/caregivers (as deemed appropriate based on age of 
patient) will be trained on injecting study drug during in-clinic visit 2 (day 1) to visit 6 (week 4). 
During weeks in which no in-clinic visit is scheduled, patients will either self-inject study drug 
or the parent/caregiver will administer study drug to the patient.  In case patients do not want to 
self-inject and the parent/caregiver do not want to administer study drug to patient, patients 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 schedule of event 
Appendix 10.2.  The end of treatment period visit will occur at week 16, two weeks after the last 
dose of study drug.  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 open-label 
extension study. 
 
Patients who complete this study (ie, up to the end of study visit at week 28) may be eligible to 
enroll in a subsequent extension study in which they will receive open-label treatment with 
dupilumab. In order to remain eligible for the open-label extension study, patients are required to 
adequately complete the assessments scheduled for the treatment period (through week 16) and 
follow-up period (week 20 through week 28), per the schedule of events. 


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As an exception to the above requirement, patients may be allowed to enroll into the open-label 
extension study earlier once they have completed the treatment period of this study (ie, at or after 
week 16), if they meet all of the following criteria: 
 
• The patient needs to have completed at least 5 on site visits (including completing the 
study assessments and procedures planned for each of those visits) during the 
16 week treatment period. 
AND 
• The patient needs to have completed at least 6 study drug administrations during the 
16-week treatment period. 
 
• Patients have completed the week 16 visit (the protocol-defined “end of treatment” 
visit). 
 
• Patients have completed the early termination visit. This visit may be conducted as 
early as week 16.  The open-label extension screening visit may be completed on the 
same day as the early termination visit. 
 
• Patients have an IGA ≥3 and BSA affected by AD lesions ≥10% at the early 
termination visit. 
 
• Patients meet the eligibility criteria for the open-label extension study. 
Patients who have study drug permanently discontinued due to safety reasons will 
not be eligible to enroll in the open-label extension study. 
 
NOTE: 
 
  In case a patient experiences a flare of disease during the follow-up period and 
would otherwise require treatment with systemic corticosteroids or systemic 
immunosuppressive drugs (eg, cyclosporine, methotrexate, 
mycophenolate-mofetil, azathioprine, etc), he/she can be enrolled directly into this 
open-label extension study at the investigator’s discretion before completion of 
the entire follow-up period.  However, it is required that an IGA be performed in 
this case and only patients who have an IGA ≥3 be considered for direct roll-over 
into this extension study. 
 
  Patients who turned 18 years of age during this study will not be eligible to enroll 
into the pediatric open-label extension study (R668-AD-1434).  In case the drug is 
not commercially available for patients aged ≥18 years at the time the patient 
completes this study, these patients may be eligible for, and might have the 
opportunity to, enroll into the adult open-label extension study (R668-AD-1225), 
if the study is still ongoing. 
  Study drug administration refers to injections of dupilumab or placebo. 
Patients who decline to enroll in the open-label extension study will be followed up for 
12 weeks.  For these patients, after week 16, follow-up visits will occur every 4 weeks from 
week 20 through week 28.  During the follow-up period, patients will be monitored for safety 
and tolerability and have laboratory and clinical assessments per schedule as noted in 
Appendix 10.2 (schedule of events). 


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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. 
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). 
 
The per-protocol set (PPS) includes all patients in the FAS except for those who are excluded 
because of major efficacy-related protocol violations.  A major efficacy-related protocol 
violation is one that may affect the interpretation of study results.  The criteria of major efficacy- 
related protocol deviation are defined as following: 
 
• Patients who were randomized more than once 
 
• Any major violations of efficacy-related entry criteria 
 
 Inclusion criteria 3, 4, 5, 6, 7, 8 and 9* 
 
 Exclusion criteria 1, 2*, 3*, 4, 5, 6*, 8, 9, 10,11, 19 
 
• Patients who received <80% of the scheduled doses during the study treatment period 
 
*Note: Will be adjudicated on a case by case basis in blinded fashion prior to 
database lock 
Final determination of the PPS will be made in a blinded manner prior to the database lock. 
All efficacy variables will be evaluated on the FAS; the primary endpoint and key secondary 
endpoints will also be evaluated on the PPS.  Analysis on the FAS will be considered to be 
primary. 
 
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 actual treatment group as treated is defined by the following rules: 
 
• For a patient randomized to dupilumab (Q2W or Q4W), if the patient received all 
placebo injections, the actual treatment will be assigned as placebo. 
 
• For a patient randomized to dupilumab (Q2W or Q4W), if the patient received at least 
one dupilumab injection, the actual treatment will be same as the planned treatment. 
 
• For patients randomized to placebo but accidentally received dupilumab injections, 
the actual treatment will be assigned as dupilumab 300 mg Q4W. 


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In addition: 
 
• Nonrandomized but treated patients will not be part of the safety population; 
however, their safety data will be presented separately. 
 
• Randomized patients for whom it is unclear whether they took the study drug will be 
included in the safety population as randomized. 
 
For safety summaries, three analysis periods are defined as follows: 
 
• 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 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. Patients 
will be analyzed according to the treatment actually received. 
 
3.4. 
The ADA Analysis Set (AAS) 
 
The ADA analysis set 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 neutralizing antibody (NAb) Analysis Set (NAS) will consist of all patients who received 
any study drug and who had at least one non-missing Nab result or who had all samples negative 
in the ADA assay after first dose of the study drug. Patients will be analyzed according to the 
treatment actually received. 


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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 (≥15 to <18, ≥12 to <15), 
sex, ethnicity, race, baseline weight (kg) with grouping (<60 kg, >=60 kg), height 
(m), BMI (kg/m2) with grouping (<20, >=20) 
•Baseline characteristics: Duration of AD disease with grouping (< 13 years, 
>=13 years), Peak Pruritus numerical rating scale (NRS), Pruritus Categorical Scale 
(PCS), 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 assessment of disease 
status, Patient Oriented Eczema Measure (POEM), Children's Dermatology Life 
Quality Index (CDLQI), Global Individual Signs score (GISS), Hospital Anxiety and 
Depression Scale (HADS) total score, HADS-Anxiety subscale score, 
HADS-Depression subscale score, Asthma Control Questionnaire (ACQ-5), and Total 
Nasal Symptom Score (TNSS), Patients with inadequate response to topicals (Yes/No) 
with the reasons for patients who are “No” for inadequate response to topicals 
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, 
Azathiophrine and other treatments) during the last 6 months will also be collected. 
 
4.3. 
Pre-treatment/Concomitant Medications and Procedures 
 
Medications/Procedures will be recorded from the day of informed consent until the 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. 
 
Pre-treatment medications/procedures:  medications taken or procedures performed prior to 
administration of the first study drug. 


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Concomitant medications/procedures:  medications taken or procedures performed following the 
first dose of study drug through the EOS visit. 
 
• Concomitant medications/procedures during the 16 week treatment period are 
medications/procedures taken after the first dose up to the week 16 visit date or date 
of study day 113 if 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 nonsteroid immunosuppressant (may be used as rescue) 
 
• Treatment with systemic corticosteroids (may be used as rescue) 
 
• Treatment with TCS or TCI (may be used as rescue) 
 
• Treatment with crisaborole (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.  For the purpose of efficacy analysis, patients who receive rescue 
treatment during the study will be considered treatment failures.  If possible, investigators are 
encouraged to consider rescue initially with topical treatment (eg, medium/high potency TCS) 
and to escalate to systemic medications only for patients who do not respond adequately after at 
least 7 days of topical treatment.  Topical calcineurin inhibitors may be used for rescue, alone or 
in combination with TCS, but the use of TCIs should be reserved for problem areas only (eg, 
face, neck, intertriginous and genital areas, etc.).  Patients who receive systemic corticosteroids 
or systemic non-steroidal immunosuppressive drugs (eg, cyclosporine, methotrexate, 
mycophenolate-mofetil, azathioprine, etc.) as rescue treatment 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 


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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. 
 
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 ex-US countries, 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 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 10% = head, 20% = upper extremities, 30% = trunk, 40% = lower extremities. 
The minimum possible EASI score is 0 and the maximum possible EASI score is 72 where a 
higher score indicates increased extent and severity of atopic dermatitis.  The EASI score of each 
sign (E, I, X and L) can be calculated in a similar way, for example, the EASI score of erythema 
= weighted sum of E x Area Score at each section. 
 
The EASI will be collected at the scheduled and unscheduled clinic visits according to 
Appendix 10.2. 


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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 peak Pruritus 
NRS 
 
• Proportion of patients with improvement (reduction) of weekly average of daily peak 
Pruritus NRS ≥3 from baseline at week 16 
 
• Proportion of patients with improvement (reduction) of weekly average of daily peak 
Pruritus NRS ≥4 from baseline at week 16 
 
Peak Pruritus Numeric Rating Scale (NRS) 
 
The Peak Pruritus NRS is a simple assessment tool that patients will use to report the intensity of 
their pruritus (itch) during a 24-hour recall period.  Patients will be asked the following 
questions: 
 
• For maximum itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 
10 being the ‘worst itch imaginable’, how would you rate your itch at the worst 
moment during the previous 24 hours?” 
 
Patients will be instructed on using the patient diary to record their Pruritus NRS score at the 
baseline visit.  Patients will complete the rating scale daily throughout the entire study (screening 
period, treatment period, and follow-up period).  Clinical sites will check and remind patients to 
complete the diary at each visit. 
 
For each day, if there are multiple NRS scores collected on the same day, the maximum value of 
all the scores collected will be used for analysis. 
 
The baseline NRS is defined as the prorated average of the NRSs reported continuously for 
7 days right before and on the baseline visit (i.e. study day -6 to day 1).  For post-baseline NRS, 
the mean weekly NRS is calculated as the prorated average of the reported daily NRS within the 
week.  For example, if there are 3 scores in a week, the prorated average = (score1 + score2 + 
score3)/3. 
 
Other secondary endpoints are: 
 
• Proportion of patients with EASI-50 at week 16 
 
• Proportion of patients with EASI-90 at week 16 
 
• Time to onset of effect on pruritus as measured by proportion of patients with 
improvement (reduction) of weekly average of daily peak Pruritus NRS ≥3 from 
baseline during the 16-week treatment period 


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• Time to onset of effect on pruritus as measured by proportion of patients with 
improvement (reduction) of weekly average of daily peak Pruritus NRS ≥4 from 
baseline during the 16-week treatment period 
 
• Change from baseline to week 16 in percent BSA affected by AD 
 
• Percent change from baseline to week 16 in SCORAD 
 
• Change from baseline to week 16 in CDLQI 
 
• Change from baseline to week 16 in POEM 
 
• Change from baseline to week 16 in weekly average of daily peak Pruritus NRS 
 
• Percent change from baseline to week 4 in weekly average of daily peak Pruritus 
NRS 
 
• Change from baseline to week 16 in HADS 
 
• Proportion of patients with improvement (reduction) of weekly average of daily peak 
Pruritus NRS ≥4 from baseline to week 4 
 
• Incidence of skin-infection TEAEs (excluding herpetic infections) through week 16* 
 
• Incidence of serious TEAEs through week 16 
 
*It will be 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 (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. 
 
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. 
 
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: 
 
•0: None 
•1: Mild 
•2: Moderate 
•3: Severe 


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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. 
For general inflammatory skin conditions a change in CDLQI score of at least 4 points is 
considered clinically important.  The CDLQI will be assessed at the scheduled and unscheduled 
clinic visits according to Appendix 10.2. 
 
Handling missing items from CDLQI: 
 
a.   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. 
 
b.   If two or more questions are left unanswered the questionnaire is not scored. 
 
c.   If two or more response options are ticked for one question, the response option with 
the highest score should be recorded. 
 
d.   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: 
 
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 


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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. 
 
Hospital Anxiety and Depression Scale (HADS) 
 
The HADS is a tool widely used to detect states of anxiety and depression in a general hospital 
setting.  The 14 items on the questionnaire, assessing how the patient has been feeling in the past 
week, include 7 items that are related to anxiety (odd numbered questions) and 7 items that are 
related to depression (even numbered questions).  Questions 2, 4, 7, 9, 12, and 14 are scored 
from 0 (less distress) to 3 (greater distress) according to the content of the item.  Questions 1, 3, 
5, 6, 8, 10, 11, and 13 are reverse scored from 0 (greater distress) to 3 (less distress).  A person 
can score between 0 and 21 for each subscale (anxiety and depression).  A high score is 
indicative of a poor state.  Scores of 11 or more on either subscale are considered to be a 'definite 
case' of psychological morbidity, while scores of 8–10 represents 'probable case’ and 0 – 7 'not a 
case' (Zigmond 1983). 
 
For each sub-scale:  if one question is missing, the response will be imputed as the mean of the 
remaining six questions.  If more than one question is missing, then the subscale is set to 
missing.  The total score is the sum of the two sub-scores. 
 
The questionnaire will be administered only to the subset of patients who fluently speak a 
language in which the questionnaire is presented (based on availability of validated translations 
in participating countries), at time points according to Appendix 10.2. 


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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 
 
• Patient global assessment of disease: proportion of patients with no symptom and 
proportion of patients with no symptom or mild symptoms at week 16 
 
• Patient global assessment of treatment: proportion of patients who rate their eczema 
symptoms as “much better” at week 16 
 
• Pruritus categorical scale: proportion of patients who achieve absence of pruritus or 
mild pruritus at week 16 
 
• Proportion of patients who achieve reduction of IGA score by ≥2 from baseline to 
week 16 
 
• Change in ACQ-5 score from baseline at week 16 
 
• Change in weekly averaged TNSS score from baseline at week 16 
 
• Change from baseline to week 16 in GISS (erythema, infiltration/papulation, 
excoriations, lichenification) 
 
• Number of missed school days assessment during the treatment period 
 
• Mean score of injection site pain as assessed by visual analogue scale for all visits 
through week 16 
 
Patient Global Assessment of Disease 
 
Patients will rate their disease based on a 5-point Likert scale.  Patients will be asked:  “Overall, 
how would you rate your eczema symptoms right now?” Response choices are: 
 
• 1:  No symptoms 
 
• 2:  Mild symptoms 
 
• 3:  Moderate symptoms 
 
• 4:  Severe symptoms 
 
• 5:  Very severe symptoms 
 
Patients will undergo this assessment at time points according to Appendix 10.2. 


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Patient Global Assessment of Treatment 
 
Patients will rate their satisfaction with the study treatment based on a 5-point Likert scale. 
Patients will be asked:  “Compared to before you started the study, how would you rate your 
eczema symptoms now?” Response choices are: 
 
• 1:  Much better 
 
• 2:  A little better 
 
• 3:  No difference 
 
• 4:  A little worse 
 
• 5:  Much worse 
 
Patients will undergo this assessment at time points according to Appendix 10.2. 
 
Patient Assessment of Pruritus Using Pruritus Categorical Scale (PCS) 
 
The pruritus categorical scale is a 4-point scale used to assess symptoms that has been used in 
clinical studies of AD and has less of a “middling” effect (Kaufmann 2006).  The scale is rated 
as follows: 
 
• 0:  Absence of pruritus 
 
• 1:  Mild, pruritus (occasional slight itching/scratching) 
 
•  2:  Moderate pruritus (constant or intermittent itching/scratching that does not disturb 
sleep) 
 
• 3:  Severe pruritus (bothersome itching/scratching that disturbs sleep). 
 
Patients will be instructed on using the patient diary to record their pruritus categorical scale 
score at the baseline visit.  Patients will complete the rating scale DAILY throughout the entire 
study (screening period, treatment period, and follow-up period).  Clinical sites will check and 
remind patient to complete the diary at each visit. 
 
For each day, if there are multiple PCS scores collected on the same day, the maximum (worst) 
of all the scores collected will be chosen.  For each week, calculate round prorated average of 
collected scores for Category Score.  For example, if there are 3 scores in a week, the prorated 
average = (score1 + score2 + score3)/3 round to 1.0. 
 
The baseline PCS is defined as the round prorated average of the PCSs reported right before and 
on the baseline visit (i.e. study day -6 to day 1). 
 
Juniper Asthma Control Questionnaire (ACQ-5) 
 
The 5-question (symptoms only) version of the Juniper ACQ is a validated questionnaire to 
evaluate asthma control.  The questionnaire will be administered only to the subset of patients 
with a medical history of asthma and who fluently speak a language in which the questionnaire is 
presented (based on availability of validated translations in participating countries), at time 
points according to Appendix 10.2. 


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The ACQ-5 has 5 questions, reflecting the top-scoring five asthma symptoms:  woken at night by 
symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of 
breath and wheeze.  Patients are asked to recall how their asthma has been during the previous 
week and to respond to the symptom questions on a 7-point scale (0 = no impairment, 
6 = maximum impairment).  A global score is calculated: the questions are equally weighted and 
the ACQ-5 score is the mean of the 5 questions and, therefore, between 0 (totally controlled) and 
6 (severely uncontrolled).  Higher score indicates lower asthma control.  On the 7-point scale of 
the ACQ-5, a change or difference in score of 0.5 is the smallest that can be considered clinically 
important, corresponding to the Minimal Clinically Important Difference (MCID) defined by the 
developer. 
 
Based on the manual of ACQ, any more than one missing value is not acceptable.  If more than 
one of the questions have missing value, the global score is invalid and will be considered as 
missing.  If only one question has missing value, it will be interpolated (pro-rated) using the 
completed questionnaires from the previous visit.  If the questionnaire from the previous visit is 
not complete either, the missing value will be imputed as the average of the completed questions 
within the current visit. 
 
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. 
 
Total Nasal Symptom Score 
 
The Total Nasal Symptoms score (TNSS) will be used to assess the effect of study drug on 
symptoms of allergic rhinitis.  The TNSS total score will be the sum of the following 5 
symptoms: rhinorrhea, nasal congestion, nasal itching, sneezing, and difficulty in sleeping, each 
rated on a 0 to 3 scale of severity. The modified TNSS total score will be the sum of 4 
symptoms: rhinorrhea, nasal congestion, nasal itching, and sneezing. Both TNSS total score and 
modified total score will be analyzed. The questionnaire will be administered only to the subset 
of patients with allergic rhinitis who fluently speak a language in which the questionnaire is 
presented (based on availability of translations in participating countries).  Patients will be 
instructed on using the patient diary to record their TNSS score at the scheduled and unscheduled 
clinic visits according to Appendix 10.2. 
 
The weekly averaged TNSS score will be calculated as the prorated average of the reported daily 
TNSS score within 7 days prior to the visit.  For example, if there are 3 scores in a week, the 
prorated average = (score1 + score2 + score3)/3. 
 
Subgroup analysis of TNSS data for patients with perennial allergic rhinitis may be performed. 


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Injection Site Pain Visual Analogue Scale 
 
Patients will be asked to provide an assessment of pain experienced during injection of study 
drug using a Visual Analogue Scale (VAS).  This assessment will be performed after injection of 
the study drug at certain in-clinic visits according to Section 6.1. 
 
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. 
 
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 emergent period is defined as the period from the 
administration of first study dose to the EOS visit. 


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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) category: 
 
• Anaphylactic reactions 
 
• Systemic or severe hypersensitivity reactions 
 
• Malignancy (except in situ carcinoma of the cervix, non-metastatic squamous or basal 
cell carcinoma of the skin) 
 
• Helminthic infections 
 
• Suicide-related events 
 
• Any type of conjunctivitis or blepharitis (severe or serious) 
 
• Keratitis (any event regardless of severity or seriousness) 
Appendix 10.54 provides a list of AESIs search criteria. 


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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 
Potassium 
Total protein, serum 
Creatinine 
Total bilirubin1 
Total cholesterol2 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Calcium 
AST 
ALT 
Uric acid 
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 
 
Urinalysis 
 
Color 
Clarity 
Glucose 
Blood 
RBC 
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), and alcohol and drug screen test. 


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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), sitting blood pressure, heart rate, and respiratory rate will also be assessed 
at 30 (±10) minutes postdose.  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). 
 
4.6. 
Pharmacokinetic (PK) Variables 
 
Serum samples for measuring functional dupilumab concentrations will be collected at time 
points according to Appendix 10.2. PK variables consist of functional dupilumab concentration 
and time (both actual and nominal). 
 
4.7. 
Antibody (ADA) Variable 
 
Serum samples for anti-dupilumab antibody will be collected at time points according to visit 
schedule (Appendix 10.2). 
 
ADA variables include ADA response status and titer as follows: 
 
• Total patients with preexisting immunoreactivity 
 
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 


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• Total patients with treatment emergent response 
 
Treatment emergent response is 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 (greater than 84 days), 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. 
 
• Total patients with treatment boosted response 
 
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 
 
• Titer Values (Titer value category) 
 
 Low (titer <1,000) 
 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 
 High (titer >10,000) 
 
Samples positive in the ADA assay will be further characterized for ADA titers and for the 
presence of neutralizing antibody (NAb) response. 
 
Total patients positive in the Neutralizing antibody assay 
Treatment-emergent or treatment boosted ADA positive patients that are positive in 
the NAb assay at any time point analyzed. 
 
4.8. 
Biomarkers Variables 
 
Biomarkers to be analyzed in this study are: 
 
• TARC 
 
• Total serum IgE 
 
• Immunoglubin profiling 
 
• Antigen-specific IgE 
 
• Lactate dehydrogenase (LDH) [which will be measured as part of the blood 
chemistry] 
 
Serum samples for measurements of biomarkers to study the PD activity of dupilumab in 
pediatric AD patients will be collected at time points according to Appendix 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, 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 (i.e. dupilumab Q2W dose, dupilumab Q4W 
dose and placebo). All placebo patients will be pooled for analysis regardless if it is 200 mg 
placebo or 300 mg 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 (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 or adult 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 who entered into open-label extension study (OLE) 
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 
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: 
(Date of last study drug injection – date of first study drug injection) + 14 
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, medians, 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:  ೦೦೦𝑢೦𝑖೦𝑢೦೦೦ = ೦೦೦೦೦೦೦೦೦ , where 𝑝 stands for the percent of responders in a treatment group
 
H1:  ೦೦೦𝑢೦𝑖೦𝑢೦೦೦ ≠  ೦೦೦೦೦೦೦೦೦ .
 
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 (≥12 to <15, ≥15 to <18) 
 
• Sex (Male, Female) 
 
• Ethnicity: Hispanic or Latino (no/yes) 
 
• Race (White, Black or African American, Asian, Other) 
 
• Duration of AD (< 13 years, ≥13 years) 
 
• Age of disease onset (<2 years, ≥2 years) 
 
• Age of disease onset (<5 years, ≥5 years) 


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•
•
•
Family history of atopic disease (Yes/No) 
Baseline weight group (<60 kg, ≥60 kg) 
Baseline BMI group (overweight: >= 85 percentile of general population based on 
age and gender, < 85 percentile) 
Baseline disease severity [moderate (IGA=3) and severe (IGA=4)] 
•Baseline severe EASI (<25, ≥25) 
•Baseline NRS (<7, ≥7) 
•Body Surface Area (BSA) (≥10% - <30%, ≥30% - <50%, ≥50%) 
•Previous usage of ciclosporin (CsA) (Yes, No) 
•Previous usage of methotrexate (MTX) (Yes, No) 
•Previous use of systemic immunosuppressants for AD (Yes, No) 
•History of asthma (Yes, No) 
•History of allergic rhinitis (Yes, No) 
•History of food allergies (Yes, No) 
5.7.1. 
Analysis of Primary Efficacy Variable 
The Cochran-Mantel-Haenszel (CMH) test adjusted by randomization strata (disease severity 
(IGA=3 or 4), weight group (<60 kg or >60kg)) 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. 
 
All efficacy data, regardless of the patient being 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 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 if 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. 
 
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. 


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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 FAS, as well as on PPS as a supporting 
analysis. 
 
5.7.2. 
Analyses of Secondary Efficacy Variables 
 
The binary secondary efficacy endpoints will be analyzed using the same approaches as that are 
used for the analysis of the primary endpoints. 
 
The endpoint “Proportion of patients with improvement (reduction) of weekly average of daily 
peak pruritus NRS ≥4 from baseline to week 16” will only be analyzed for patients with baseline 
peak pruritus NRS ≥4.  Similarly the endpoint “Proportion of patients with improvement 
(reduction) of weekly average of daily peak pruritus NRS ≥3 from baseline to week 16” will only 
be analyzed for patients with baseline peak pruritus NRS ≥3. 
 
The continuous endpoints will be analyzed using the multiple imputation (MI) with analysis of 
covariance (ANCOVA) model 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 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.  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 adjustment for covariates including treatment groups, 
randomization strata (disease severity, age group), 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 (disease severity, age 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 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 (disease severity, weight group) 
 
• Measured endpoint values at every clinic visit (i.e. week 1, 2, 3, 4, 8, 12 and week 16) 


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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. 
 
Sensitivity analyses 
 
In addition to the MI method described previously, sensitivity analyses for the continuous 
endpoints for EASI and/or Pruritus NRS 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 peak Pruritus NRS >=4 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 any event during the treatment period will 
have their time censored at the end of treatment period.  Time 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. 
 
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. 


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Multiplicity Considerations 
 
The following multiplicity adjustment approach, a hierarchical procedure, will be used to control 
the overall Type-I 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). 
 
Endpoints 
Dupilumab 
Q4W 
group 
Q2W group 
Primary endpoint 
Proportion of patients with IGA 0 to 1 (on a 5-point scale) 
at week 16 
10 
1 
Co-primary 
endpoint for ex-US 
countries, key 
secondary for US 
Proportion of patients with EASI-75 (>=75% 
improvement from baseline) at week 16 
9 
2 
Key Secondary 
endpoints 
Percent change in EASI score from baseline to week 16 
11 
3 
Percent change from baseline to week 16 in weekly 
average of daily peak Pruritus NRS 
12 
4 
Proportion of patients with improvement (reduction) of 
weekly average of daily peak Pruritus NRS >=3 from 
baseline to week 16 
13 
5 
Proportion of patients with improvement (reduction) of 
weekly average of daily peak Pruritus NRS >=4 from 
baseline to week 16 
14 
6 
Secondary 
endpoints 
Proportion of patients with EASI-50 at week 16 
15 
7 
Proportion of patients with EASI-90 at week 16 
16 
8 
Time to onset of effect on pruritus during the 16-week 
treatment period (≥3 point reduction of weekly average of 
peak Pruritus NRS from baseline) 
25 
17 
Time to onset of effect on pruritus during the 16-week 
treatment period (≥4 point reduction of weekly average of 
peak Pruritus NRS from baseline) 
26 
18 
Change from baseline to week 16 in percent BSA affected 
by AD 
27 
19 
Percent change from baseline to week 16 in SCORAD 
28 
20 
Change from baseline to week 16 in CDLQI 
29 
21 
Change from baseline to week 16 in POEM 
30 
22 
Change from baseline to week 16 in weekly average of 
daily peak Pruritus NRS 
31 
23 
Percent change from baseline to week 4 in weekly average 
of daily peak Pruritus 
32 
24 
Change from baseline to week 16 in HADS 
35 
33 
Proportion of patients with improvement (reduction) of 
weekly average of daily peak Pruritus NRS >=4 from 
baseline to week 4 
36 
34 
Incidence of skin-infection TEAEs (excluding herpetic 
infections) through week 16 
39 
37 
Incidence of serious TEAEs through week 16 
40 
38 


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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, and treatment by subgroup interaction as factors.  P-values for the 
interaction term will be reported. 
 
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. 
 
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 10.3.  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 (≥12 to <15, ≥15 to <18) 
 
• Sex (Male, Female) 
 
• Ethnicity (Hispanic or Latino (no/yes)) 
 
• Race (White, Black, Asian, Other) 
 
• Duration of AD (< 13 years, ≥13 years) 
 
• Baseline BMI group (overweight: >= 85 percentile of general population based on 
age and gender, < 85 percentile) 
 
• Baseline weight group (<60 kg, ≥60 kg) 


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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 
 
 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 10.5) 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. 


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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. 
 
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. 


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5.9. 
Analysis of Pharmacokinetic Data 
 
The following analyses will be conducted: 
 
• Descriptive statistics of functional dupilumab serum concentrations 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. 
 
5.10. 
Analysis of Immunogenicity Data 
 
5.10.1. 
Analysis of ADA Data 
 
The incidence of ADA variables described in Section 4.7 will be summarized using absolute 
occurrence (n) and percent of patients (%) with pre-existing immunoreactivity, treatment- 
emergent, treatment-boosted, persistent ADA responses and titer categories by treatment groups. 
Listing of all ADA peak titer levels will be provided for ADA positive subjects. 
 
5.10.2. 
Analysis of Neutralizing Antibodies (NAb) 
 
The absolute occurrence (n) and percent of patients (%) with Nab positive or negative status will 
be provided by treatment group for patients in the NAb analysis set. 
 
5.11. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
 
5.11.1. 
Immunogenicity and Exposure 
 
Associations between key ADA variables and systemic exposure to dupilumab may be explored 
for the dupilumab treated patients. Plots of dupilumab concentration may be provided for 
analyzing the potential impact of treatment-emergent, persistent and titer ADA responses (high, 
moderate or low) on PK. 


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5.11.2.       Immunogenicity and Safety and Efficacy 
 
Associations between the ADA response and safety events may be explored. 
 
Associations between the ADA variables and key efficacy endpoints may be explored for the 
dupilumab treated group. Plots of efficacy variables may be analyzed for potential impact of 
treatment-emergent ADA on efficacy. 
 
The above mentioned safety and efficacy analyses will be conducted using the following ADA 
response categories: 
 
• ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response, 
 
• ADA negative patients, that is patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points 
 
 
• Patients with persistent ADA response, 
 
• NAb positive patients, that is patients who had positive in the NAb assay at any time 
point analyzed. 
 
• Peak post-baseline titer level in treatment emergent or treatment boosted ADA 
positive patients: 
 
o High, 
 
o Moderate, 
 
o 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) 
 
• antigen-specific IgE 
 
• Lactate dehydrogenase (LDH) 
 
The Wilcoxon signed-rank test stratified by the baseline disease severity will be used to test if 
the change or percentage change from baseline value is significantly different from zero. P-value 
will be reported. 


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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 and the baseline disease severity as fixed effects, 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), absolute change or 
percent change from baseline value of baseline TARC (measured value) and IgE 
(measured value) with the following clinical endpoints will be explored using the Spearman’s 
rho test.  Both Spearman correlation coefficients and p-value will be reported. 
 
• Percent change from baseline to week 16 in EASI score 
 
• Percent change from baseline to week 16 in weekly average of peak daily pruritus 
NRS 
 
• 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 ANOVA model.  The model includes the baseline 
biomarker data as the dependent variable, and treatment group, the responder/nonresponder of 
below clinical endpoint as the predictor variable.  P-value will be provided to indicate 
significance of the responder/non-responder factor. 
 
• IGA 0-1 at week 16 
 
• EASI-75 at week 16 
 
• improvement (reduction) of weekly average of peak daily pruritus NRS ≥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 the baseline disease severity.  The risk ratio and 
p-value from the chi squared test will be provided. 
 
• IGA 0-1 at week 16 
 
• EASI-75 at week 16 
 
• improvement (reduction) of weekly average of peak daily pruritus NRS ≥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 


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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. 
 
 
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 NRS 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. 


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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’. 
 
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’. 


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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’. 
 
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. 


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6.4. 
Analysis Visit Window 
 
Data analyzed by-visit-analysis (including efficacy, laboratory data, visit sign, and ECG) will be 
summarized by the study scheduled visits described in the study protocol and SAP, “Schedule of 
Event”.  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: 
 
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. 


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• 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 except TNSS 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 -6 to 1 = BL, 2 to 8 = week 1, 9 to 15 = week 2, etc., with 7 
days interval between visit windows. 
 
For TNSS data, the analysis visit windows will be implemented following the procedure below: 
 
Analysis visit window 
Baseline 
[Date of Visit 2 – 6, Date of Visit 2] 
Week 4 
[date of Visit 6 - 6, Date of Visit 6] 
Week 16 
[date of Visit 18 - 6, Date of Visit 18] 
Week 28 
[date of Visit 21 - 6, Date of Visit 21] 
 
 
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. 


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8. 
SOFTWARE 
 
All analyses will be done using SAS Version 9.2 or above. 
 
 
9. 
REFERENCES 
 
Caproni M, et al; "Serological detection of eotaxin, IL-4, IL-13, IFN-g,MIP-1a, TARC and IP-10 
in chronic autoimmune urticaria and chronic idiopathic urticaria." J Dermatol. Science (2004) 36, 
57-59 
 
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 
 
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. 
 
K. Jahnz-Rozyk, et al,"Serum thymus and activation-regulated chemokine, macrophage derived 
chemokine and eotaxin as markers of severity of atopic dermatitis." Allergy 2005: 60: 685 688 
 
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. 
 
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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10. 
APPENDIX 
 
10.1. 
Summary of Statistical Analyses 
 
Efficacy Analysis: 
 
Parameter(s) 
Endpoints 
Primary Statistical Method 
Supportive/Sensitivity 
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 Numeric Rating 
Scale (NRS) 
• % change from baseline 
• reduction of ≥4 points from baseline 
• Change from baseline 
• CMH test adjusted by randomization 
strata for categorical variables 
• Multiple imputation (MI) with 
ANCOVA for continuous variables 
Yes for % change and 
reduction >=4 
Yes for % 
change and 
reduction >=4 
Pruritus Categorical Scale 
(PCS) 
• Number (%) of patients 
• CMH test adjusted by randomization 
strata 
No 
No 
Body Surface Area (BSA) 
Involvement of Atopic 
Dermatitis 
• % change from baseline 
• Change from baseline 
• Multiple imputation (MI) with 
ANCOVA 
No 
No 
SCORing Atopic Dermatitis 
(SCORAD) 
• % change from baseline 
• Change from baseline 
• SCORAD50 
• SCORAD75 
• SCORAD90 
• Multiple imputation (MI) with 
ANCOVA for continuous variables 
• CMH test adjusted by randomization 
strata for categorical variables 
No 
No 


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Parameter(s) 
Endpoints 
Primary Statistical Method 
Supportive/Sensitivity 
Statistical Method 
Subgroup 
Analysis 
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 
• Multiple imputation (MI) with 
ANCOVA for continuous variables 
No 
No 
Children Dermatology Life 
Quality Index (CDLQI) 
• Change from baseline 
• Multiple imputation (MI) with 
ANCOVA for continuous variables 
No 
No 
Hospital Anxiety and 
Depression Scale (HADS) 
• % change from baseline 
• Change from baseline 
• Multiple imputation (MI) with 
ANCOVA for continuous variables 
No 
No 
Patient Global Assessment 
of Disease Status 
• Number (%) of patients with no 
symptom 
• Number (%) of patients with no 
symptom or mild symptoms 
• CMH test adjusted by randomization 
strata 
No 
No 
Patient Global Assessment 
of Treatment 
• 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 patients 
• Descriptive statistics by visit/time 
No 
No 
TNSS 
• Change from baseline 
• Multiple imputation (MI) with 
ANCOVA for continuous variables 
No 
No 
VAS score of injection site 
pain 
• Mean value 
• Descriptive statistics 
No 
No 


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Safety Analyses: 
 
Endpoint 
Analysis Populations 
Statistical Method 
Supportive Analysis 
Subgroup Analysis 
Other 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, Baseline and Treatment Periods 
 
Screening 
Treatment Period 
BL 
In-clinic Visit (V) or Phone 
Visit (PV) 
a 
V1 
V2 
V3 
V4 
V5 
V6 
PV7 
PV8a 
PV9a 
V10 
PV11a 
PV12a 
PV13a 
V14 
Week (W) 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
Study Day (D) 
D-35 to 
D-1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
Window in days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/Baseline: 
Informed consent/assent 
X 
Informed consent/assent for 
X 
b 
optional genomic sub-study 
Medical history 
X 
Demographics 
X 
Inclusion/exclusion criteria 
X 
X 
Randomization 
 
X 
Patient ediary training for 
X 
X 
pruritus assessments, TNSS 
assessment, and emollient use 
c 
d 
Treatment: 
Injection training/observation 
e 
X 
X 
X 
X 
X 
 
f 
Study drug administration 
X 
Patient/parent(s) or caregiver 
paper diary training for 
dosing 
Patient dosing diary 
completion 
Xf 
Xf 
X 
X 
X 
X 
X 
 
 
X 
X 
g 
Study drug dispensation 
X 
X 
X 
Study drug accountability g                                                                                                                                                                                                                                 X                                                            X 
Review home ediary                                                  X             X        X        X        X         X           X            X            X            X             X             X            X 
Concomitant                                        X                   X             X        X        X        X         X           X            X            X            X             X             X            X 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
Page 55 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
Screening 
Treatment Period 
BL 
In-clinic Visit (V) or Phone 
Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
PV7 
PV8a 
PV9a 
V10 
PV11a 
PV12a 
PV13a 
V14 
Week (W) 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
Study Day (D) 
D-35 to 
D-1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
Window in days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
medications/procedures 
Efficacy:d 
Patient assessment of pruritus 
intensity using NRS via diary 
h 
(daily) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient assessment of pruritus 
intensity using PCS via diary 
(daily) h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient global assessment of 
disease h 
X 
X 
X 
X 
X 
X 
Patient global assessment of 
treatment h 
X 
X 
X 
X 
h Patient-reported CDLQIi, 
i 
POEMi, HADS 
X 
X 
X 
X 
X 
X 
h Patient-reported ACQ-5i, j 
X 
X 
Patient-reported TNSSh, i, k 
X 
X 
Patient assessment of 
injection pain using VASh 
X 
X 
X 
X 
X 
IGA, EASI, GISS, SCORAD, 
BSA 
X 
X 
X 
X 
X 
X 
X 
X 
Assess missed school days 
X 
X 
X 
X 
Photograph AD areas 
(select sites) 
X 
Safety: d 
Weight 
X 
X 
Height 
X 
Vital signs 
X 
Xf 
X 
Xf 
X 
Xf 
X 
X 
Physical examination 
X 
ECG 
X 
Adverse events 
X 
Xf 
X 
Xf 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
a 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
Page 56 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
Screening 
Treatment Period 
BL 
In-clinic Visit (V) or Phone 
Visit (PV) 
V1 
V2 
V3 
V4 
V5 
V6 
PV7 
PV8a 
PV9a 
V10 
PV11a 
PV12a 
PV13a 
V14 
Week (W) 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
Study Day (D) 
D-35 to 
D-1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
Window in days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Laboratory Testing: d 
Hematology 
X 
X 
X 
X 
Chemistrym 
X 
X 
X 
X 
Urinalysism 
X 
X 
X 
Alcohol & drug screen test 
X 
Pregnancy test, WOCBP only 
Serum 
Ur 
Ur 
Ur 
Ur 
Ur 
Ur 
Ur 
HIV, HBsAg, HBsAb, 
HBcAb, Hep C Ab, TBl 
X 
Biomarker: d 
TARC 
X 
X 
X 
X 
X 
X 
Total serum IgE, 
immunoglobulin profiling, 
antigen specific IgE 
X 
X 
X 
X 
X 
Biomarker samples 
(serum/plasma) 
X 
X 
X 
Optional Genomics Study: d 
Optional DNA and RNA 
(whole blood) sample b 
X 
Drug Concentration and 
ADA: d 
Functional dupilumab 
concentration sample 
X 
X 
X 
X 
X 
ADA sample 
X 
X 
 
 
 
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BL = baseline; Ur = urine; WOCBP = women of childbearing potential; TB = tuberculosis 
a  The site will contact the patient/caregiver by telephone to conduct these visits. The patient/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. 
b  For patients who decide to participate and provide a specific written informed consent for the optional genomics sub-study (DNA and RNA sample collection). 
DNA sample should be collected at the day 1 visit, but can be collected at any visit during the study. RNA sample must be collected before the administration 
of the first dose of study drug. 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
Page 57 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
c  Training of patients regarding completion of diary to record (1) completion of assessment of Pruritus NRS scale, (2) completi on of assessment of Pruritus 
Categorical Scale, (3) completion of assessment of Total Nasal Symptoms Score (TNSS), and (4) emollient usage. 
d  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, and optional DNA and RNA) , and administration of 
study drug. PK and ADA samples to be collected prior to the administration of the drug. 
e  Patients or parents/caregivers will be trained on how to administer study drug. This will enable administration at home in between clinic visits. 
f  Patients will be monitored at the study site at visits 2, 4, and 6 for a minimum of 30 minutes after study drug administratio n. Vital signs (sitting blood pressure, 
heart rate, and respiratory rate) and AEs will be assessed at 30 minutes (±10 minutes) post-injection. 
g  Starting at visit 6, study drug will be dispensed to the patients or parents/caregivers for the dose that will be administered before the next clinic visit. Patients or 
parents/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 patients or parents/caregivers have returned to the site. 
h  Patient-reported assessments are to be completed only by the patient. 
i  The questionnaires will be administered only to the subset of patients who speak fluently the language in which the questionnaire is presented (based on 
availability of validated translations in participating countries). 
j   ACQ-5 will be administered only to patients with ongoing asthma. 
k  TNSS will be administered only to patients with medical history of allergic rhinitis throughout the screening period (at least 7 days b efore baseline/day 1) and 
only for 7 days preceding visit 6. 
l   Tuberculosis testing will be performed on a country-by-country basis, according to local guidelines if required by regulatory authorities or ethics boards. 
m If baseline/day 1 visit occurs within 14 days of screening, hematology and serum chemistry do not need to be repeated at the baseline/day 1 visit as long as 
these assessments were performed at the screening visit 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
Page 58 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
Table 2: 
Schedule of Events (Treatment Period cont, Follow-Up Period, Unscheduled Visits, and Early Termination) 
 
Study Procedure 
Treatment Period 
Follow-Up Periodi 
Unscheduled 
Visitb 
Early 
Termination Visit 
EOTi 
EOS 
In-clinic Visit (V) 
PV15a 
PV16a 
PV17a 
V18 
V19 
V20 
V21 
Week (W) 
W13 
W14 
W15 
W16 
W20 
W24 
W28 
Study Day (D) 
D92 
D99 
D106 
D113 
D141 
D169 
D197 
Window in days 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
Treatment:c 
Study drug administration 
X 
Patient dosing paper diary completion 
X 
Study drug accountability d 
X 
X 
X 
Review home ediary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:c 
Patient assessment of pruritus intensity using 
NRS via diary (daily) e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient assessment of pruritus intensity using 
PCS via diary (daily) e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient global assessment of disease e 
X 
X 
X 
X 
X 
X 
Patient global assessment of treatment e 
X 
X 
X 
X 
X 
X 
e Patient-reported CDLQIf, POEMf, HADSf 
X 
X 
X 
X 
X 
X 
e Patient-reported ACQ-5 g 
X 
X 
X 
Patient-reported TNSS e, f, h 
X 
X 
Patient assessment of injection pain using 
VASh 
IGA, EASI, GISS, SCORAD, BSA 
X 
X 
X 
X 
X 
X 
Assess missed school days 
X 
X 
X 
X 
X 
X 
Photograph AD areas (select sites) 
X 
X 
X 
Safety:c 
Weight 
X 
X 
X 
Height 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
Page 59 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
Study Procedure 
Treatment Period 
Follow-Up Periodi 
Unscheduled 
Visitb 
Early 
Termination Visit 
EOTi 
EOS 
In-clinic Visit (V) 
PV15a 
PV16a 
PV17a 
V18 
V19 
V20 
V21 
Week (W) 
W13 
W14 
W15 
W16 
W20 
W24 
W28 
Study Day (D) 
D92 
D99 
D106 
D113 
D141 
D169 
D197 
Window in days 
±3 
±3 
±3 
±3 
±4 
±4 
±4 
Laboratory Testing:c 
Hematology 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Pregnancy test, WOCBP only 
Urine 
Urine 
Urine 
Urine 
Biomarker: c 
TARC 
X 
X 
X 
X 
Total Serum IgE, immunoglobulin profiling, 
antigen specific IgE 
X 
X 
X 
X 
Biomarker samples (serum/plasma) 
X 
Drug Concentration and ADA Samples: c 
Functional dupilumab concentration sample 
X 
X 
X 
X 
ADA sample 
X 
X 
X 
X 
EOT = End of Treatment; EOS = End of Study 
a  The site will contact the patient/caregiver by telephone to conduct these visits. The patient/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. 
b Unscheduled visits may be necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any other reason (eg, before a rescue 
medication/procedure is used), as warranted. 
c  Assessments/procedures should be conducted in the following order: patient reported outcomes(other than patient assessment of injection pain), investigator 
assessments, and safety and laboratory assessments (including sample collection for ADA, PK, and biomarkers). Samples positive in the ADA assay will be 
analyzed in the neutralizing antibody (NAb) assay. PK and ADA samples to be collected prior to the administration of the drug . 
d  Patients or parents/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 patients or parents/caregivers have returned to the site. 
e  Patient-reported assessments are to be completed only by the patient. 
f   The questionnaires will be administered only to the subset of patients who speak fluently the language in which the questionnaire is presented (based on 
availability of validated translations in participating countries). 
g  ACQ-5 will be administered only to patients with ongoing asthma. 
h  Total Nasal Symptoms Score will be administered only to patients with medical history of allergic rhinitis for 7 days preceding visit 18 and visit 21. i  
The follow-up period will be for those patients who decline to enter the open-label extension study. 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
Page 60 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
 
10.3. 
Criteria for Treatment-Emergent Potentially Clinical Significant 
Value for Pediatric Patients 
 
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 
 
 
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. 
 
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 or 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. 
 
Creatinine 
≥132µmol/L and baseline < 132µmol/L 
(or ≥1.5 mg/dL and baseline <1.5 mg/dL) 
 
>=30% change from baseline 
Benichou C., 1994 
Two independent criteria 
 
 
 
 
 
 
 
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 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
Page 61 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
 
Parameter 
Treatment Emergent PCSV1 
Comments 
 
Uric Acid 
Hyperuricemia 
 
 
Hypouricemia 
 
 
Blood Urea 
Nitrogen 
>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) 
 
≥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) 
 
Triglycerides 
Fasting level ≥ 5.64 mmol/Land < 5.64 mmol/L Threshold for therapeutic intervention with 
at baseline 
(or ≥ 500 mg/dL and < 500 mg/dL at baseline) 
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) 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
Page 62 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
 
Parameter 
Treatment Emergent PCSV1 
Comments 
 
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 
<4.0 Giga/L and ≥4.0 Giga/L at baseline 
 
>13.5 Giga/L and ≤13.5 Giga/L at baseline 
 
Lymphocytes 
<0.6 Giga/L and ≥0.6 Giga/L at baseline 
 
>6.0 Giga/L and ≤6.0 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 
>1.2 Giga/L and <= 1.2 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 Two criteria are independent 
and >=100 g/L at baseline) 
 
≥20 g/dL and <20 g/dL at baseline (or >=200 
g/L and <200 g/L at baseline) 
 
Hematocrit 
For males: 
<0.37 v/v and ≥0.37 v/v at baseline; 
>0.52 v/v and ≤0.52 v/v at baseline 
 
For females: 
<0.33 v/v and ≥0.33 v/v at baseline 
<0.47 v/v and ≥0.47 v/v at baseline 
 
Two Criteria are independent 
 
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 


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Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
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VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
 
Parameter 
Treatment Emergent PCSV1 
Comments 
 
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                         Hypotension: SBP<5th percentile for gender, 
age and height; baseline >=5th percentile and 
decrease from baseline ≥20 mmHg 
 
Hypertension: At or above the 95th percentile 
for age, sex and height postbaseline; baseline < 
95% percentile; and increase from baseline 
≥20 mmHg 
 
DBP                        Hypotension: DBP<5th percentile for gender, 
age and height; baseline >=5th percentile and 
decrease from baseline ≥10 mmHg 
 
Hypertension: At or above the 95th percentile 
for age, sex and height postbaseline; baseline 
< 95% percentile and increase from baseline 
≥10 mmHg 
 
 
 
 
 
 
Based on definition of hypotension as 
SBP<5th percentile for gender, age and height 
 
 
Based on definition of Hypertension as 
average SBP ≥ 95th percentile for gender, 
age, and height on ≥ 3 occasions 
 
 
Based on definition of Hypertension as 
average DBP ≥ 95th percentile for gender, 
age, and height on ≥ 3 occasions 
 
Temperature 
Rectal, ear: >100.4 °F/38.0 °C 
Oral: >99.5 °F/37.5 °C 
Axillary: >99 °F/37.2 °C 
 
Respiratory rate 
<12 per minute and ≥12 per minute at baseline 
 
>20 per minute and ≤20 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 
≥200 ms and < 200 ms at baseline 
 
QRS 
≥110 ms & < 110 ms at baseline 


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Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
Page 64 of 68 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
 
Parameter 
Treatment Emergent PCSV1 
Comments 
 
QTc 
Absolute values (ms) 
Borderline: 
431-450 ms and < 431ms at baseline for Male; 
 
Bazett’s formula (measured QT interval 
divided by the square root of the R-R) to be 
applied to arrive at corrected QT value 
451-470 ms and < 451 ms at baseline for Female interval) 
 
Prolonged: 
>450 to <500 ms and <= 450 ms at baseline for 
Male; 
>470 to <500 ms and <= 470 ms at baseline for 
Female 
 
Additional: 
≥500 ms and < 500 ms at baseline 
 
Increase from baseline 
Borderline: Increase from baseline 30-60 ms 
Prolonged: Increase from baseline >60 ms 
 
QTc prolonged and QTc>60 ms are the 
PCSA to be identified in individual 
subjects/patients listings. 
 
independent criteria 


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Statistical Analysis Plan 
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April 16, 2018 
CONFIDENTIAL 
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VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
 
10.4. 
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 
- Severity = “severe” 
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 
-HLT = Helminthic infections NEC 
-HLT = Nematode infections 
-HLT = Trematode infection 
Suicidal behavior 
Include the following PTs 
•   Completed suicide 
•   Suicidal ideation 
•   Suicide attempt 
•   Depression suicidal 


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April 16, 2018 
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•   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 


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Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
CONFIDENTIAL 
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VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
 
10.5. 
Algorithm for RESCUE TREATMENTS 
 
1.   Not required to adjudicate rescue treatment: 
 
Post-baseline medications (WHODD-coded) given for indications consistent with AD1. 
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 
 Preferred Drug Name = Crisaborole, if used after day 29 
 ATC2 = CORTICOSTEROIDS, DERMATOLOGICAL PREPARATIONS, if 
used after day 29 
 
 Preferred Drug Name = Tacrolimus, if used after day 29 
 Preferred Drug Name = Pimecrolimus, if used day 29 
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 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-AD-1526 
April 16, 2018 
VV-RIM-00043851-1.0 Approved - 18 Apr 2018 GMT-5:00 
 
 
 
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. 
 
2.   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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 68 of 68 


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