Clinical trial NCT03912259
Conditions: Atopic Dermatitis
Sponsor: Sanofi
Start date: 2018-12-19; Completion date: 2020-02-14
Enrollment: 165 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To evaluate the efficacy of dupilumab monotherapy compared to placebo treatment in adult participants with moderate-to-severe atopic dermatitis (AD).

Secondary Objectives:

* To evaluate the safety of dupilumab monotherapy compared to placebo treatment in adult participants with moderate-to-severe AD.
* To evaluate the effect of dupilumab on improving patient reported outcomes (PROs).
* To evaluate dupilumab immunogenicity.

Detailed description:
The maximum study duration was 33 weeks per participants, including a screening period of up to 5 weeks, a 16-week randomized treatment period, and a 12-week follow-up period.

Arms: arm 1: Placebo matched to dupilumab 600 milligrams (mg) (loading dose), subcutaneously (SC) on Day 1 followed by placebo matched to dupilumab 300 mg once every 2 weeks (Q2W) for 16 weeks. arm 2: Dupilumab at a loading dose of 600 mg, SC on Day 1 followed by 300 mg, Q2W for 16 weeks.
Interventions: intervention 1: Dupilumab intervention 2: Placebo intervention 3: Emollient (moisturizer)
Intervention descriptions: intervention 1: Pharmaceutical form: solution,

Route of administration: SC intervention 2: Pharmaceutical form: solution,

Route of administration: SC intervention 3: Pharmaceutical form: cream,

Route of administration: topical use

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 01 
COMPOUND: dupilumab/SAR231893 
A randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of dupilumab in Chinese adult patients with moderate-to-severe atopic 
dermatitis 
STUDY NUMBER: EFC15116 
VERSION DATE / STATUS: Approval date (21-Jun-2018) / Approved 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 21-Jun-2018 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 20-Dec-2016 
EudraCT  
Not applicable 
IND Number 
Not applicable 
Version Number: 
1 
WHO universal trial number 
U1111-1189-5140 
Date: 
21-Jun-2018
Total number of pages: 
97 
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NCT03912259


Amended Clinical Trial Protocol No. 01 
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
Tel: 
Fax: 
E-mail:
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
Tel: 
Fax: 
E-mail:
SPONSOR 
Company: 
Address: 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
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Amended Clinical Trial Protocol No. 01 
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CLINICAL TRIAL SUMMARY 
COMPOUND: dupilumab/SAR231893
STUDY No: EFC15116 
TITLE 
A randomized, double-blind, placebo-controlled study to evaluate the efficacy 
and safety of dupilumab in Chinese adult patients with moderate-to-severe 
atopic dermatitis (AD) 
INVESTIGATOR/TRIAL LOCATION 
China 
PHASE OF DEVELOPMENT 
Phase 3 
STUDY OBJECTIVES 
Primary objective: 
The primary objective is to evaluate the efficacy of dupilumab monotherapy 
compared to placebo treatment in adult patients with moderate-to-severe AD. 
Secondary objectives: 
•
To evaluate the safety of dupilumab monotherapy compared to
placebo treatment in adult patients with moderate-to-severe AD.
•
To evaluate the effect of dupilumab on improving patient reported
outcomes (PROs)
•
To evaluate dupilumab immunogenicity
Other objectives: 
•
To evaluate dupilumab systemic exposure
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, parallel group study to 
assess the efficacy and safety of dupilumab monotherapy in adults with 
moderate-to-severe AD. The study duration includes 16-week treatment period 
and 12-week follow-up. 
After providing informed consent, patients will be assessed for study eligibility at 
the screening visit. Patients will undergo screening for 7-35 days prior to 
randomization. During the screening period, treatments for AD will be washed 
out, as applicable, according to eligibility requirements. Patients may be 
rescreened once if they fail the screening evaluation for reasons related to 
incidental transitory conditions. Patients will be required to apply moisturizers 
(emollients) 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 ratio to receive one 
of the following:  
•
Dupilumab 300 mg subcutaneously (SC) once every 2 weeks (q2w),
following a loading dose of 600 mg on Day 1,
OR
•
Matching placebo (double the amount of placebo on Day 1 to match
the loading dose) SC q2w
Randomization will be stratified by baseline disease severity (moderate 
[Investigator’s Global Assessment (IGA) = 3] versus severe [IGA = 4] AD). 
Following the initial dose of 600 mg, the investigational medicinal product (IMP) 
will be administered 300 mg at Weeks 2, 4, 6, 8, 10, 12, and 14. Patients will 
remain at the study site for a minimum of 30 minutes after each injection at the 
study site. Patients will have the option to self-administer the IMP (or have a 
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caregiver administer the IMP) outside the study site during weeks in which no 
clinic visit is scheduled (ie, Weeks 6, 10, and 14). Patients (and/or caregivers) 
will be trained on injecting the IMP at Visit 2 (Day 1) through Visit 4 (Week 4), or 
until competency has been demonstrated. Patients who do not want to self-
inject may have the clinic staff administer all the IMP injections in the clinic. 
During the 16-week treatment period, patients will have study visits at Weeks 0, 
2, 4, 8, 12, and 16. The end of treatment visit will occur at Week 16, 2 weeks 
after the last dose of the IMP. The primary endpoint will be determined at 
Week 16. 
Follow-up visits will occur every 4 weeks from Week 20 through Week 28. The 
duration of the 12-week follow-up period is based on the time expected for drug 
levels to reach below the lower limit of quantification in most patients after the 
last dose of dupilumab. The end of study visit will occur at Week 28. 
Safety laboratory tests, collection of samples for dupilumab concentrations and 
anti-drug antibodies (ADA), and clinical assessments will be performed at 
specified clinic visits.  
STUDY POPULATION  
Main selection criteria 
The study population consists of adults 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), see below: 
Inclusion criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
I 01. 
Male or female, 18 years or older  
I 02. 
Atopic dermatitis (according to American Academy of Dermatology 
Consensus Criteria, 2014) (1) that has been present for at least 
3 years before the screening visit  
I 03. 
Eczema Area and Severity Index (EASI) score ≥16 at the screening 
and baseline visits  
I 04. 
Investigator’s Global Assessment (IGA) score ≥3 (on the 0 to 4 IGA 
scale, in which 3 is moderate and 4 is severe) at the screening and 
baseline visits  
I 05. 
≥10% body surface area (BSA) of AD involvement at the screening 
and baseline visits 
I 06. 
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.  
I 07. 
Documented recent history (within 6 months before the screening visit) 
of inadequate response to treatment with topical medications or for 
whom topical treatments are otherwise medically inadvisable (eg, 
because of important side effects or safety risks);  
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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 topical corticosteroids (TCS) of medium to higher potency  
(± topical calcineurin inhibitors [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 for AD, of sufficient 
dose and duration, 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, 
subject to approval by the sponsor. 
- 
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 re-screened after such 
documentation is obtained (ie, patients are shown to fail a 28-day 
course of medium-to-higher potency TCS [±TCI]). 
I 08. 
Have applied a stable dose of topical emollient (moisturizer) twice daily 
for at least the 7 consecutive days immediately before the baseline 
visit (NOTE: See E 07 for limitations regarding emollients) (See 
background treatment with topical emollient inSection 8.2) 
I 09. 
Willing and able to comply with all clinic visits and study-related 
procedures  
I 10. 
Able to understand and complete study-related questionnaires  
I 11. 
Signed written informed consent 
Exclusion criteria 
E 01. 
Participation in a prior dupilumab clinical study 
E 02. 
Treatment with an investigational drug within 8 weeks or within 
5 half-lives (if known), whichever is longer, before the baseline visit 
E 03. 
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: 
- 
Immunosuppressive/immunomodulating drugs (eg, systemic 
corticosteroids, cyclosporine, mycophenolate-mofetil, interferon-
gamma [IFN-γ], Janus kinase inhibitors, azathioprine, and 
methotrexate) 
- 
Phototherapy for AD 
E 04. 
Treatment with TCS or TCI within 1 week before the baseline visit 
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E 05. 
Treatment with systemic traditional Chinese medicine (TCM) within 
4 weeks before the baseline visit or treatment with topical TCM within 
1 week before the baseline visit. 
E 06. 
Treatment with biologics as follows: 
-
Any cell-depleting agents including but not limited to rituximab:
within 6 months before the baseline visit or until lymphocyte
count returns to normal, whichever is longer
-
Other biologics: within 5 half-lives (if known) or 16 weeks prior to
baseline visit, whichever is longer
E 07. 
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) 
E 08. 
Regular use (more than 2 visits per week) of a tanning booth/parlor 
within 4 weeks of the baseline visit 
E 09. 
Planned or anticipated use of any prohibited medications (see 
Section 8.8.1) and procedures during study treatment 
E 10. 
Treatment with a live (attenuated) vaccine within 12 weeks before the 
baseline visit 
E 11. 
Active chronic or acute infection requiring treatment with systemic 
antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals 
within 2 weeks before the baseline visit, or superficial skin infections 
within 1 week before the baseline visit 
NOTE: patients may be rescreened after infection resolves 
E 12. 
Known or suspected history of immunosuppression, including history 
of invasive opportunistic infections (eg, histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystosis, and aspergillosis) despite 
infection resolution, or unusually frequent, recurrent, or prolonged 
infections, per Investigator’s judgment 
E 13. 
Active tuberculosis (TB), latent untreated TB, or a history of potentially 
incompletely treated TB or non-TB mycobacterial infection, unless it is 
well documented by a specialist that the patient has been adequately 
treated and can now start treatment with a biologic agent, in the 
medical judgment of the Investigator and/or infectious disease 
specialist. Tuberculosis testing would be performed according to local 
guidelines if required by regulatory authorities or ethics commitees 
E 14. 
History of human immunodeficiency virus (HIV) infection or positive 
HIV serology at screening 
E 15. 
Active hepatitis or patients with positive hepatitis B surface antigen 
(HBsAg), or patients with positive hepatitis B core antibody (HBcAb) 
plus positive hepatitis B virus (HBV) DNA, or positive hepatitis C virus 
(HCV) antibody (confirmed with presence of HCV RNA if needed) at 
screening. 
E 16. 
At baseline, presence of any conditions listed as criteria for IMP 
discontinuation (see Section 10.3) 
E 17. 
Presence of skin comorbidities that may interfere with study 
assessments 
E 18. 
History of malignancy within 5 years before the screening visit, except 
completely treated in situ carcinoma of the cervix, completely treated 
and resolved non-metastatic squamous or basal cell carcinoma of the 
skin 
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E 19. 
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 
E 20. 
History of alcohol or drug abuse within 2 years of the screening visit 
E 21. 
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 (Glycated hemoglobin 
[HbA1C] ≥9%), patients with cardiovascular conditions (eg, stage III or 
IV cardiac failure according to the New York Heart Association 
classification), severe renal conditions (eg, patients on dialysis), 
hepatobiliary conditions (eg, Child-Pugh class B or C), neurological 
conditions (eg, demyelinating diseases), active major autoimmune 
diseases (eg, lupus, inflammatory bowel disease, and rheumatoid 
arthritis), and 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 [CRFs], etc) 
E 22. 
Any other medical or psychological condition (including relevant 
laboratory abnormalities at screening) that, in the opinion of the 
Investigator, may 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, CRFs, etc) 
E 23. 
Planned or anticipated major surgical procedure during the patient’s 
participation in this study 
E 24. 
Patient is a member of the investigational team or his/her immediate 
family 
E 25. 
Pregnant or breastfeeding women, or women planning to become 
pregnant or breastfeed during the study 
E 26. 
Woman of childbearing potential (WOCBP) not protected by 
highly-effective method(s) of birth control and/or who are unwilling or 
unable to be tested for pregnancy (see contraceptive guidance in 
Appendix A) 
Total expected number of patients 
160 patients 
STUDY TREATMENTS 
 
Investigational medicinal products 
Formulation 
Dupilumab or matching placebo 
Dupilumab: 150 mg/mL in a prefilled glass syringe to deliver 300 mg in 2 mL; 
Placebo: prefilled syringe to deliver 2 mL 
Route of administration 
Subcutaneous 
Dose regimen 
Patients will be randomized 1:1 to the following regimen from Week 0 through 
Week 14: 
• 
Dupilumab 300 mg SC q2w following a 600 mg (ie, two 300 mg SC 
injections) loading dose 
• 
Placebo SC q2w in prefilled syringe to deliver 2 mL following a 
placebo loading dose  
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Noninvestigational medicinal 
product 
 
Background treatment  
Moisturizers (emollients) 
Rescue treatment 
If medically necessary (ie, to control intolerable AD symptoms), rescue 
treatment for AD is allowed (see Section 8.2.2).  
Formulation 
Moisturizers (emollients): topical formulation 
Rescue treatment: referring to label 
Route of administration 
Moisturizers (emollients): topical use 
Rescue treatment: referring to label 
Dose regimen 
Moisturizers (emollients): twice daily for at least 7 days before randomization 
and to continue the treatment throughout the study. 
Rescue treatment: referring to label 
ENDPOINTS 
 
Primary endpoint 
Proportion of patients with both an IGA 0 to 1 (on a 5-point scale) and a 
reduction from baseline of ≥2 points at Week 16 
Secondary endpoints 
Efficacy: 
• 
Proportion of patients with EASI-75 response (reduction of EASI score 
by ≥75% from baseline) at Week 16 
• 
Proportion of patients with reduction of weekly average of peak daily 
Pruritus NRS ≥4 from baseline to Week 16 
• 
Proportion of patients with reduction of weekly average of peak daily 
Pruritus NRS ≥3 from baseline to Week 16 
• 
Percent change from baseline to Week 16 in weekly average of peak 
daily Pruritus NRS 
• 
Change from baseline to Week 16 in weekly average of peak daily 
Pruritus NRS 
• 
Percent change in EASI score from baseline to Week 16 
• 
Change from baseline to Week 16 in percent BSA of AD involvement 
• 
Change from baseline to Week 16 in Dermatology Life Quality Index 
(DLQI) 
• 
Change from baseline to Week 16 in Patient Oriented Eczema 
Measure (POEM) 
• 
Percent change from baseline to Week 2 in weekly average of peak 
daily Pruritus NRS 
• 
Absolute and percent change from baseline to Week 16 in EuroQol 
five dimensions questionnaire (EQ-5D) 
• 
Proportion of patients who achieve reduction of IGA score by ≥2 from 
baseline to Week 16 
• 
The proportion of patients with EASI-50 (≥50% improvement from 
baseline) at Week 16 
• 
The proportion of patients with EASI-90 (≥90% improvement from 
baseline) at Week 16 
• 
Proportion of patients achieving IGA 0 to 1 and a reduction of 
≥2 points from baseline through Week 16 
• 
Absolute and percent changes in EASI score from baseline through 
Week 16 
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• 
Absolute and percent changes in weekly average of peak daily 
pruritus NRS score from baseline through Week 16 
• 
The proportion of patients who responded “absence of pruritus” or 
“mild pruritus” in the pruritus categorical scale at Week 16 
• 
Number of days and proportion of patients with sick leave/missed 
school days 
Safety: 
Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), 
adverse events of specific interest (AESIs), clinical laboratory evaluations, vital 
signs, physical examination, weight and height, electrocardiogram (ECG). 
Immunogenicity. 
ASSESSMENT SCHEDULE 
Screening period: 7-35 days 
Randomized treatment period: 16 weeks 
Post-treatment period: 12 weeks 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
A total of 160 patients (with a randomization ratio of 1:1, 80 patients in each of 
the dupilumab 300 mg q2w and the placebo groups) will be enrolled in this 
study.  
The study will have 94% power to detect the difference between dupilumab and 
the placebo. It is based on the following assumptions: 
• 
The percentages of patients who achieve an IGA score of 0 to 1 and a 
reduction from baseline ≥2 points at Week 16 are 37% and 12% for 
dupilumab and placebo, respectively. 
• 
A two-sided continuity corrected Chi-square test with the significance 
level of 0.05. 
Analysis population: 
The intent-to-treat (ITT) population includes all randomized patients. Efficacy 
analysis will be based on treatment allocated at randomization (as randomized). 
The per protocol (PP) population includes all patients in the ITT population 
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. The criteria of major protocol deviations are defined as the 
following: 
• 
A patient who does not receive treatment as randomized 
• 
Any major violations of efficacy-related entry criteria  
• 
The percentage of a patient’s compliance with the IMP injection is 
<80% or >120% of the scheduled doses during the study treatment 
period 
The safety population includes all randomized patients who received any IMP; it 
is based on the treatment patients actually received (as treated).  
Primary analysis: 
The Cochran-Mantel-Haenszel test adjusted by baseline disease severity 
(moderate or severe) will be used for the percentage of patients with IGA 0 or 1 
and a reduction from baseline of ≥2 points at Week 16 on the ITT population. If 
rescue medication or procedure is used, the patient will be specified as a non-
responder from the time the rescue is used. If a patient withdraws from the 
study, this patient will be counted as a non-responder for endpoints after 
withdrawal. 
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Analysis of secondary endpoints: 
For binary endpoints, the secondary efficacy analysis will use the same 
approach as that used for the primary analysis. To account for the impact of 
rescue medication or procedure on the efficacy effect: for continuous efficacy 
endpoints, if a patient receives rescue medication or procedure that specifies 
the patient as a non-responder according to the above rules for binary efficacy 
endpoints, the data collected after rescue medication or procedure is initiated 
will be treated as missing; if a patient withdraws from the study, this patient will 
be counted as a non-responder for endpoints after withdrawal.  
The continuous efficacy endpoints will be analyzed using the multiple imputation 
(MI) with analysis of covariance (ANCOVA) model with treatment, randomization 
strata (disease severity), and relevant baseline value included in the model as 
the primary analysis. Patient’s efficacy data after rescue medication up to 
Week 16 will be set to missing and then imputed by the MI method. 
Safety Analysis: Will be based on the safety population.This includes TEAEs 
and other safety information (ie, clinical laboratory evaluations, vital signs, and 
ECG results). A summary of safety results for each treatment group will be 
presented. Anti-drug antibody results will be presented. 
DURATION OF STUDY PERIOD (per 
patient)  
28 weeks, including 16-week treatment period and 12-week follow-up. The total 
study duration will be up to 33 weeks. 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
Figure 1 - Graphical Study Design 
Screening:1-5 weeks  
 
 
Treatment1: 16 weeks 
 
Follow-up: 12 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Patients will receive a loading dose of the IMP on Day 1 and then receive the IMP every two weeks during the subsequent 14 weeks. 
IMP = investigational medicinal product, q2w = once every 2 weeks. 
Screening 
Dupilumab 300 mg q2w 
(80 patients) 
Placebo q2w 
(80 patients) 
Follow-up 
D1 (V2) : Randomization 
D-7 to D-35 
D 113(V7) End of treatment 
D197(V10) End of Study 
Primary  
Endpoint 
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1.2 
STUDY FLOW CHART 
Table 1 - Schedule of Events  
Study Procedure 
SCR 
RND 
Treatment 
EOT 
Follow-up 
EOS 
VISIT(V) 
V1 
V2 
V3 
V4 
 
V5 
 
V6 
 
V7 
V8 
V9 
V10 
Week(W) 
 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
Day (D) 
D-7 to D-35 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
Visit Window (d) 
 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
Unscheduled 
visita (if 
applicable) 
Early 
termination 
(if applicable) 
Screening/baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training on pruritus reporting systemb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection training/observation 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Administer IMPc 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Dispense/review patient dosing diaryd 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
IMP dispensation/accounte 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Con meds/procedures 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Efficacyf,g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus NRS (daily)b 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Pruritus categorical scale (daily)b 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
POEM, DLQIh 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
EQ-5Dh 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
IGA, EASI, BSA 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Assess sick-leave/missed school days 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Photograph AD area (selected sites)i 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
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Study Procedure 
SCR 
RND 
Treatment 
EOT 
Follow-up 
EOS 
VISIT(V) 
V1 
V2 
V3 
V4 
 
V5 
 
V6 
 
V7 
V8 
V9 
V10 
Week(W) 
 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
Day (D) 
D-7 to D-35 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
Visit Window (d) 
 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
Unscheduled 
visita (if 
applicable) 
Early 
termination 
(if applicable) 
Safetyf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Physical examinationj 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Adverse events 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Laboratory Testingf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV ab, HBsAg, HbsAb, HBcAbk, and 
Hep C Abk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistry 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Pregnancy test (WOCBP only) 
Serum 
Urine 
 
Urine 
 
Urine 
 
Urine 
 
Serum 
 
 
Serum 
Urine 
Serum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, anti-dsDNA (if ANA positive) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/Drug Concentration and ADA Samplesf 
Functional dupilumab PK sample 
 
X 
  
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
Anti-dupilumab antibody sample 
 
X 
  
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
Abbreviations: AD = atopic dermatitis, ADA = anti-drug antibody, ANA = anti-nuclear antibody, anti-dsDNA = anti-double-strand DNA, BSA = body surface area, DLQI = Dermatology Life Quality Index, EASI = Eczema 
Area and Severity Index, EQ-5D = EuroQol five dimensions questionnaire, EOS = end-of-study, EOT = end-of-treatment, HBcAb = hepatitis B core antibody, HBsAb = hepatitis B surface antibody, HBsAg = hepatitis B 
surface antigen, Hep C Ab = hepatitis C antibody, HIV ab = human immunodeficiency virus antibody, IGA = investigator global assessment, 
, IMP = investigational medicinal product,  
NRS = numerical rating scale, PK = pharmacokinetics, POEM = Patient Oriented Eczema Measure, RND = randomization, SCR = screening, 
, WOCBP = woman of 
child bearing potential. 
a During an unscheduled visit, any of the study procedures noted may be performed, but not all are required. 
b Patients will be trained at the screening visit on using the appropriate diary system to report pruritus daily and provide other information as required. Investigators will check patients’ reports at each visit.  
c Patients will be monitored at the study site for a minimum of 30 minutes after the IMP administration for any signs or symptoms of a hypersensitivity reaction. Adverse event assessments will be done at 30 minutes 
(±10 minutes) post-injection. 
d For patients who choose to self-administer the IMP at Weeks 6, 10, and 14, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
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e For patients who choose to self-administer the IMP, the IMP will be dispensed to the patient for the dose that will be administered before the next clinic visit. Patients will return the original kit box for the prefilled 
syringe at each clinic visit. 
f 
To be collected before the injection of the IMP. 
g Assessments/procedures should be conducted in the following order: patient reported outcomes (PROs), Investigator assessments, safety and laboratory assessments, and then administration of the IMP. 
h All questionnaires will be administered before any invasive procedures (blood draws, IMP injection, etc). 
i 
Selected sites only - photograph AD area 
j 
If patients have any symptom or sign of ocular surface diseases, eg, conjunctivitis and blepharitis, at screening or during study period, ophthalmological examinations should be done. 
k Heptitis B virus (HBV) DNA testing should be performed during screening period for patients presenting with HBsAg (-) and HBcAb (+).In case of results showing HCV Ab positive, an HCV RNA testing may be 
performed to rule out a false positivity, if the Investigator believes the patient is a false positive. 
 
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2 
TABLE OF CONTENTS 
1 
FLOW CHARTS.............................................................................................................................11 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................11 
1.2 
STUDY FLOW CHART ..................................................................................................................12 
2 
TABLE OF CONTENTS ................................................................................................................15 
3 
LIST OF ABBREVIATIONS ..........................................................................................................21 
4 
INTRODUCTION AND RATIONALE.............................................................................................23 
4.1 
INTRODUCTION............................................................................................................................23 
4.2 
RATIONALE...................................................................................................................................24 
4.2.1 
Rationale for Study Design ............................................................................................................24 
4.2.2 
Rationale for Dose Selection .........................................................................................................25 
5 
STUDY OBJECTIVES ...................................................................................................................26 
5.1 
PRIMARY.......................................................................................................................................26 
5.2 
SECONDARY ................................................................................................................................26 
5.3 
OTHER OBJECTIVES ...................................................................................................................26 
6 
STUDY DESIGN ............................................................................................................................27 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................27 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................28 
6.2.1 
Duration of study participation for each patient .............................................................................28 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................28 
6.2.2.1 
Premature termination of the study................................................................................................28 
6.2.2.2 
Close-out of a site ..........................................................................................................................28 
6.3 
INTERIM ANALYSIS......................................................................................................................28 
6.4 
STUDY COMMITTEES..................................................................................................................28 
7 
SELECTION OF PATIENTS..........................................................................................................29 
7.1 
INCLUSION CRITERIA..................................................................................................................29 
7.2 
EXCLUSION CRITERIA ................................................................................................................30 
8 
STUDY TREATMENTS .................................................................................................................33 
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8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................33 
8.1.1 
Dupilumab......................................................................................................................................33 
8.1.2 
Placebo ..........................................................................................................................................33 
8.1.3 
Dosing schedule.............................................................................................................................33 
8.1.4 
Dose modification and investigational medicinal product discontinuation rules ............................33 
8.1.4.1 
Drug modification ...........................................................................................................................33 
8.1.4.2 
Investigational medicinal product discontinuation..........................................................................34 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS.....................................................................34 
8.2.1 
Background treatment....................................................................................................................34 
8.2.2 
Rescue treatment...........................................................................................................................34 
8.3 
BLINDING PROCEDURES............................................................................................................35 
8.3.1 
Methods of blinding........................................................................................................................35 
8.3.2 
Randomization code breaking during the study.............................................................................35 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................35 
8.5 
PACKAGING AND LABELING ......................................................................................................36 
8.6 
STORAGE CONDITIONS..............................................................................................................36 
8.7 
RESPONSIBLILITIES ....................................................................................................................37 
8.7.1 
Treatment accountability and compliance......................................................................................37 
8.7.2 
Return and/or destruction of treatments ........................................................................................38 
8.8 
CONCOMITANT MEDICATION.....................................................................................................38 
8.8.1 
Prohibited medications and procedures.........................................................................................38 
8.8.2 
Permitted medications and procedures .........................................................................................39 
8.8.2.1 
Prohibited concomitant medications or procedures as rescue......................................................39 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................40 
9.1 
PRIMARY ENDPOINT ...................................................................................................................40 
9.1.1 
Investigator’s global assessment...................................................................................................40 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................40 
9.2.1 
Efficacy endpoints..........................................................................................................................40 
9.2.1.1 
Eczema area and severity index....................................................................................................41 
9.2.1.2 
Patient assessment of pruritus: numerical rating scale .................................................................41 
9.2.1.3 
Body surface area involvement of atopic dermatitis ......................................................................42 
9.2.1.4 
Patient-reported dermatology life quality index..............................................................................42 
9.2.1.5 
Patient oriented eczema measure .................................................................................................42 
9.2.1.6 
Patient-assessed EQ-5D ...............................................................................................................42 
9.2.1.7 
Patient-assessed pruritus categorical scale ..................................................................................42 
9.2.1.8 
Sick Leave/Missed School Days....................................................................................................43 
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9.2.1.9 
Atopic Dermatitis Area Photographs..............................................................................................43 
9.2.2 
Safety endpoints ............................................................................................................................43 
9.2.2.1 
Adverse events ..............................................................................................................................43 
9.2.2.2 
Laboratory safety variables............................................................................................................43 
9.2.2.3 
Vital Signs ......................................................................................................................................44 
9.2.2.4 
Physical examination .....................................................................................................................44 
9.2.2.5 
Weight and Height..........................................................................................................................44 
9.2.2.6 
ECG ...............................................................................................................................................45 
9.2.2.7 
Immunogenicity..............................................................................................................................45 
9.3 
OTHER ENDPOINTS.....................................................................................................................46 
9.3.1 
Pharmacokinetics parameters .......................................................................................................46 
9.3.1.1 
Pharmacokinetic measurements....................................................................................................46 
9.3.1.2 
Pharmacokinetic parameters .........................................................................................................46 
9.3.2 
Pharmacodynamics........................................................................................................................46 
9.3.2.1 
Pharmacodynamic measurements ................................................................................................46 
9.3.2.2 
Pharmacodynamic variables..........................................................................................................47 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................47 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................47 
10 
STUDY PROCEDURES ................................................................................................................48 
10.1 
VISIT SCHEDULE..........................................................................................................................48 
10.1.1 
Visit 1/Screening/Day -7 to -35 ......................................................................................................48 
10.1.2 
Treatment Period ...........................................................................................................................49 
10.1.2.1 Visit 2/Baseline/Day 1 (Randomization).........................................................................................49 
10.1.2.2 Visit 3/Week 2/Day 15 (±3 days)....................................................................................................50 
10.1.2.3 Visit 4/Week 4/Day 29 (±3 days)....................................................................................................50 
10.1.2.4 Visit 5/ Week 8/Day 57 (±3 days)...................................................................................................51 
10.1.2.5 Visit 6/Week 12/Day 85 (±3 days)..................................................................................................52 
10.1.2.6 Visit 7/End of Treatment/Week 16/Day 113 (±3 days)...................................................................53 
10.1.3 
Follow-up Period ............................................................................................................................53 
10.1.3.1 Visit 8/Week 20/Day 141 (±3 days)................................................................................................53 
10.1.3.2 Visit 9/Week 24/Day 169 (±3 days)................................................................................................54 
10.1.4 
Visit 10/End of Study Visit/Week 28/Day 197 (±3 days)................................................................54 
10.1.5 
Early Termination Visit ...................................................................................................................55 
10.1.6 
Unscheduled Visits.........................................................................................................................56 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................57 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................57 
10.3.1 
Temporary treatment discontinuation with investigational medicinal products..............................57 
10.3.2 
Permanent treatment discontinuation with investigational medicinal products .............................58 
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10.3.3 
List of criteria for permanent treatment discontinuation.................................................................58 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................58 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................59 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................60 
10.4.1 
Definitions of adverse events.........................................................................................................60 
10.4.1.1 Adverse event ................................................................................................................................60 
10.4.1.2 Serious adverse event ...................................................................................................................60 
10.4.1.3 Adverse event of special interest...................................................................................................61 
10.4.2 
General guidelines for reporting adverse events ...........................................................................61 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................62 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................63 
10.4.5 
Guidelines for management of specific laboratory abnormalities ..................................................63 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................63 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................64 
10.6.1 
Hypersensitivity..............................................................................................................................64 
10.6.2 
Severe injection site reactions .......................................................................................................64 
10.6.3 
Infections, including parasitic infections.........................................................................................65 
10.6.4 
Elevated liver function tests ...........................................................................................................65 
10.6.5 
Ocular surface disease ..................................................................................................................66 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................66 
11 
STATISTICAL CONSIDERATIONS..............................................................................................67 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................67 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................67 
11.3 
ANALYSIS POPULATIONS...........................................................................................................67 
11.3.1 
Efficacy population.........................................................................................................................67 
11.3.2 
Safety population ...........................................................................................................................68 
11.3.3 
Other analysis populations.............................................................................................................68 
11.4 
STATISTICAL METHODS .............................................................................................................68 
11.4.1 
Demography and Baseline Characteristics....................................................................................68 
11.4.2 
Extent of study treatment exposure and compliance.....................................................................69 
11.4.2.1 Extent of investigational medicinal product exposure....................................................................69 
11.4.2.2 Compliance ....................................................................................................................................69 
11.4.3 
Analyses of efficacy endpoints.......................................................................................................69 
11.4.3.1 Analysis of primary efficacy endpoint.............................................................................................69 
11.4.3.2 Analyses of secondary efficacy endpoints.....................................................................................70 
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11.4.3.3 Multiplicity considerations ..............................................................................................................71 
11.4.4 
Analyses of safety data..................................................................................................................71 
11.4.4.1 Adverse Events..............................................................................................................................72 
11.4.4.2 Clinical laboratory evaluations .......................................................................................................73 
11.4.4.3 Vital signs.......................................................................................................................................73 
11.4.4.4 Analysis of anti-drug antibody variables ........................................................................................73 
11.4.5 
Analysis of pharmacokinetic variables...........................................................................................73 
11.4.6 
Analysis of quality of life and health economics variables.............................................................74 
11.4.7 
...................................................................................................................74 
11.4.8 
Data Handling Conventions ...........................................................................................................74 
11.5 
INTERIM ANALYSIS......................................................................................................................74 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................75 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................75 
12.2 
INFORMED CONSENT .................................................................................................................75 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................75 
13 
STUDY MONITORING...................................................................................................................77 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS .........................................................................77 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................77 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................78 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................78 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................78 
14 
ADDITIONAL REQUIREMENTS...................................................................................................79 
14.1 
CURRICULUM VITAE....................................................................................................................79 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................79 
14.3 
CONFIDENTIALITY .......................................................................................................................79 
14.4 
PROPERTY RIGHTS.....................................................................................................................80 
14.5 
DATA PROTECTION.....................................................................................................................80 
14.6 
INSURANCE COMPENSATION....................................................................................................80 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................81 
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14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................81 
14.8.1 
By the sponsor ...............................................................................................................................81 
14.8.2 
By the Investigator .........................................................................................................................82 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................82 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................82 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................83 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................84 
17 
APPENDICES................................................................................................................................86 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION......................................................................................................87 
APPENDIX B 
LIST OF PROHIBITED LIVE, ATTENUATED VACCINES..................................................90 
APPENDIX C DEFINITION OF ANAPHYLAXIS ........................................................................................91 
APPENDIX D OPPORTUNISTIC INFECTION...........................................................................................92 
APPENDIX E 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI......................................................................................................93 
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3 
LIST OF ABBREVIATIONS 
 
AD: 
atopic dermatitis 
ADA: 
anti-drug antibody 
ADR: 
adverse drug reaction 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANA: 
anti-nuclear antibody 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
BSA: 
body surface area 
CFDA: 
China Food and Drug Administration 
CPK: 
creatine phosphokinase 
CRF: 
case report form 
CV: 
curriculum vitae 
CYP: 
cytochrome P450 
DLQI: 
dermatology life quality index  
DRF: 
discrepancy resolution form 
EASI: 
eczema area and severity index 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EQ-5D: 
EuroQol five dimensions questionnaire 
EQVAS: 
EQ visual analogue scale 
FSH: 
follicle stimulating hormone 
GCP: 
good clinical practice 
GSO: 
Global Safety Officer 
HbA1C: 
glycated hemoglobin 
HBcAb: 
hepatitis B core antibody 
HBsAg: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HCV: 
hepatitis C virus 
HIV: 
human immunodeficiency virus 
HLGT: 
high-level group term 
HLT: 
high level term 
HRT: 
hormonal replacement therapy 
IB: 
Investigator’s Brochure 
ICF: 
informed consent form 
ICH: 
International Conference on Harmonization 
IEC: 
Independent Ethics Committee 
IFN-γ: 
interferon-gamma 
IGA: 
Investigator’s Global Assessment 
IgE: 
immunoglobulin E  
IL: 
interleukin 
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IL-4Rα: 
IL-4 receptor alpha 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ISR: 
injection site reaction 
ITT: 
intent-to-treat 
LDH: 
lactate dehydrogenase 
LOCF: 
last observation carried forward 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MI: 
multiple imputation 
MMRM: 
mixed-effect model repeated measures 
NIMP: 
noninvestigational medicinal product 
NRS: 
numerical rating scale 
PCP: 
pneumocystis pneumonia 
PCSA: 
potentially clinically significant abnormality 
PK: 
pharmacokinetic 
POEM: 
patient oriented eczema measure 
PP: 
per protocol 
PRO: 
patient reported outcome 
PT: 
preferred term 
q2w: 
every 2 weeks 
QOL: 
quality of life 
RBC: 
red blood cell 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SIT: 
allergen-specific immunotherapy 
SOC: 
system organ class 
SUSAR: 
suspected unexpected adverse drug reaction 
TARC: 
thymus and activation regulated chemokine  
TB: 
tuberculosis 
TCI: 
topical calcineurin inhibitors 
TCM: 
Traditional Chinese Medicine 
TCS: 
topical corticosteroids  
TEAE: 
treatment-emergent adverse event 
Th1: 
type 1 helper T cell 
Th2: 
type 2 helper T cell 
TNF: 
tumor necrosis factor 
ULN: 
upper limit of normal 
WBC: 
white blood cell 
WOCBP: 
woman of childbearing potential 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Atopic dermatitis (AD) is a chronic/relapsing inflammatory skin disease characterized by intense 
pruritus (ie, itchiness), xerosis (skin dryness), and eczematous lesions whose features include 
erythema, infiltration/papulation, oozing with crusting, excoriations, and lichenification. It is often 
associated with other atopic disorders, such as allergic rhinitis and asthma. Severe disease can be 
extremely disabling due to several factors: major psychological problems, significant sleep loss, 
and impaired quality of life (QOL) that lead to a high socioeconomic cost. An estimated 2% to 
10% of adults worldwide are affected by AD (2). 
The pathophysiology of AD is influenced by a complex interplay between inflammation, 
environmental factors, genetics, and skin barrier dysfunction. 
Skin-infiltrating lymphocytes are thought to play a pivotal role in the initiation and amplification 
of atopic inflammation. The key cells involved in the pathophysiologic mechanism of AD are 
classified into 4 general subgroups. First, dendritic cell subtypes including Langerhans cells and 
inflammatory dendritic epithelial cells polarize T-helper cells via Immunoglobulin E (IgE)- and 
non-IgE-mediated mechanisms. Dendritic cells in the skin take up and present allergens to 
lymphocytes, causing a Type 2 helper T cell (Th2) polarization and subsequent release of 
pro-inflammatory cytokines, which include interleukin (IL)-4, IL-5, and IL-13. The T-helper cells 
are the second group of cells. In acute exudative skin lesions, chemokine “C” receptor (CCR4+) 
Th2 cells are abundant and secrete cytokines IL-4, IL-13, and IL-5, whereas Type 1 helper T cells 
(Th1), which secrete IFN-γ, are also seen in chronic, lichenified lesions. Activated eosinophils are 
the third group of cells, causing local inflammation at lesional sites. Keratinocytes are the fourth 
cell-type involved in the pathophysiology of AD. These skin cells express high levels of the Th2 
polarizing cytokine and thymic stromal lymphopoietin in AD lesions, which may amplify and 
sustain the allergic response. 
The goal in treating AD is reducing skin inflammation. Therapy has been focused on trying to 
control the T helper cell response. Topical corticosteroids (TCS) are overwhelmingly the most 
frequently prescribed class of drugs. However, long-term application of TCS is not recommended 
because of the risk of skin atrophy, dyspigmentation, acneiform eruptions, and risks associated 
with systemic absorption (eg, hypothalamic pituitary axis effects, and Cushing’s disease). Topical 
calcineurin inhibitors (TCI) are generally effective and safe as short-term treatments, but concerns 
of skin malignancies and increased risk of lymphomas have prompted regulatory authorities to 
require a warning regarding the long-term safety of topical tacrolimus and pimecrolimus in their 
prescribing information. Repeated application of any topical therapy over a long period of time or 
too large surface areas also leads to reduced patient compliance. First generation antihistamines 
are widely prescribed for acute symptomatic treatment of pruritus, although their effectiveness is 
limited and largely attributed to their sedating effect. Oral immunosuppressants (3) and 
glucocorticoids are effective, but are sometimes associated with severe toxicity and side effects, 
thus limiting their use to short courses and/or intermittent therapy. Diabetes, hypertension, and 
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osteoporosis are side effects associated with systemic corticosteroids, and there is also the risk of 
rebound after steroid discontinuation.  
Cyclosporine, a current therapy for severe AD in some regions, is a potent immunosuppressant 
affecting both humoral and cellular immune responses. This results in increased susceptibility to 
infections and decreased cancer immunosurveillance. Other commonly recognized toxicities 
include hypertension and impaired renal and hepatic function. In addition, cyclosporine interacts 
with other commonly used medicines potentially affecting their metabolism and effect. Patients’ 
disease often rebounds when the treatment is stopped, especially after the administration of 
systemic glucocorticoids (4, 5, 6). Biological agents, including anti-tumor necrosis factor (TNF) α 
(infliximab and etanercept), anti-IgE (omalizumab), anti-IL-5 (mepolizumab), and anti-CD11a 
(efalizumab), have generally been ineffective in clinical trials (7, 8, 9). Therefore, there exists a 
significant unmet medical need for an alternative treatment for AD. 
Up-regulation of IL-4 and IL-13 has been implicated as an important inflammatory component of 
AD disease progression. Dupilumab, a fully human monoclonal antibody, is directed against the 
IL-4 receptor alpha subunit (IL-4Rα), which is a component of IL-4 receptors Type I and Type II, 
as well as the IL-13 receptor system. The binding of dupilumab to IL-4Rα results in the blockade 
of both IL-4 and IL-13 signal transduction. 
Dupilumab is being developed for the treatment of moderate-to-severe AD in patients intolerant 
of, or not adequately controlled with, topical treatments. This population includes patients who are 
often treated with systemic corticosteroids, as well as other non-selective immunosuppressants, 
including cyclosporine, which are associated with significant toxicities. Dupilumab is being 
developed as a potential alternative to oral corticosteroids, calcineurin inhibitors, and other 
systemic immonosuppressive drugs, which are used for treatment of AD patients and have 
numerous, considerable adverse drug reactions (ADRs), and may increase the risk of serious 
infection. A more focused immunomodulatory agent such as dupilumab may have more limited 
effects on the immune system and potentially fewer ADRs. 
Data with dupilumab have, to date, demonstrated efficacy, safety, and tolerability in a patient 
population with moderate-to-severe AD. In global phase 2 and phase 3 studies, treatment with 
dupilumab monotherapy consistently and significantly cleared or reduced the extent and severity 
of AD lesions and relieved pruritus, with superior treatment effect to placebo demonstrated by an 
array of clinically relevant endpoints. 
The dupilumab safety database consists of over 3000 subjects exposed to dupilumab across all 
indications, including over 2500 in AD. Dupilumab was well tolerated and generally safe when 
used in patients with moderate-to-severe AD. 
4.2 
RATIONALE 
4.2.1 Rationale for Study Design 
This study has been designed as a Phase 3, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety in Chinese adult patients with moderate-to-severe AD whose 
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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). The design is 
similar to global pivotal studies, R668-AD-1334 and R668-AD-1416. The primary objective is to 
demostrate the efficacy of dupilumab (300 mg q2w) monotherapy, assessed by proportion of 
patients with both an IGA 0 to 1 (on a 5-point scale) and a reduction from baseline of ≥2 points at 
Week 16 comparing with placebo. This study will generate information in Chinese AD patients 
regarding monotherapy with dupilumab compared to placebo. The choice of placebo as a control 
is appropriate for the objectives of this study, since it will provide the most robust assessment of 
the efficacy and safety of dupilumab. 
4.2.2 Rationale for Dose Selection 
The dose regimen of SC dupilumab selected for this study is 300 mg q2w. All patients 
randomized to receive treatment with dupilumab will get an initial loading dose of 600 mg on 
Day 1. 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. 
The doses of dupilumab in this study were based on the efficacy and safety results from global 
pivotal Phase 3 studies (R668-AD-1334 and R668-AD-1416). Dupliumab phase 3 studies have 
shown that dupilumab dose regimens (300 mg qw and 300 mg q2w) result in statistically 
significant, clinically meaningful improvements in objective signs, subjective symptoms, mental 
health, and QOL in patients with moderate-to-severe AD. These 2 dose regimens were very 
similar when used as a monotherapy, with no meaningful differences observed in the response 
rate of the 300 mg qw regimen over the 300 mg q2w regimen during the 16-week treatment 
period.  
These clinical data indicate that 300 mg q2w is adequate for patients with moderate-to-severe AD 
to help them reach their maximal response. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of the study is to evaluate the efficacy of dupilumab monotherapy 
compared to placebo treatment in adult patients with moderate-to-severe AD. 
5.2 
SECONDARY 
• 
To evaluate the safety of dupilumab monotherapy compared to placebo treatment in 
patients with moderate-to-severe AD. 
• 
To evaluate the effect of dupilumab on improving PROs 
• 
To evaluate dupilumab immunogenicity 
5.3 
OTHER OBJECTIVES 
• 
To evaluate dupilumab systemic exposure 
 
 
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is a randomized, double-blind, placebo-controlled, parallel-group, phase 3 study to evaluate 
the efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe AD. The 
study period includes 16-week treatment period and 12-week follow-up.  
After providing informed consent, patients will be assessed for study eligibility at the screening 
visit. Patients will undergo screening for 7-35 days prior to randomization. During the screening 
period, treatments for AD will be washed out, as applicable, according to eligibility requirements. 
Patients may be rescreened once if they fail the screening evaluation for reasons related to 
incidental transitory conditions. Patients will be required to apply moisturizers (emollients) at 
least 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 ratio to receive q2w SC injections of 300 mg 
dupilumab following a loading dose of 600 mg on Day 1, or matching placebo (including 
doubling the amount of placebo on Day 1 to match the loading dose). Randomization will be 
stratified by baseline disease severity (moderate [IGA 3] versus severe [IGA 4] AD); details will 
be specified in the interactive response technology (IRT) specifications document. Eligible 
patients must have a documented history of inadequate response or intolerance to treatment with 
topical AD medications. Following the initial dose of 600 mg, the IMP will be administered 
300 mg at Weeks 2, 4, 6, 8, 10, 12, and 14 (Figure 1). Patients will remain at the study site for a 
minimum of 30 minutes after each injection at the study site. Patients will have the option to 
self-administer the IMP (or have a caregiver administer the IMP) outside the study site during 
weeks in which no clinic visit is scheduled (ie, Weeks 6, 10, and 14). Patients (and/or caregivers) 
will be trained on injecting the IMP at Visit 2 (Day 1) through Visit 4 (Week 4), or until 
competency has been demonstrated. Patients who do not want to self-inject may have the clinic 
staff administer all the IMP injections in the clinic. 
During the 16-week treatment period, patients will have study visits at Weeks 0, 2, 4, 8, 12, and 
16. Safety laboratory tests, collection of samples for dupilumab concentrations and ADA, and 
clinical assessments will be performed at specified clinic visits as noted in the Schedule of Events 
(Table 1). 
The end of treatment visit will occur at Week 16, 2 weeks after the last dose of the IMP. The 
primary endpoint will be determined at Week 16. 
Follow-up visits will occur every 4 weeks from Week 20 through Week 28. The duration of the 
12-week follow-up period is based on the time expected for drug levels to reach below the lower 
limit of quantification in most patients after the last dose of dupilumab. The end of study visit will 
occur at Week 28. 
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6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
Each patient will experience 7 to 35-day screening, 16-week treatment and 12-week follow-up 
period. The total study duration will be up to 33 weeks. 
6.2.2 Determination of end of clinical trial (all patients) 
The last patient last visit will occur when the last patient who has completed the 12-week 
follow-up period. The end of the clinical trial is defined as the last patient’s last visit. 
6.2.2.1 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. 
6.2.2.2 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 International 
Conference on Harmonization (ICH) guidelines 
• 
The total number of patients required for the study are enrolled earlier than expected  
In all cases, the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and Health Authorities must be informed according to applicable regulatory requirements, 
and adequate consideration must be given to the protection of the patients’ interests. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
6.4 
STUDY COMMITTEES 
Not applicable. 
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7 
SELECTION OF PATIENTS 
The study population consists of adults 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). 
7.1 
INCLUSION CRITERIA 
A patient must meet the following criteria to be eligible for inclusion in the study: 
I 01. Male or female, 18 years or older  
I 02. Atopic dermatitis (according to American Academy of Dermatology Consensus Criteria, 
2014) (1) that has been present for at least 3 years before the screening visit  
I 03. EASI score ≥16 at the screening and baseline visits  
I 04. IGA score ≥3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at the 
screening and baseline visits  
I 05. ≥10% BSA of AD involvement at the screening and baseline visits  
I 06. Baseline Pruritus 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 
I 07. Documented recent history (within 6 months before the screening visit) of inadequate 
response to treatment with topical medications or for whom topical treatments are 
otherwise medically inadvisable (eg, because of important side effects or safety risks);  
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 for AD, of sufficient dose and duration, 
in the past 6 months are also considered as inadequate responders to topical treatments 
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and are potentially eligible for treatment with dupilumab after appropriate washout, 
subject to approval by the sponsor. 
- 
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 re-screened after such documentation is obtained (ie, patients 
are shown to fail a 28-day course of mid-to-higher potency TCS [±TCI]).  
I 08. Have applied a stable dose of topical emollient (moisturizer) twice daily for at least the 
7 consecutive days immediately before the baseline visit (NOTE: See E 07 for limitations 
regarding emollients) (See background treatment with topical emollient in Section 8.2) 
I 09. Willing and able to comply with all clinic visits and study-related procedures  
I 10. Able to understand and complete study-related questionnaires  
I 11. Signed written informed consent 
7.2 
EXCLUSION CRITERIA 
A patient who meets any of the following criteria will be excluded from the study: 
E 01. Participation in a prior dupilumab clinical study 
E 02. Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), 
whichever is longer, before the baseline visit  
E 03. 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: 
- 
Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, 
cyclosporine, mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, and 
methotrexate) 
- Phototherapy for AD 
E 04. Treatment with TCS or TCI within 1 week before the baseline visit  
E 05. Treatment with systemic TCM within 4 weeks before the baseline visit or treatment with 
topical TCM within 1 week before the baseline visit 
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E 06. Treatment with biologics as follows: 
- Any cell-depleting agents including but not limited to rituximab: within 6 months 
before the baseline visit or until lymphocyte count returns to normal, whichever is 
longer 
- 
Other biologics: within 5 half-lives (if known) or 16 weeks prior to baseline visit, 
whichever is longer 
E 07. 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) 
E 08. Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the 
baseline visit  
E 09. Planned or anticipated use of any prohibited medications (see Section 8.8.1) and 
procedures during study treatment 
E 10. Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit  
E 11. Active chronic or acute infection requiring treatment with systemic antibiotics, 
antivirals,antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline 
visit, or superficial skin infections within 1 week before the baseline visit 
NOTE: patients may be rescreened after infection resolves 
E 12. Known or suspected history of immunosuppression, including history of invasive 
opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, and aspergillosis) despite infection resolution, or unusually frequent, 
recurrent, or prolonged infections, per Investigator’s judgment 
E 13. Active TB, latent untreated TB, or a history of potentially incompletely treated TB or 
non-TB mycobacterial infection, unless it is well documented by a specialist that the 
patient has been adequately treated and can now start treatment with a biologic agent, in 
the medical judgment of the Investigator and/or infectious disease specialist. Tuberculosis 
testing would be performed according to local guidelines if required by regulatory 
authorities or ethics commitees 
E 14. History of HIV infection or positive HIV serology at screening 
E 15. Active hepatitis or patients with positive HBsAg, or patients with positive HBcAb plus 
positive HBV DNA, or positive HCV antibody (confirmed with presence of HCV RNA if 
needed) at screening 
E 16. At baseline, presence of any conditions listed as criteria for IMP discontinuation (see 
Section 10.3) 
E 17. Presence of skin comorbidities that may interfere with study assessments 
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E 18. History of malignancy within 5 years before the screening visit, except completely treated 
in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous 
or basal cell carcinoma of the skin 
E 19. 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 
E 20. History of alcohol or drug abuse within 2 years of the screening visit 
E 21. 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 (HbA1c ≥9%), patients with 
cardiovascular conditions (eg, stage III or IV cardiac failure according to the New York 
Heart Association classification), severe renal conditions (eg, patients on dialysis), 
hepatobiliary conditions (eg, Child-Pugh class B or C), neurological conditions 
(eg, demyelinating diseases), active major autoimmune diseases (eg, lupus, inflammatory 
bowel disease, and rheumatoid arthritis), and 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, 
CRFs, etc) 
E 22. Any other medical or psychological condition (including relevant laboratory abnormalities 
at screening) that, in the opinion of the Investigator, may 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, CRFs, etc) 
E 23. Planned or anticipated major surgical procedure during the patient’s participation in this 
study 
E 24. Patient is a member of the investigational team or his/her immediate family 
E 25. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed 
during the study 
E 26. Woman of childbearing potential (WOCBP) not protected by highly-effective method(s) of 
birth control and/or who are unwilling or unable to be tested for pregnancy (see 
contraceptive guidance in Appendix A) 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
8.1.1 Dupilumab 
Dupilumab 150 mg/mL: Each 2.25 mL single-use, prefilled glass syringe with snap-off cap 
delivers 2.0 mL of a 150 mg/mL solution (300 mg) of dupilumab. 
8.1.2 Placebo 
Placebo matching dupilumab is prepared in the same formulation without the addition of protein 
(ie, active substance, anti-IL-4Rα monoclonal antibody). 
8.1.3 Dosing schedule 
Patients will receive q2w SC injections of 300 mg dupilumab following a loading dose of 600 mg 
(ie, two 300 mg SC injections) on Day 1, or q2w injections of matching placebo (following a 
placebo “loading dose”) during the 16-week treatment period. Subsequently q2w SC injections 
after loading dose of IMP will be given every 14 ± 3 days (q2w). The doses of the IMP must be 
separated by ≥11 days. Patients will be monitored at the study site for a minimum of 30 minutes 
after the injection of the IMP for any signs or symptoms of a hypersensitivity reaction. Patients 
will have the option to administer the IMP (or have a caregiver administer the IMP) outside the 
study site during weeks in which no clinic visit is scheduled (ie, Weeks 6, 10, and 14). The study 
staff will train the patient/caregiver on preparation and administration of the IMP 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 the IMP under the supervision of the clinic staff at 
Visits 3 and 4 (Weeks 2 and 4, respectively). Patients who prefer to have the clinic staff 
administer the IMP may choose to have injections administered in the clinic.  
The procedure for preparing the dupilumab dose for SC injection will be provided in the 
pharmacy manual. Subcutaneous injection sites 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 twice consecutively. To allow for adequate assessment of possible 
injection site reactions (ISRs), the IMP should be administered only into areas of normal-looking 
skin. Instructions for recording and reporting ISRs will be provided in the user guidance. 
8.1.4 Dose modification and investigational medicinal product discontinuation rules 
8.1.4.1 Drug modification 
Dose modification for an individual patient is not allowed. 
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8.1.4.2 Investigational medicinal product discontinuation 
Patients who temporarily or permanently discontinue from the IMP and who do not withdraw 
from the study will be asked to return to the clinic for all remaining study visits and complete all 
study assessments per the study schedule. The reasons for temporarily or permanently 
discontinuation of the IMP are described in Section 10.3. 
Patients who opt to withdraw from the study will be asked to complete study assessments, per 
Section 10.1.5. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS 
8.2.1 Background treatment 
All patients are required to apply moisturizers (emollients) at least twice daily for at least 7 days 
before randomization and to continue the treatment throughout the study (all 28 weeks where 
applicable). However, to allow adequate assessment of skin dryness, moisturizers should not be 
applied on the area(s) of nonlesional skin designated for such assessments for at least 8 hours 
before each clinic visit. All types of moisturizers are permitted, but patients may not initiate 
treatment with prescription moisturizers 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. 
8.2.2 Rescue treatment 
If medically necessary (ie, to control intolerable AD symptoms), rescue treatment for AD with 
otherwise prohibited medications or procedure (see Section 8.8.1) may be provided to study 
patients at the discretion of the Investigator. Please refer to the label of the product for the usage 
of rescue treatment. For the purpose of efficacy analysis, patients who receive rescue treatment 
during the study treatment period will be considered treatment failures, but they will continue 
study treatment if rescue consisted of topical medications. Topical calcineurin inhibitors may be 
used for rescue, but should be reserved for problem areas only, eg, face, neck, intertriginous, and 
genital areas. If possible, Investigators should attempt to limit the first step of rescue therapy to 
topical medications, and escalate to systemic medications only for patients who do not respond 
adequately after at least 7 days of topical treatment. If a patient receives rescue treatment with 
systemic corticosteroids or nonsteroidal systemic immunosuppressive/immunomodulating drugs 
(cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, Janus kinase inhibitors, 
biologic agents, etc), the IMP will be immediately discontinued. After the treatment with these 
medications is completed, the IMP may be resumed if deemed appropriate by the Investigator and 
the sponsor, but not sooner than 5 half-lives after the last dose of systemic rescue medication. All 
patients will complete the schedule of study visits and assessments whether or not they complete 
the treatment with the IMP 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 labs) immediately before administering any rescue treatment. An unscheduled visit may be 
used for this purpose if necessary. 
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8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
Dupilumab and placebo will be provided in identically matched 2 mL prefilled syringes. To 
protect the blind, each treatment kit of 2 mL (dupilumab/placebo) glass prefilled syringes will be 
prepared such that the IMPs are identical and indistinguishable, and will be labeled with a 
treatment kit number. The randomized treatment kit number list will be generated by the sponsor. 
In accordance with the double-blind design, study patients, Investigators, and study site personnel 
will remain blinded to study treatment and will not have access to the randomization (treatment 
codes) except under circumstances described in Section 8.3.2. 
8.3.2 Randomization code breaking during the study 
In case of an adverse event (AE), the code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient.  
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the sponsor for that purpose. If the blind is broken, 
the Investigator should document the date, time of day, and the reason for code breaking. 
Subject withdrawal will only occur when the code break call is made at the site level, not the 
study level. This means that if the Emergency Unblinding transaction is performed by the 
Investigator (ie, at the site level), then the subject will be withdrawn from treatment. See 
Section 10.3.4 for the handling of patients after permanent treatment discontinuation. However, if 
the emergency unblinding transaction is performed by the Global Safety Officer (GSO) (ie, at the 
study level, as the GSO is not site based), then the subject will not be withdrawn from treatment.  
At the facilities where the systemic drug concentration measurements, ADA, and selected 
biomarkers are determined, the samples will be analyzed prior to data base lock leading to 
unblinding of responsible bioanalysts. Bioanalysts are excluded from the clinical trial team.  
 
 
 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
A total of 160 patients will be randomized on Day 1 in a 1:1 ratio to receive q2w SC injections of 
300 mg dupilumab, or matching placebo for 16 weeks. Patients will be randomized to a treatment 
group according to a central randomization scheme provided by an IRT to the designated site 
personnel or clinical staff members. Randomization will be stratified by disease severity (IGA 3 
versus IGA 4); details will be specified in the IRT specifications document and will be 
documented in the clinical study report. 
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A randomized treatment kit number list will be generated centrally by the sponsor. The IMP 
(dupilumab or placebo) will be packaged in accordance with this list. 
The sponsor will provide the randomized treatment kit number list and the Study Biostatistician 
will provide the randomization scheme to the centralized treatment allocation system. This 
centralized treatment allocation system will generate the patient randomization list, according to 
which it will allocate the treatments to the patients. 
Patients may be rescreened once if they fail the screening evaluation for reasons related to 
incidental transitory conditions. A different patient identification will be issued. There is no 
requirement for a waiting period between the screen-failure date and the rescreening date. The 
IRT report will flag rescreened patients. Patients that are rescreened must sign a new consent form 
and all Visit 1 procedures must be repeated.  
A randomized patient is defined as a patient who is registered and assigned with a treatment kit 
number from the centralized treatment allocation system, as documented from its log file. 
A patient cannot be randomized more than once in the study. 
8.5 
PACKAGING AND LABELING 
Dupilumab and placebo will be supplied as one glass prefilled syringe packed in a patient kit box. 
Both the glass prefilled syringe and the box will be labeled. Packaging is in accordance with the 
administration schedule. The content of the labeling is in accordance with the local regulatory 
specifications and requirements. 
A medication numbering system will be used in labeling blinded IMP. Lists linking medication 
numbers with product lot numbers will be maintained by the groups (or companies) responsible 
for IMP packaging. In order to maintain the blind, these lists will not be accessible to individuals 
involved in study conduct. 
8.6 
STORAGE CONDITIONS  
Investigational medicinal products will be stored at the site at a temperature of 2°C to 8°C in an 
appropriate, locked room under the responsibility of the Investigator or other authorized persons 
(eg, pharmacists) in accordance with local regulations, policies and procedures. Control of the 
IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the compound should be managed 
according to the rules provided by the sponsor. 
The IMP will be shipped at a temperature of 2°C to 8°C to the Investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened IMP will be destroyed or returned to the sponsor or 
designee. 
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8.7 
RESPONSIBLILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the sponsor and in accordance with applicable regulatory requirements.  
All IMPs will be dispensed in accordance with the Investigator’s prescription, and it is the 
Investigator’s responsibility to ensure that an accurate record of IMP issued and returned is 
maintained.  
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
sponsor. Some deficiencies may be recorded through a complaint procedure.  
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the sponsor, in order to recall IMP and eliminate potential hazards.  
Under no circumstances will the Investigator supply the IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose the IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
The Investigator or pharmacist will also keep accurate records of the quantities of the IMP 
dispensed, used, and returned by each patient. The IMP dispensation/accountability log is to be 
updated each time the IMP is dispensed or returned. Any IMP not returned (even if considered 
empty) must be accounted for with a comment in the log. The study monitor will periodically 
check the supplies of the IMP held by the Investigator or pharmacist to verify accountability. 
All drug accountability records must be kept current. 
The Investigator must be able to account for all opened and unopened IMPs. These records should 
contain the dates, quantity, and IMP 
• 
dispensed to each patient, 
• 
returned from each patient (if applicable), and 
• 
disposed of at the site or returned to the sponsor or designee. 
Patients will be instructed to return their used and unused IMP to the investigation site. 
Compliance with IMP administration will be reviewed with the patient at each visit. Compliance 
will be assessed by inspection of the kit box and checking the unused glass pre-filled syringe. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
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8.7.2 Return and/or destruction of treatments 
All used, partially-used or unused treatments will be retrieved by the sponsor or destroyed at study 
site. All used prefilled syringes should be kept in a sharp container by the patients and be returned 
to sites for destroy. 
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will 
not destroy the unused IMP unless the sponsor provides written authorization.  
For noninvestigational medicinal product (NIMP) not provided by the sponsor, tracking and 
reconciliation has to be achieved by the Investigator and need to be captured in standard site 
documents and records (eg, medical notes).  
8.8 
CONCOMITANT MEDICATION 
Any treatment administered from the time of informed consent 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. 
8.8.1 Prohibited medications and procedures 
The following treatments are prohibited during the study: 
• 
Treatment with a live (attenuated) vaccine (See Appendix B) 
• 
Treatment with immunomodulating biologics 
• 
Treatment with an investigational drug (other than dupilumab) 
• 
Treatment with TCS or TCI 
• 
Treatment with systemic corticosteroids or nonsteroidal systemic 
immunosuppressive/immunomodulating drugs (eg, cyclosporine, methotrexate, 
mycophenolate-mofetil, azathioprine, and Janus kinase inhibitors) 
• 
Initiation or uptitration of allergen-specific immunotherapy (SIT). Patients on SIT prior to 
the screening visit must be on a stable dose and remain on that dose during the study 
• 
Any other medications for AD that could have interfered with efficacy outcomes or 
affected the evaluation for AD severity. Examples of such medications include coal tar 
products, other staining topical products, TCM, or any other therapeutic agents for AD that 
were not properly evaluated in clinical trials 
However, at the discretion of the Investigator, patients were permitted to receive rescue treatment 
with some of the otherwise prohibited medications noted below. Rescue treatment (see 
Section 8.2.2 for details) is only to be performed when medically necessary for worsening AD 
signs and/or symptoms requiring initiation or escalation of treatment.  
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The IMP will be discontinued if the following is used through Week 16: 
• 
Treatment with a live (attenuated) vaccine 
• 
Treatment with immunomodulating biologics 
• 
Treatment with an investigational drug (other than dupilumab) 
• 
Treatment with systemic corticosteroids or nonsteroidal systemic 
immunosuppressive/immunomodulating drugs (eg, cyclosporine, methotrexate, 
mycophenolate-mofetil, azathioprine, and Janus kinase inhibitors) 
If a patient receives treatment with systemic corticosteroids or other systemic 
immunosuppressive/immunomodulating drugs (cyclosporine, methotrexate, mycophenolate 
mofetil, azathioprine, Janus kinase inhibitors, biologic agents, etc), the IMP will be immediately 
discontinued. After the treatment with these medications is completed, the IMP may be resumed if 
deemed appropriate by the Investigator and the sponsor, but not sooner than 5 half-lives after the 
last dose of systemic rescue medication.  
The following concomitant procedures are prohibited during study participation: 
• 
Major elective surgical procedures 
• 
Phototherapy except as rescue for AD 
• 
Tanning in a bed/booth 
8.8.2 Permitted medications and procedures 
Other than the prohibited medications listed in Section 8.8.1, treatment with concomitant 
medications is permitted during the study. This includes basic skin care (cleansing and bathing, 
including bleach baths), emollients (required as background treatment), topical anesthetics, 
antihistamines, and topical and systemic anti-infective medications for any duration. 
Medications used to treat chronic disease such as diabetes, hypertension, and asthma are also 
permitted; if there is any question regarding whether a concomitant medication may be used 
during the study, the study site should contact the sponsor. 
Cytochrome P450 
Study R668-AD-1433, designed to investigate the potential impact of dupilumab on 
cytochrome P450 (CYP) enzyme activity, shows no evidence for a clinically meaningful effect of 
dupilumab on the activity of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. No specific 
monitoring of CYP enzymes activities is needed. 
8.8.2.1 Prohibited concomitant medications or procedures as rescue 
If medically necessary (eg, to control intolerable AD symptoms), rescue treatment for AD may be 
provided to study patients at the discretion of the Investigator (see Section 8.2.2 for details). 
Blinded adjudication of concomitant medications may be performed to identify concomitant 
medications that confound study endpoints. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
The primary endpoint is 
• 
Proportion of patients with both IGA 0 to 1 (on a 5-point scale) and a reduction from 
baseline of ≥2 points at Week 16 
9.1.1 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 1.2. 
The IGA is provided in the user guidance. 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Efficacy endpoints 
• 
Proportion of patients with EASI-75 response (reduction of EASI score ≥75% from 
baseline) at Week 16  
• 
Proportion of patients with reduction of weekly average of peak daily Pruritus NRS ≥4 
from baseline to Week 16 
• 
Proportion of patients with reduction of weekly average of peak daily Pruritus NRS ≥3 
from baseline to Week 16 
• 
Percent change from baseline to Week 16 in weekly average of peak daily Pruritus NRS 
• 
Change from baseline to Week 16 in weekly average of peak daily Pruritus NRS 
• 
Percent change in EASI score from baseline to Week 16 
• 
Change from baseline to Week 16 in percent BSA of AD involvement 
• 
Change from baseline to Week 16 in DLQI 
• 
Change from baseline to Week 16 in POEM 
• 
Percent change from baseline to Week 2 in weekly average of peak daily Pruritus NRS 
• 
Absolute and percent change from baseline to Week 16 in EQ-5D 
• 
Proportion of patients who achieve reduction of IGA score by ≥2 from baseline to 
Week 16 
• 
The proportion of patients with EASI-50 (≥50% improvement from baseline) at Week 16 
• 
The proportion of patients with EASI-90 (≥90% improvement from baseline) at Week 16 
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• 
Proportion of patients achieving IGA 0 to 1 and a reduction of ≥2 points from baseline 
through Week 16 
• 
Absolute and percent changes in EASI score from baseline through Week 16 
• 
Absolute and percent changes in weekly average of peak daily pruritus NRS score from 
baseline through Week 16 
• 
The proportion of patients who responded “absence of pruritus” or “mild pruritus” in the 
pruritus categorical scale at Week 16 
• 
Number of days and proportion of patients with sick leave/missed school days 
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 will be administered prior to obtaining 
Investigator assessments, safety and laboratory assessments, and IMP administration. Please see 
the user guidance on the administration and use of all patient reported instruments (including 
POEM, DLQI, and EQ-5D). 
9.2.1.1 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 (10). 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%). 
9.2.1.2 Patient assessment of pruritus: 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 daily recall period using a pruritus reporting system. Patients will be asked 
the following questions: 
• 
For average 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 overall (on average) during the 
previous 24 hours?” 
• 
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 pruritus reporting system to record their Pruritus NRS 
score at the screening visit. Patients will complete the rating scale daily. Clinical sites will receive 
alerts when patients do not complete the pruritus reporting system items. Sites will be expected to 
contact patients who have missed 2 consecutive entries to encourage patient compliance. The 
Investigator will check patients’ reports at each visit. 
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9.2.1.3 Body surface area 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. 
9.2.1.4 Patient-reported dermatology life quality index 
The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to 
assess the impact of AD disease symptoms and treatment on QOL (11). The format is a simple 
response (0 to 3, where 0 is “not at all” and 3 is “very much”) to 10 questions, which assess QOL 
over the past week, with an overall scoring system of 0 to 30; a high score is indicative of a poor 
QOL.  
9.2.1.5 Patient oriented eczema measure 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults (12). The format is a response to 7 items (dryness, 
itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency during the past 
week (ie, 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days) with a 
scoring system of 0 to 28; the total score reflects disease-related morbidity.  
9.2.1.6 Patient-assessed EQ-5D 
The EQ-5D is a standardized measure of health status developed by the EuroQOL Group in order 
to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D 
consists of 2 parts: the descriptive system and the EQ visual analogue scale (EQVAS). The 
EQ-5D descriptive system comprises the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels of perceived 
problems: “no problem” (level 1), “some problems” (level 2), “extreme problems” (level 3). The 
respondent is asked to indicate his/her health state by ticking (or placing a cross) in the box 
against the most appropriate statement (ie, no problems, some problems, or severe problems) in 
each of the 5 dimensions; this results in a 1-digit number expressing the level for that dimension. 
The digits for 5 dimensions can be combined in a 5-digit number describing the respondent’s 
health state. 
The EQVAS records the respondent’s self-rated health on a vertical, visual analogue scale where 
the endpoints are labeled “best imaginable health state (100)” and “worst imaginable health 
state (0)”. This information can be used as a quantitative measure of health outcome as judged by 
the individual respondents. 
9.2.1.7 Patient-assessed pruritus categorical scale 
The pruritus categorical scale is a 4-point scale used to assess symptoms that has been used in 
clinical studies of AD and there is less of a tendency for patients to provide an “average” response 
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than there might be with a 5-point scale (13). 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 pruritus reporting system to complete the pruritus 
categorical scale at the screening visit. Patients will complete the categorical scale daily. Clinical 
sites will receive alerts when patients do not complete the pruritus reporting system items. Sites 
will be expected to contact patients who have missed 2 consecutive entries to encourage patient 
compliance. The Investigator will check patients’ reports at each visit. 
9.2.1.8 Sick Leave/Missed School Days 
Patients who are employed or enrolled in school will be asked to report the number of sick 
leave/missed school days since the last study assessment. Patients will undergo this assessment at 
time points according to Section 1.2. 
The assessment tool is provided in the user guidance. 
9.2.1.9 Atopic Dermatitis Area Photographs 
At selected study sites, photographs will be taken of a representative area of AD involvement 
(eg, the lesional area used for EASI assessments on Day 1/baseline [pre-dose]). Subsequent 
photographs of the same area will be taken at Week 16 (end of treatment) and Week 28 (end of 
study).  
Instructions for taking the photographs are provided in the photography reference manual. 
9.2.2 Safety endpoints 
9.2.2.1 Adverse events 
Refer to Section 10.4 to Section 10.6 for details. 
9.2.2.2 Laboratory safety variables 
Hematology, chemistry, urinalysis, and serum pregnancy testing samples will be analyzed by a 
central laboratory. The urine pregnancy test kit will be provided to the site by the laboratory. 
Blood samples for serum chemistry and hematology testing will be collected to measure overall 
patient health at screening. Total basophil and eosinophil counts are of particular interest in AD 
patients, due to the occurrence of basophil histamine release and eosinophilia in this population. 
Understanding the lymphocyte profiles of AD patients may help researchers understand disease 
heterogeneity. Blood samples should be collected after a 6 to 8 hour fast, if possible; fasting is not 
mandatory. Detailed instructions for blood sample collection are in the laboratory manual 
provided to study sites. 
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Samples for laboratory testing will be collected at time points according to Section 1.2. Tests will 
include 
• 
Blood chemistry: sodium, potassium, chloride, carbon dioxide, calcium, glucose, albumin, 
total protein (serum), creatinine, blood urea nitrogen, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), alkaline phosphatase, lactate dehydrogenase (LDH), total 
bilirubin, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, 
uric acid, creatine phosphokinase (CPK) 
Note: Direct and indirect bilirubin will be measured when the total bilirubin is above the 
upper limit of normal (ULN); CPK isoenzymes will be reflexly measured when CPK 
>5 ULN. 
• 
Hematology: hemoglobin, hematocrit, red blood cells (RBCs), white blood cells (WBCs) 
and differential (neutrophils, lymphocytes, monocytes, basophils, eosinophils), red cell 
indices, platelet count 
• 
Urinalysis: Color, clarity, pH, specific gravity, ketones, protein, glucose, blood, bilirubin, 
leukocyte esterase, nitrite, WBC, RBC, hyaline and other casts, bacteria, epithelial cells, 
crystals, yeast 
Microscopic analysis will only be done in the event of abnormal dipstick results. 
• 
Pregnancy testing (serum or urine) will be performed for all women of childbearing 
potential. 
• 
Testing for HIV antibody, HBsAg, HBsAb, HBcAb, HBV DNA (for patients presenting 
with HBsAg [-] and HBcAb [+]) and hepatitis C antibody, and ANA will be performed at 
screening 
Hepatitis C virus (HCV) RNA testing may be performed to rule out a false positivity, if 
the Investigator believes the patient is a false positive. Anti-dsDNA antibody will be tested 
if ANA is positive. 
9.2.2.3 Vital Signs 
Vital signs, including heart rate, blood pressure, body temperature, and respiration rate, will be 
collected. 
9.2.2.4 Physical examination 
A thorough and complete physical examination will be performed at time points according to 
Section 1.2. Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the patient’s medical history. If patients have any symptom or sign of ocular surface 
diseases, eg, conjunctivitis and blepharitis, at screening or during study period, ophthalmological 
examinations should be done.  
9.2.2.5 Weight and Height 
Weight and height will be determined at time points according to Section 1.2. 
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9.2.2.6 ECG 
Electrocardiograms will be performed before blood is drawn during visits requiring blood draws. 
A standard 12-lead ECG will be performed at time points according to Section 1.2. The ECG 
strips or reports will be retained with the source documentation, and the results will be 
documented in the electronic case report form (eCRF). 
9.2.2.7 Immunogenicity 
Anti-drug antibody measurements: 
Samples for ADA assessment will be collected at time points listed in Section 1.2. 
Anti-drug antibody variable definition: 
• 
Negative in ADA assay at all time points analyzed 
• 
Preexisting immunoreactivity (defined as either an ADA positive response in the ADA 
assay at baseline with all post first dose ADA results negative, OR a positive response at 
baseline in the ADA assay with all post first dose ADA results less than 4-fold baseline 
titer levels) 
• 
Treatment emergent response in the ADA assay (defined as a positive response in the 
ADA assay post first dose when baseline results are negative or missing). The treatment 
emergent responses may be further characterized as 
- 
Persistent (defined as treatment emergent ADA positive response with two or more 
consecutive ADA positive sampling time points separated by greater than 12-week 
period [greater than 85 days], with no ADA negative samples or any missing sample in 
between) 
- 
Indeterminate (defined as treatment-emergent response with only the last collected 
sample positive in the ADA assay) 
- 
Transient (defined as treatment emergent ADA positive response that is not considered 
persistent or indeterminate) 
• 
Treatment boosted response in the ADA assay (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) 
ADA titer value category definition: 
• 
Low (titer <1000) 
• 
Moderate (1000 ≤titer ≤10 000) 
• 
High (titer >10 000) 
All samples that are positive in the ADA assay will be further tested for the presence of anti-
dupilumab neutralizing antibodies. 
Descriptive statistics for the incidence of anti-dupilumab antibodies response variables will be 
summarized for the ADA population. Listings of anti-dupilumab antibody status, neutralizing 
status, and titers per time point and treatment group will be provided. 
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Plots of concentrations of functional dupilumab will be examined and the potential influence of 
ADA on individual concentration-time profiles will be evaluated. Assessment of the potential 
impact of ADA on safety and efficacy may be provided. 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics parameters 
9.3.1.1 Pharmacokinetic measurements 
Samples for measurement of functional dupilumab concentration in serum will be collected at 
time points listed in Section 1.2. 
9.3.1.2 Pharmacokinetic parameters 
The PK variables may include, but are not limited to, the following: 
• 
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9.4 
FUTURE USE OF SAMPLES 
Not applicable. 
9.5 
APPROPRIATENESS OF MEASUREMENTS  
The efficacy and safety assessments used in this study are standard for the evaluation of therapy in 
patients with AD. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE  
Study assessments and procedures are presented by study period and visit in Table 1. 
Assessments/procedures at a clinic visit should be performed in the following order: 
1. Patient reported outcomes. 
2. Investigator assessments (performed only by adequately trained Investigators or 
sub-Investigators; the same Investigator or sub-Investigator should perform all the 
evaluations for a given patient throughout the entire study period). 
3. Safety and laboratory assessments. 
4. Administration of the IMP. 
10.1.1 Visit 1/Screening/Day -7 to -35 
After the patient has provided informed consent, the following information will be collected: 
• 
Inclusion/exclusion 
• 
Medical history and concurrent illnesses 
• 
Demographics 
• 
Concomitant medications/procedures 
• 
AEs 
The following procedures and assessments will be conducted: 
• 
Training on the pruritus reporting system 
• 
Pruritus NRS and pruritus categorical scale 
• 
All questionnaires will be administered before any invasive procedures 
- 
Patient oriented eczema measure (POEM) 
- 
Dermatology life quality index (DLQI) 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA involvement of AD 
• 
Weight 
• 
Height 
• 
Physical examination (If patients have any symptom or sign of ocular surface diseases, 
eg, conjunctivitis and blepharitis, at screening or during study period, ophthalmological 
examinations should be done.)  
• 
ECG 
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• 
Laboratory testing: 
- 
HIV ab 
- 
HBsAg, HBsAb, HBcAb, HBV DNA testing should be done for patients presenting 
with HBsAg (-) and HBcAb (+) 
- 
Hepatitis C antibody (in case of results showing HCV Ab positive, an HCV RNA 
testing may be performed to rule out a false positivity, if the Investigator believes the 
patient is a false positive) 
- 
Hematology and chemistry 
- 
Urinalysis 
- 
Serum pregnancy test (WOCBP only) 
 
 
 
 
- 
Anti-nuclear antibody (ANA) 
- 
Anti-dsDNA (only for ANA positive patients) 
10.1.2 Treatment Period 
10.1.2.1 Visit 2/Baseline/Day 1 (Randomization) 
The following information will be collected: 
• 
Inclusion/Exclusion 
• 
Concomitant medications/procedures 
• 
AEs 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
• 
All questionnaires will be administered before any invasive procedures: 
- 
POEM 
- 
DLQI 
- 
EQ-5D 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
• 
Photograph AD area (select sites only) 
• 
Weight 
• 
Laboratory testing: 
- 
Hematology and chemistry 
- 
Urinalysis 
- 
Urine pregnancy test (WOCBP only) 
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- 
Functional dupilumab pharmacokinetic (PK) sample 
- 
Anti-dupilumab antibody sample 
• 
Randomization 
• 
Administer the IMP after all the other assessments have been performed. Train 
patient/caregiver in injection technique if the patient chooses to self-administer the IMP at 
selected weeks. 
- 
The patient will be monitored in the clinic for at least 30 minutes after the injection for 
any signs or symptoms of a hypersensitivity reaction. In addition to the predose 
assessments, AE assessments will be done at 30 minutes (±10 minutes) postinjection. 
10.1.2.2 Visit 3/Week 2/Day 15 (±3 days) 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
• 
All questionnaires will be administered before any invasive procedures: 
- 
POEM 
- 
DLQI 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
• 
Administer the IMP after all the other assessments have been performed. Train 
patient/caregiver in injection technique if the patient chooses to self-administer the IMP at 
selected weeks. 
- 
The patient will be monitored in the clinic for at least 30 minutes after the injection for 
any signs or symptoms of a hypersensitivity reaction. In addition to the predose 
assessments, AE assessments will be done at 30 minutes (±10 minutes) postinjection 
10.1.2.3 Visit 4/Week 4/Day 29 (±3 days) 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
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• 
All questionnaires will be administered before any invasive procedures: 
- 
POEM 
- 
DLQI 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
• 
Laboratory testing: 
- 
Urine pregnancy test (WOCBP only) 
• 
Administer the IMP after all the other assessments have been performed. Train 
patient/caregiver in injection technique if the patient chooses to self-administer the IMP at 
selected weeks. 
- 
The patient will be monitored in the clinic for at least 30 minutes after the injection for 
any signs or symptoms of a hypersensitivity reaction. In addition to the predose 
assessments, AE assessments will be done at 30 minutes (±10 minutes) postinjection 
• 
Dispense the patient dosing diary and the IMP for Week 6 if the patient chooses to 
self-inject at home at Week 6. 
10.1.2.4 Visit 5/ Week 8/Day 57 (±3 days) 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
• 
If the patient chose to self-inject the IMP on Week 6, review the patient dosing diary and 
account for the IMP. Collect any unused IMP. 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
• 
All questionnaires will be administered before any invasive procedures: 
- 
POEM 
- 
DLQI 
- 
EQ-5D 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
• 
Laboratory testing: 
- 
Hematology and chemistry 
- 
Urine pregnancy test (WOCBP only) 
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• 
Administer the IMP after all the other assessments have been performed. Train 
patient/caregiver in injection technique (if needed) if the patient chooses to self-administer 
the IMP at selected weeks. 
- 
The patient will be monitored in the clinic for at least 30 minutes after the injection for 
any signs or symptoms of a hypersensitivity reaction. In addition to the predose 
assessments, AE assessments will be done at 30 minutes (±10 minutes) postinjection 
• 
Dispense the patient dosing diary and the IMP for Week 10 if the patient chooses to 
self-inject at home at Week 10. 
10.1.2.5 Visit 6/Week 12/Day 85 (±3 days) 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
• 
If the patient chose to self-inject the IMP on Week 10, review the patient dosing diary and 
account for the IMP. Collect any unused IMP. 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
• 
All questionnaires will be administered before any invasive procedures: 
- 
POEM 
- 
DLQI 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
• 
Laboratory testing: 
- 
Urine pregnancy test (WOCBP only) 
- 
Functional dupilumab PK sample 
- 
Anti-dupilumab antibody sample 
• 
Administer the IMP after all the other assessments have been performed. Train 
patient/caregiver in injection technique (if needed) if the patient chooses to self-administer 
the IMP at selected weeks. 
- 
The patient will be monitored in the clinic for at least 30 minutes after the injection for 
any signs or symptoms of a hypersensitivity reaction. In addition to the predose 
assessments, AE assessments will be done at 30 minutes (±10 minutes) postinjection 
• 
Dispense the patient dosing diary and the IMP for Week 14 if the patient chooses to 
self-inject at home at Week 14. 
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10.1.2.6 Visit 7/End of Treatment/Week 16/Day 113 (±3 days) 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
• 
If the patient chose to self-inject the IMP on Week 14, review the patient dosing diary and 
account for the IMP. Collect any unused IMP. 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
• 
All questionnaires will be administered before any invasive procedures: 
- 
POEM 
- 
DLQI 
- 
EQ-5D 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
• 
Photograph AD area (select sites only) 
• 
Weight 
• 
Physical examination 
• 
ECG 
• 
Laboratory testing: 
- 
Hematology and chemistry 
- 
Urinalysis 
- 
Serum pregnancy test (WOCBP only) 
 
 
 
- 
Functional dupilumab PK sample 
- 
Anti-dupilumab antibody sample 
10.1.3 Follow-up Period 
10.1.3.1 Visit 8/Week 20/Day 141 (±3 days) 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
The following procedures and assessments will be conducted: 
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• 
Pruritus NRS and pruritus categorical scale 
• 
POEM 
• 
DLQI 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
10.1.3.2 Visit 9/Week 24/Day 169 (±3 days) 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
• 
POEM 
• 
DLQI 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
10.1.4 Visit 10/End of Study Visit/Week 28/Day 197 (±3 days) 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
• 
POEM 
• 
DLQI 
• 
EQ-5D 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
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• 
BSA 
• 
Photograph AD area (select sites only) 
• 
Weight 
• 
Physical examination 
• 
ECG 
• 
Laboratory testing: 
- 
Hematology and chemistry 
- 
Urinalysis 
- 
Serum pregnancy test (WOCBP only) 
- 
Functional dupilumab PK sample 
- 
Anti-dupilumab antibody sample 
10.1.5 Early Termination Visit 
Patients who are withdrawn from the study before the primary endpoint visit (Week 16) will be 
asked to return to the clinic for 2 visits: once for early termination assessments, and again at 
Week 16 (primary endpoint visit), as described in Section 10.1.2.6. Patients who are withdrawn 
from the study after the primary endpoint visit will be asked to return to the clinic for early 
termination assessments. 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
• 
POEM 
• 
DLQI 
• 
EQ-5D 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
• 
Photograph AD area (select sites only) 
• 
Weight 
• 
Physical examination 
• 
ECG 
• 
Laboratory testing: 
- 
Hematology and chemistry 
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- 
Urinalysis 
- 
Serum pregnancy test (WOCBP only) 
 
 
 
 
- 
Functional dupilumab PK sample 
- 
Anti-dupilumab antibody sample 
10.1.6 Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. During an unscheduled visit, any of the procedures noted may be 
performed, but not all are required. 
The following information will be collected: 
• 
Concomitant medications/procedures 
• 
AEs 
The following procedures and assessments will be conducted: 
• 
Pruritus NRS and pruritus categorical scale 
• 
POEM 
• 
DLQI 
• 
Assess sick leave/missed school days 
• 
Vital signs 
• 
IGA 
• 
EASI 
• 
BSA 
• 
Photograph AD area (select sites only) 
• 
Weight 
• 
Laboratory testing: 
- 
Hematology and chemistry 
- 
Urinalysis 
- 
Urine pregnancy test (WOCBP only) 
 
 
 
 
- 
Functional dupilumab PK sample 
- 
Anti-dupilumab antibody sample 
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10.2 
DEFINITION OF SOURCE DATA 
Source data is all information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents. Source documents are 
original documents, data and records such as hospital records, clinic and office charts, laboratory 
notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, etc.  
All the data collected in the e-CRF should be transcribed directly from source documents. Data 
downloaded from the study-associated central laboratories and patient electronic diary will be 
considered source data. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the CRF. In any case, the 
patient should remain in the study as long as possible.  
10.3.1 Temporary treatment discontinuation with investigational medicinal products 
Temporary treatment discontinuation may be considered by the Investigator because of AEs. 
Reinitiation of treatment with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator considers, according to his/her best medical judgment, 
that the AE is sufficiently resolved and unlikely to recur after resuming therapy with the IMP. 
The following conditions(s) will be causes for temporary treatment discontinuation: 
• 
Any laboratory abnormality that meets temporary treatment discontinuation criteria as per 
Appendix E 
• 
Other intercurrent illnesses or major surgery 
• 
Infections or infestations that do not respond to medical treatment  
The IMP should be discontinued until the infection is resolved. 
• 
Treatment with prohibited concomitant medication or procedure as described in 
Section 8.8.1 
After the lab abnormality leading to suspension of dosing normalizes sufficiently, the IMP may be 
resumed at the discretion of the principal Investigator in consultation with the sponsor. Similarly, 
the IMP may be resumed after the medication leading to suspension of dosing is discontinued. A 
decision to discontinue the IMP and/or to reinstitute the IMP should be discussed with the 
sponsor. The Investigator may suspend the IMP at any time, even without consultation with the 
sponsor if the urgency of the situation requires immediate action and if this is determined to be in 
the patient’s best interest. However, the sponsor should be contacted as soon as possible in any 
case of the IMP discontinuation. Resumption of study treatment after temporary discontinuation 
should always be discussed with the sponsor. 
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10.3.2 Permanent treatment discontinuation with investigational medicinal products 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to reexpose the patient to the IMP at 
any time. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the CRF or 
e-CRF. 
Patients must be withdrawn from the treatment (ie, from any further IMP administration) for the 
following reasons:  
• 
At their own request or at the request of their legally authorized representative (Legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient’s participation in 
the procedure(s) involved in the research). 
• 
If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
patient’s well-being 
• 
At the specific request of the sponsor 
• 
In the event of a protocol deviation, at the discretion of the Investigator or the sponsor 
• 
Any code broken requested by the Investigator will lead to permanent treatment 
discontinuation. 
• 
Pregnancy 
• 
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment. 
• 
Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin 
• 
Any opportunistic infection or other infections whose nature or course may suggest an 
immunocompromised status (see Appendix D) 
• 
Serum ALT >3 ULN and total bilirubin >2 ULN (see Appendix E) 
• 
Serum ALT >5 ULN if baseline ALT <2 ULN or ALT >8 ULN if baseline ALT >2 ULN 
(see Appendix E) 
• 
Certain AEs deemed related to the IMP (eg, severe and prolonged injection site reactions) 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
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Patients who permanently discontinue the IMP will be asked and encouraged to return to the 
clinic for study visits and participate in assessments according to the visit schedule until the end of 
the study with a ± 3 day window (see Section 10.1.5). Under exceptional circumstances when a 
patient cannot come to the site for the scheduled visit, a phone contact can be made after sponsor 
approval is given. During the phone contact, at least information about AEs and concomitant 
medication should be collected.  
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. 
10.3.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. 
Withdrawal of consent for follow-up should be accompanied by documentation of the reason for 
withdrawal. Withdrawal of consent for treatment should be distinguished from withdrawal of 
consent for follow-up visits and from withdrawal of consent for non-patient contact follow-up, 
eg, medical records checks. Patients requesting withdrawal should be informed that withdrawal of 
consent for follow-up will jeopardize the public health value of the study. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any adverse event information elicited should be documented.  
Patients may withdraw consent verbally or in writing and, if verbal, then the site needs to 
document in source records that patient withdrew consent verbally. 
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit including a systemic drug concentration sample, if appropriate, and 3 posttreatment 
follow-up period visits. 
For patients who fail to return to the site, the Investigator should make the best effort to recontact 
the patient (eg, contacting patient’s family or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, including at least his/her vital status. 
Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contacts, and receipt for sending a registered letter). 
A subject should only be designated as lost to follow-up if the site is unable to establish contact 
with the subject after 3 documented attempts via 2 different methods (phone, text, e-mail, certified 
letter, etc). 
The statistical analysis plan (SAP) will specify how these patients lost to follow-up for their 
primary endpoints will be considered.  
Patients who have withdrawn from the study cannot be rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
Patients prematurely discontinued from the study will not be replaced. 
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Is life-threatening, or  
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect 
• 
Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered as a medically important event. The 
list is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Anaphylaxis (refer to Appendix C for definition of Anaphylaxis) 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 ULN + total bilirubin >2 ULN or ALT increase >10 ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
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10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added or removed 
during a study by protocol amendment. 
For these AESIs, the sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described Section 10.4.3, even if not fulfilling a seriousness criterion, using the 
corresponding pages in the CRF (to be sent) or screens in the e-CRF.  
• 
Anaphylactic reactions  
• 
Systemic or extensive hypersensitivity reactions 
• 
Malignancy 
• 
Helminthic infections  
• 
Suicide-related events 
• 
Blepharitis (severe or serious or lasting ≥4 weeks) 
• 
Any type of conjunctivitis (severe or serious or lasting ≥4 weeks) 
• 
Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/NIMP 
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2) 
- 
In the event of pregnancy in a female participant, IMP should be discontinued 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined 
• 
Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient and defined as at least twice 
the intended dose within the intended therapeutic interval (eg, 11 days for dupilumab). 
The circumstances (ie, accidental or intentional) should be clearly specified in the 
verbatim and symptoms, if any, entered on separate adverse event forms. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
10.4.2 General guidelines for reporting adverse events 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that patient, are 
to be recorded on the corresponding page(s) or screen(s) of the CRF. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, intensity, action taken with respect to IMP, 
corrective treatment/therapy given, additional investigations performed, outcome, and his/her 
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opinion as to whether there is a reasonable possibility that the AE was caused by the IMP or by 
the study procedure(s). 
The Investigator should take appropriate measures to follow all AEs until clinical recovery is 
complete and laboratory results have returned to normal, or until progression has been stabilized, 
or until death, in order to ensure the safety of the patients. This may imply that observations will 
continue beyond the last planned visit per protocol, and that additional investigations may be 
requested by the monitoring team up to as noticed by the sponsor. Patients who experience an 
ongoing SAE or an AESI, at the prespecified study end-date, should be followed until resolution, 
stabilization, or death and related data will be collected.  
When treatment is prematurely discontinued, the patient’s observations will continue until the end 
of the study as defined by the protocol for that patient. 
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if  
• 
Symptomatic, and/or  
• 
Requiring either corrective treatment or consultation, and/or  
• 
Leading to IMP discontinuation or modification of dosing, and/or  
• 
Fulfilling a seriousness criterion, and/or  
• 
Defined as an AESI 
Instruction for AE reporting timeframes are summarized in Table 2. 
Table 2 - Summary of adverse event reporting instructions 
Event category 
Specific events 
Reporting timeframe 
Adverse event (non-SAE, non-AESI) 
Any AE that is not SAE or AESI 
Routine 
Serious adverse event 
Any AE meeting seriousness criterion per Section 10.4.1.2 
Expedited (within 24 hours) 
Adverse event of special interest 
Anaphylactic reactions 
Expedited (within 24 hours) 
 
Systemic or extensive hypersensitivity reactions 
Expedited (within 24 hours) 
 
Malignancy 
Expedited (within 24 hours) 
 
Helminthic infections 
Expedited (within 24 hours) 
 
Suicide-related events 
Expedited (within 24 hours) 
 
Blepharitis (severe or serious or lasting ≥4 weeks) 
Expedited (within 24 hours) 
 
Any type of conjunctivitis (severe or serious or lasting 
≥4 weeks) 
Expedited (within 24 hours) 
 
Pregnancy of a female subject or a female partner of a 
male subject 
Expedited (within 24 hours) 
 
Symptomatic overdose 
Expedited (within 24 hours) 
Abbreviations: SAE: serious adverse event; AESI: adverse event of special interest 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
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• 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient’s identity is protected and the patient’s 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the sponsor. For laboratory results, include the laboratory normal ranges. 
• 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 
• 
A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest 
For AESIs, the sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
10.4.5 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix E. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices: 
• 
Neutropenia 
• 
Thrombocytopenia 
• 
Increase of ALT 
• 
Acute renal insufficiency 
• 
Suspicion of rhabdomyolysis 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the sponsor will report in an expedited manner: 
• 
All SAEs, that are both unexpected and at least reasonably related to the IMP suspected 
unexpected adverse drug reactions (SUSARs), to the regulatory authorities, IECs/IRBs as 
appropriate and to the Investigators. 
• 
All SAEs, that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
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In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected (please refer to the Investigator’s Brochure [IB]). 
Any other AE not listed as an expected event in the IB or in this protocol will be considered 
unexpected. 
For safety, the treatment code will be unblinded by the sponsor for reporting to the Health 
Authority of any SUSAR and reasonably associated with the use of the IMP according to the 
judgment of the Investigator and/or the sponsor.  
In case of a SUSAR, Sanofi Global Pharmacovigilance and Epidemiology will utilize XGRID to 
reveal medication assignment for regulatory reporting requirements for the particular case.  
The sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypersensitivity 
Allergic reaction is a risk associated with the administration of most therapeutic monoclonal 
antibodies, including dupilumab.  
Acute allergic reactions may be defined as allergic reaction-mediated signs and symptoms 
experienced by patients, during or shortly after the pharmacologic or biologic agent is given. 
These reactions may present in a variety of ways, including dizziness, headache, anxiety, dyspnea, 
hypotension, tachycardia, pruritus, rash, urticaria/angioedema, flushing, nausea, or vomiting. 
Anaphylaxis may represent the most severe form of infusion reaction, but these events may also 
occur via non-IgE mediated mechanisms (eg, anaphylactoid reactions), or may occur via other 
immune-mediated mechanisms (eg, cytokine-mediated). Allergic reactions may begin within a 
few hours and persist up to 24 hours postdosing. Refer to Appendix C “Definition of 
Anaphylaxis”, which describes the clinical criteria for the diagnosis of anaphylaxis. 
Patients should be monitored for at least 30 minutes after each injection of the IMP at study site 
for any signs or symptoms of a hypersensitivity reaction. Any anaphylactic reactions or systemic 
allergic reactions that are related to IMP and require treatment are AESI (report within 24 hours) 
and study medication should be permanently discontinued. Trained personnel and medications 
should be available to treat anaphylaxis or any severe allergic reaction if it occurs. Furthermore, 
the patients will be advised, when the IMP is administered at home, to self-monitor for potential 
signs and symptoms that may suggest a hypersensitive reaction for 30 minutes after 
administration. 
10.6.2 Severe injection site reactions  
Based on the SC mode of administration of a therapeutic protein, severe injection site reactions 
are considered as a potential risk. Patients who experience an injection site reaction must be 
closely monitored for the possibility of a more intense injection site reaction with a future 
injection. 
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10.6.3 Infections, including parasitic infections  
Since dupilumab binds to IL-4Rα, preventing IL-4 and IL-13 binding and activation of their 
respective receptors, it inhibits the Th2 cytokines productions. Infections with a diversity of 
helminthic parasites elicit eosinophilia via stimulation of Th2-like lymphocyte responses. The Th2 
response is characterized by production of IL-4 and IL-5, subsequently generating IgG1 and 
IgE-secreting cells, and eliciting eosinophilia. Eosinophilia is prominent in a number of 
helminthic parasitic diseases. The eosinophilic response to helminths is determined both by the 
host’s immune response and by the parasite, including its distribution, migration, and 
development within the infected host. Therefore, patient with treatment of dupilumab may 
potentially have an increased risk of helminthic parasitic infection 
In order to minimize this risk, any patient with an active parasitic infection should be excluded 
from the study. Similarly, patients with suspected parasitic infection, or those at high risk of 
parasitic infection are also excluded, unless clinical and (if necessary) laboratory assessments 
have ruled out active infection before randomization. During the study, appearance of signs or 
symptoms (such as abdominal pain, cough, diarrhea, fever, fatigue, and hepatosplenomegaly) that 
could be associated with a parasitic infection should be carefully evaluated, especially if there is a 
history of parasitic exposure through recent travel to/or residence in endemic areas, especially 
when conditions are conducive to infection (eg, extended stay, rural or slum areas, lack of running 
water, consumption of uncooked, undercooked, or otherwise potentially contaminated food, close 
contact with carriers and vectors). Subsequent medical assessments (eg, stool exam, blood tests) 
must be performed in order to rule out parasitic infection/infestation. 
Helminthic infections defined in Section 10.4.1.3 should be reported as AESIs within 24 hours. 
A complete diagnostic work-up should be performed (ie, cultures, histopathological or cytological 
evaluation, antigen detection and serum antibody titers). Patients should be referred to an 
infectious disease specialist if deemed necessary for diagnostic work up and appropriate treatment. 
Infections or infestations that do not respond to medical treatment should have the IMP 
discontinued until the infection is resolved. 
For any opportunistic infection or other infections, whose nature or course may suggest an 
immunocompromised status (see Appendix D), patients MUST be permanently discontinued from 
the IMP. 
10.6.4 Elevated liver function tests  
No pre-clinical and clinical data suggested any hepatic toxicity of anti-IL4 agent; however, as 
general consideration of clinical development, the administration of immunosuppressant or 
immunomudulating agents may represent an additional risk factor for hepatotoxicity.  
In order to closely follow potential liver abnormalities, assessment of total protein, albumin, total 
bilirubin (in case of values above the normal range, differentiation in conjugated and 
nonconjugated bilirubin), alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase are measured as part of the clinical laboratory testing (see Section 9.2.2.2). Clinical 
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laboratory testing at Visit 1 adds hepatitis screen (HBsAg, HBsAb, HBcAb [HBV DNA will be 
tested for patients who present with HBsAg negative and HBcAb positive at screening and may 
be performed prior to randomization], and HCV Ab [in case of results showing HCV Ab positive, 
an HCV RNA testing may be performed to rule out a false positivity, if the Investigator believes 
the patient is a false positive]). Active hepatitis or patients with positive HBsAg, or patients with 
positive HBcAb plus positive HBV DNA, or positive HCV Ab (confirmed with presence of HCV 
RNA if needed) at Visit 1 are excluded from the study. 
Guidance for the investigation of elevated ALT as well as concurrent management of IMP is 
provided in Appendix E. 
10.6.5 Ocular surface disease 
Patients with signs of any ocular surface disease, eg, conjunctivitis and blepharitis, will be 
referred to an ophthalmologist. Any baseline findings will be documented as part of the patient’s 
medical history and/or physical exam, as appropriate. 
Any inflammatory ophthalmological condition that occurs post-baseline will be captured as an AE. 
Patients with any ocular surface diseases post-baseline (even lasting for less than 4 weeks) should 
be referred to an ophthalmologist for further evaluation and treatment. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
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 9. 
11.1 
DETERMINATION OF SAMPLE SIZE 
A total of 160 patients (with a randomization ratio of 1:1, 80 patients in each of the dupilumab 
300 mg q2w and the placebo groups) will be enrolled in this study. 
The study will have 94% power to detect the difference between dupilumab and the placebo. It is 
based on the following assumptions: 
• 
The percentages of patients who achieve an IGA score of 0 to 1 and a reduction from 
baseline ≥2 points at Week 16 are 37% and 12% for dupilumab and placebo, respectively. 
• 
A two-sided continuity corrected Chi-square test with the significance level of 0.05. 
Calculations were made using nQuery Advisor 7.0 Software. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who signed the informed consent. 
Randomized patients consist of all patients, who have been allocated a treatment kit based on a 
randomization process. For studies using IRT for drug allocations, it will consist of all patients 
with a treatment kit number allocated and recorded in the IRT database, and regardless of whether 
the treatment kit was used or not. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population.  
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy population 
Efficacy analyses will be based on the ITT population which includes all randomized patients. 
Patients will be analyzed according to the treatment allocated by the IRT at randomization (as 
randomized). 
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The PP population includes all patients in the ITT population 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. The criteria of major protocol deviations are defined as 
the following: 
• 
A patient who does not receive treatment as randomized 
• 
Any major violations of efficacy-related entry criteria 
• 
The percentage of a patient’s compliance with the IMP injection is <80% or >120% of the 
scheduled doses during the study treatment period 
11.3.2 Safety population 
The safety population consists of all randomized patients who received any IMP. Patients will be 
analyzed according to the treatment they actually received (as treated).  
In addition: 
• 
Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately. 
• 
Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized. 
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
safety analysis population. 
11.3.3 Other analysis populations 
The PK population includes all randomized patients with at least 1 post-baseline drug 
concentration result. The ADA population includes all randomized patients with at least 
1 postbaseline ADA result. Patients will be analyzed according to the treatment actually received. 
11.4 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1 Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group.  
No statistical tests will be performed on demographic characteristics. 
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11.4.2 Extent of study treatment exposure and compliance 
11.4.2.1 Extent of investigational medicinal product exposure 
The duration of IMP exposure during the study will be presented by treatment and calculated as: 
(Date of last IMP injection – date of first IMP injection) + 14 days regardless of unplanned 
intermittent discontinuations. 
The number (%) of patients randomized and exposed to double-blind IMP 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. 
11.4.2.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. The compliance with study treatment will be calculated as follows: 
Treatment compliance = (number of IMP injections during exposure period)/(number of planned 
IMP injections during exposure period) x 100%. 
Treatment compliance will be summarized descriptively and presented by specific ranges for each 
treatment group. The ranges of interest will be specified in the SAP. 
11.4.3 Analyses of efficacy endpoints 
11.4.3.1 Analysis of primary efficacy endpoint 
Primary Hypotheses: 
The following hypotheses will be tested: 
H0: No treatment difference between dupilumab and placebo 
H1: There is a treatment difference between dupilumab and placebo 
Primary analysis 
The Cochran-Mantel-Haenszel test adjusted by baseline disease severity (moderate or severe) 
will be used for the percentage of patients with both IGA 0 or 1 and a reduction from baseline of 
≥2 points at Week 16 on the ITT population. The analysis of primary endpoint on the PP 
population will be supportive. 
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To account for the impact of rescue medication on the efficacy effect, 
• 
For the binary efficacy endpoints, if rescue medication or procedure is used 
(see Section 8.2.2 for rescue), the patient will be specified as a non-responder from the 
time the rescue is used. 
• 
If a patient withdraws from the study, this patient will be counted as a non-responder for 
endpoints after withdrawal. 
The primary efficacy analyses will be performed on the PP population as a supportive analysis. 
Sensitivity analysis using 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. 
In addition, the Cochran-Mantel-Haenszel method adjusted by randomization strata will also be 
performed on the observed response regardless of rescue medication or procedure use, and 
patients with missing values will be counted as non-responders. 
11.4.3.2 Analyses of secondary efficacy endpoints 
For binary endpoints, the secondary efficacy analysis will use the same approach as that used for 
the primary analysis. 
The continuous endpoints will be analyzed using the MI with ANCOVA model as the primary 
analysis. Patients’ efficacy data after rescue medication up to Week 16 will be set to missing and 
then imputed by the MI method. Missing data will be imputed 50 times to generate 50 complete 
data sets by using the SAS MI procedure (using Markov Chain Monte Carlo method). The 
Week 16 data of each of the 50 complete datasets will be analyzed using an ANCOVA model 
with treatment, randomization strata (disease severity), and relevant baseline value included in the 
model, and the SAS MIANALYZE procedure will be used to generate valid statistical inferences 
by combining results from the 50 analyses using Rubin’s formula. 
The imputation model will include 
• 
The variables in the ANCOVA model, including treatment group, randomization strata 
and relevant baseline value. 
• 
Measured continuous endpoint values in each scheduled visit up to Week 16 
Categorical variables included in above model (ie, treatment group and randomization strata) are 
not expected to be missing. 
To account for the impact of rescue medication or procedure on the efficacy effect: 
• 
Continuous efficacy endpoints: if a patient receives rescue medication or procedure that 
specifies the patient as a non-responder according to the above rules for binary efficacy 
endpoints, the data collected after rescue medication or procedure is initiated will be 
treated as missing. 
• 
If a patient withdraws from the study, this patient will be counted as a non-responder for 
endpoints after withdrawal. 
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The mixed-effect model repeated measures (MMRM) will be used to assess the robustness of the 
analysis with regards to handling of missing data. The MMRM model includes factors (fixed 
effects) for treatment, randomization strata, visit, treatment-by-visit interaction, and relevant 
baseline values. It will provide baseline adjusted least-squares means at Week 16 and at other time 
points for each treatment group with the corresponding standard error and the confidence interval, 
as well as the p values for treatment comparisons. 
There will be other sensitivity analyses using MI method based on all observed data regardless if 
rescue treatment is used or if data are collected after withdrawal and using LOCF method. 
Additional details will be provided in the SAP. 
11.4.3.3 Multiplicity considerations 
If the primary endpoint is significant at the 0.05 level, the secondary endpoints will be tested 
following the hierarchical testing procedure with a pre-specified order, that is, inferential 
conclusions about successive secondary endpoints require statistical significance at the 
0.05 significance level of the prior one. The testing hierarchy will be detailed in the SAP. 
11.4.4 Analyses of safety data 
The summary of safety results will be presented by treatment group. All safety analyses (includes 
reported TEAEs and other safety information as clinical laboratory evaluations, vital signs, and 
12-lead ECG results) will be performed on the safety population using the following common 
rules: 
• 
The baseline value is defined generally as the last available value before randomization.  
For safety variables, two observation periods are defined: 
• 
The pre-treatment period is defined as the time from signing the informed consent form 
(ICF) to before the first dose of IMP. 
• 
The TEAE period is defined as the time from first dose of IMP (Day 1) to the end of the 
study. 
The following definitions will be applied to clinical laboratory evaluations, vital signs and ECG. 
• 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the sponsor according to predefined 
criteria/thresholds based on literature review and defined by the sponsor for clinical 
laboratory tests, vital signs, and ECG.  
• 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage.  
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11.4.4.1 Adverse Events 
All Adverse events reported in this study will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA®) in effect at the time of database lock. The analyses of adverse events will 
focus on TEAEs. 
Definitions 
Pretreatment AEs are defined as AEs that developed or worsened during the pre-treatment period. 
Treatment-emergent adverse events are defined as AEs that developed or worsened during the 
treatment-emergent period. The treatment-emergent period is from first administration of IMP to 
end of the follow-up period. 
Treatment-emergent adverse events (TEAE) 
The incidence tables will present by system organ class (SOC) (sorted by internationally agreed 
order), high-level group term (HLGT), high level term (HLT) and preferred term (PT) sorted in 
alphabetical order for each treatment group, the number (n) and percentage (%) of patients 
experiencing an TEAE. Multiple occurrences of the same event in the same patient will be 
counted only once in the tables within a treatment phase. The denominator for computation of 
percentages is the safety population within each treatment group. 
TEAEs will also be summarized by severity and relationship to IMP for each treatment group, 
presented by SOC and PT. 
Death 
The following deaths summaries will be generated: 
• 
Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population by treatment received. 
• 
Death in nonrandomized patients or randomized and not treated patients 
• 
TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT. 
Listings will be provided for all deaths by treatment group and patient with flags indicating on-
treatment status. 
Serious adverse events:  
Number (%) of patients with at least one treatment emergent SAE will be summarized by 
treatment group and presented by primary SOC (sorted by internationally agreed order), HLGT, 
HLT, and PT sorted in alphabetical order. SAEs will also be listed by treatment group and patient. 
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TEAEs leading to permanent treatment discontinuation: 
Number (%) of patients with at least one TEAE leading to permanent treatment discontinuation 
will be summarized by treatment group and presented by primary SOC (sorted by internationally 
agreed order), HLGT, HLT, and PT sorted in alphabetical order. TEAE leading to permenant 
treatment discontinuation will be listed by treatment group and patient. 
Adverse events of special interest:  
Treatment-emergent AESI will present number (%) of patients overall, by AESI category and PT, 
sorted by decreasing incidence of PT within each AESI category. 
11.4.4.2 Clinical laboratory evaluations 
Laboratory test results will be summarized by baseline and change from baseline to each visit 
with descriptive statistics. 
Number and percentage of patients with a treatment-emergent PCSA will be summarized for each 
clinical laboratory test. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
11.4.4.3 Vital signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to visit with descriptive statistics. 
Number and percentage of patients with a treatment-emergent PCSA will be summarized for each 
vital sign variable.  
11.4.4.4 Analysis of anti-drug antibody variables 
The ADA variables described in Section 9.2.2.7 will be analyzed using descriptive statistics. Drug 
concentration data will be examined and the influence of ADAs on individual concentration-time 
profiles will be evaluated. Assessment of impact of ADA on safety and efficacy may be provided. 
11.4.5 Analysis of pharmacokinetic variables 
The following analyses may be conducted: 
• 
Sparse sampling: 
- 
Descriptive statistics at each sampling time 
• 
Correlation analyses: 
- 
Body weight versus serum concentrations 
- 
Serum concentrations versus clinical outcomes 
No formal statistical analysis will be performed.  
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11.4.6 Analysis of quality of life and health economics variables 
All QOL data analyses will be performed on the ITT and no multiplicity adjustment is planned. 
Analyses of QOL endpoints will be provided in the SAP. 
  
 
 
11.4.8 Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline: 
• 
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of study drug. If any 
randomized patients are not treated, the baseline will be the last value on or prior to the 
randomization. 
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 non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries. If more than 1 laboratory value is available for a given visit, 
the first observation will be used in summaries and all observations will be presented in 
listings. 
11.5 
INTERIM ANALYSIS 
No interim analysis is planned. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for 
good clinical practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study in language and terms they are able to understand.  
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
The informed consent form used by the Investigator for obtaining the patient’s informed consent 
must be reviewed and approved by the sponsor prior to submission to the appropriate ethics 
committee (IRB/IEC) for approval/favorable opinion. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party a 
copy of the written and dated approval/favorable opinion signed by the Chairman with IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, IB, Investigator’s curriculum vitae [CV], 
etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
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IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the sponsor.  
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. They should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the IB will 
be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial. 
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by sponsor representatives.  
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred.  
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information.  
13.2 
RESPONSIBILITIES OF THE SPONSOR  
The sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial.  
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
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13.3 
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. 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the preidentified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the sponsor’s duly authorized 
personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the CRFs (eg, patient's medical file, 
appointment books, original laboratory records). These personnel, bound by professional secrecy, 
must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the sponsor to record (according to sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the IB and the results obtained during 
the course of the clinical trial, is confidential, prior to the publication of results. The Investigator 
and any person under his/her authority agree to undertake to keep confidential and not to disclose 
the information to any third party without the prior written approval of the sponsor.  
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality.  
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party’s account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the sponsor or its designee are and remain the 
sole property of the sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the sponsor. 
The sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the sponsor, at the sponsor’s expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
The patient’s personal data, which are included in the sponsor database, shall be treated in 
compliance with all applicable laws and regulations; 
When archiving or processing personal data pertaining to the Investigator and/or to the patients, 
the sponsor shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. 
The sponsor also collects specific data regarding Investigator as well as personal data from any 
person involved in the study which may be included in the sponsor’s databases, shall be treated by 
both the sponsor and the Investigator in compliance with all applicable laws and regulations. 
Subject race and ethnicity will be collected in this study because these data are required by the 
regulatory authority (ie, on Chinese population for the China Food and Drug Administration 
[CFDA]). 
The data collected in this study will only be used for the purposes of the study and to document 
the evaluation of the benefit/risk ratio, efficacy and safety of the product. They may be further 
processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION 
The sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the sponsor does not relieve the Investigator and the collaborators from any 
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obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document. 
Financing and insurance information is provided as a separate agreement. 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the sponsor 
and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the sponsor and authorize the sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the sponsor. 
The Investigator shall take appropriate measures required by the sponsor to take corrective actions 
for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the sponsor 
The sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio; 
• 
Patient enrollment is unsatisfactory; 
• 
The Investigator has received from the sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
• 
Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP; 
• 
The total number of patients are included earlier than expected. 
In any case the sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days’ prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the sponsor’s written consent, being understood that the sponsor will 
not unreasonably withhold its approval.  
As the study is being conducted at multiple sites, the sponsor agrees that, consistent with scientific 
standards, a primary presentation or publication of the study results based on global study 
outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the sponsor 
deems appropriate to establish and preserve its proprietary rights. 
The Investigator shall not use the name(s) of the sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the sponsor. The sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s).  
The sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol.  
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the sponsor and the signed amendment will be filed with this 
clinical trial protocol.  
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be recollected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. 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;70(2):338-51. Epub 2013 Nov 27. 
2. Bieber T. Mechanisms of disease: atopic dermatitis. N Engl J Med. 2008;358(14):1483-94. 
3. 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(5):606-19. 
4. Schmitt J, Schakel K, Folster-Holst R, Bauer A, Oertel R, Augustin M, et al. Prednisolone vs. 
ciclosporin for severe adult eczema. An investigator-initiated double-blind placebo-controlled 
multicentre trial. Br J Dermatol. 2010;162(3):661-8. Epub 2009 Oct 26. 
5. Schram ME, Spuls PI, Leeflang MM, Lindeboom R, Bos JD, Schmitt J. EASI, (objective) 
SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important 
difference. Allergy. 2012;67(1):99-106. Epub 2011 Sep 27. 
6. Akhavan A, Rudikoff D. Atopic dermatitis: systemic immunosuppressive therapy. Semin 
Cutan Med Surg. 2008;27(2):151-5. 
7. Walling HW, Swick BL. Update on the management of chronic eczema: new approaches and 
emerging treatment options. Clin Cosmet Investig Dermatol. 2010;3(2):99-117. 
8. Makris MP, Papadavid E, Zuberbier T. The use of biologicals in cutaneous allergies - present 
and future. Curr Opin Allergy Clin Immunol. 2014;14(5):409-16. 
9. Ibler K, Dam TN, Gniadecki R, Kragballe K, Jemec GB, Agner T. Efalizumab for severe 
refractory atopic eczema: retrospective study on 11 cases. J Eur Acad Dermatol Venereol. 
2010;24(7):837-9. Epub 2009 Apr 2. 
10. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and 
severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. 
Exp Dermatol. 2001;10(1):11-8. 
11. Badia X, Mascaro JM, Lozano R. Measuring health-related quality of life in patients with mild 
to moderate eczema and psoriasis: clinical validity, reliability and sensitivity to change of the 
DLQI. The Cavide Research Group. Br J Dermatol. 1999;141(4):698-702. 
12. 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. Arch Dermatol. 2004;140(12):1513-9. 
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13. Kaufmann R, Bieber T, Helgesen AL, Andersen BL, Luger T, Poulin Y, et al. Onset of 
pruritus relief with pimecrolimus cream 1% in adult patients with atopic dermatitis: a 
randomized trial. Allergy. 2006;61(3):375-81. 
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17 
APPENDICES 
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Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
2. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Male subjects 
• Male subjects with heterosexual partners of reproductive potential (WOCBP) are eligible 
to participate if they agree to use the following during the protocol defined timeline: 
- 
Refrain from donating sperm  
and 
- 
At least 1 of the following conditions applies: 
- 
Are and agree to remain abstinent from penile-vaginal intercourse on a long term 
and persistent basis, when this is their preferred and usual lifestyle.  
or 
- 
Agree to use a male condom plus an additional contraceptive method with a failure 
rate of <1% per year (see table for female subjects) 
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom for the time defined in the protocol 
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Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationb 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationb 
- 
oral 
- 
injectable 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective 
method(s) of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the subject.) 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. In 
this case TWO highly effective methods of contraception should be used during the treatment period and for at least 12 weeks after the last 
dose of study treatment. 
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Female subjects: 
 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulationb 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationb 
- 
oral 
- 
injectable 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective 
method(s) of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the subject.) 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. In 
this case TWO highly effective methods of contraception should be used during the treatment period and for at least 12 weeks after the last 
dose of study treatment. 
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Appendix B 
List of Prohibited Live, Attenuated Vaccines 
Bacillus Calmette-Guérin (BCG) anti-tuberculosis vaccine  
Chickenpox (Varicella)  
Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection is 
permitted  
Measles (Rubeola)  
Measles-mumps-rubella (MMR) combination  
Measles-mumps-rubella-varicella (MMRV) combination  
Mumps  
Oral polio (Sabin)  
Oral typhoid  
Rotavirus  
Rubella  
Smallpox (Vaccinia)  
Varicella Zoster (shingles)  
Yellow fever 
 
 
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Appendix C 
Definition of Anaphylaxis 
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.”  
(Adapted from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum 
A, et al. Second symposium on the definition and management of anaphylaxis: Summary report—
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol 2006; 117: 391-397)  
Clinical criteria for diagnosing anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1. 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, 
generalized hives, pruritus, or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, incontinence) 
2. 
Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several 
hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch0flush, swollen lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. 
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BPa 
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that person’s baseline 
Abbreviations: PEF: peak expiratory flow; BP: blood pressure. 
a Low systolic pressure for children is defined as less than 70 mmHg from 1 month to 1 year, less than (70 mmHg + [2 * age]) from 1 to 
10 years, and less than 90 mmHg from 11 to 17 years. 
 
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Appendix D 
Opportunistic infection 
The list below is indicative and not exhaustive: 
• 
Aspergillosis 
• 
Blastomyces dermatitidis  
• 
Candidiasis – only systemic or extensive mucosal or cutaneous cases. 
• 
Coccidioides immitis  
• 
Cryptococcus 
• 
Cytomegalovirus 
• 
Herpes Simplex (disseminated) 
• 
Herpes Zoster (disseminated; ophthalmic; involvement of 2 or more dermatomes) 
• 
Histoplasmosis (pulmonary or disseminated; most common in tropical areas) 
• 
Listeriosis 
• 
Mycobacterium avium 
• 
Nontuberculosis mycobacteria 
• 
Pneumocystis pneumonia (PCP) 
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Appendix E 
General Guidance for the follow-up of laboratory abnormalities by 
Sanofi 
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
 
Neutropenia is to be recorded as AE only if at least one of the criteria listed in the General 
guidelines for reporting adverse events in Section 10.4.2 is met. 
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
 
Thrombocytopenia is to be recorded as AE only if at least one of the criteria listed in the General 
guidelines for reporting adverse events in Section 10.4.2 is met. 
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INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or episode of 
arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances suggesting hepatic 
encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to normal/baseline or clinical 
resolution.
8.
FREEZE serum sample (5ml x 2)
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
• “Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the 
baseline visit. The algorithm does not apply to the instances of increase in ALT during screening. 
• See Section 10.4 for guidance on safety reporting. 
• Normalization is defined as ≤ ULN or baseline value, if baseline value is >ULN. 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
 
Acute renal failure is to be recorded as AE only if at least one of the criteria listed in the General 
guidelines for reporting adverse events in Section 10.4.2 is met. 
(electronic 
 
 
 
1.0)


Amended Clinical Trial Protocol No. 01  
21-Jun-2018 
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Version number: 1 
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Page 97 
If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK ≤10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
 
Suspicion of rhabdomyolysis is to be recorded as AE only if at least one of the criteria in the 
General guidelines for reporting adverse events in Section 10.4.2 is met. 
(electronic 
 
 
 
1.0)

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Title: 
A randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of dupilumab in Chinese 
adult patients with moderate-to-severe atopic dermatitis 
Protocol:  
EFC15116 
Investigational product: 
Dupilumab 
Sponsor:  
Sanofi (China) Investment Co., Ltd 
Statistician:   
 
Clinical Trial Manager: 
 
Clinical Study Director: 
 
Author: 
______________________________________________________________________ 
 
 
 
Date 
Approvers: 
______________________________________________________________________ 
Statistical Group Head 
 
 
 
 
 
 
Date 
______________________________________________________________________ 
Clinical Development Physician 
 
 
 
 
 
Date 
VV-CLIN-0555577 1.0
NCT03912259


Statistical Analysis Plan                                                                                               27-Nov-2019 
EFC15116 - dupilumab                                                                                    Version Number: 1.0 
Property of the Sanofi Group – strictly confidential 
 
2
Table of Contents 
Table of Contents ................................................................................................................ 2 
List of abbreviations and definition of terms ...................................................................... 5 
1 
OVERVIEW ........................................................................................................... 8 
1.1 
Background and Rationale ...................................................................................... 8 
1.2 
Study Objectives ................................................................................................... 10 
1.2.1 Primary Objective ................................................................................................. 10 
1.2.2 Secondary Objectives ............................................................................................ 10 
1.2.3 Other Objectives .................................................................................................... 10 
1.3 
Modifications from the Statistical Section in the Final Protocol .......................... 10 
1.4 
Modification from the Previously Approved SAP ................................................ 10 
2 
INVESTIGATIONAL PLAN ............................................................................... 11 
2.1 
Study Design and Randomization ......................................................................... 11 
2.2 
Sample Size and Power Considerations ................................................................ 11 
2.3 
Study Plan ............................................................................................................. 11 
3 
ANALYSIS POPULATIONS ............................................................................... 13 
3.1 
Intent-to-treat Population ...................................................................................... 13 
3.2 
Per Protocol Population ......................................................................................... 13 
3.3 
Safety Population .................................................................................................. 13 
3.4 
Pharmacokinetic (PK) Population ......................................................................... 14 
3.5 
Anti-Drug Antibody (ADA) Population ............................................................... 14 
4 
ANALYSIS VARIABLES .................................................................................... 15 
4.1 
Demographic and Baseline Characteristics ........................................................... 15 
4.2 
Medical History and Atopic Disease Medical History ......................................... 15 
4.3 
Pre-treatment/ Concomitant Medications and Procedures .................................... 15 
4.4 
Efficacy Variables ................................................................................................. 17 
4.4.1 Primary Efficacy Variable ..................................................................................... 17 
4.4.2 Secondary Efficacy Variables ............................................................................... 17 
4.5 
Safety Variables .................................................................................................... 21 
4.5.1 Adverse Events and Serious Adverse Events Variables ....................................... 21 
4.5.2 Laboratory Safety Variables ................................................................................. 22 
4.5.3 Vital Sign Variables .............................................................................................. 23 
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4.5.4 12-Lead Electrocardiography (ECG) Variable ..................................................... 23 
4.5.5 Physical Examination Variable ............................................................................. 23 
4.5.6 Immunogenicity Variables .................................................................................... 23 
4.6 
Pharmacokinetic (PK) Variables ........................................................................... 24 
4.7 
Pharmacodynamic Variables ................................................................................. 24 
5 
STATISTICAL METHODS ................................................................................. 26 
5.1 
Demographics and Baseline Characteristics ......................................................... 26 
5.2 
Medical History and Atopic Disease Medical History ......................................... 26 
5.3 
Pre-treatment/Concomitant Medications/Procedures ............................................ 26 
5.4 
Patient Disposition ................................................................................................ 26 
5.5 
Dose administration .............................................................................................. 27 
5.6 
Treatment Exposure and Observation Period ....................................................... 27 
5.7 
Analyses of Efficacy Variables ............................................................................. 28 
5.7.1 Analysis of Primary Efficacy Variables ................................................................ 28 
5.7.2 Analyses of Secondary Efficacy Variables ........................................................... 29 
5.8 
Analysis of Safety Data ......................................................................................... 31 
5.8.1 Analysis of Adverse Events .................................................................................. 31 
5.8.2 Analysis of Clinical Laboratory Measurements .................................................... 33 
5.8.3 Analysis of Vital Signs .......................................................................................... 33 
5.8.4 Analysis of Physical Examination ........................................................................ 34 
5.8.5 Analysis of 12-Lead ECG ..................................................................................... 34 
5.8.6 Analysis of Immunogenicity Data ........................................................................ 34 
5.8.6.1 
Analysis of ADA Data ..................................................................................... 34 
5.8.6.2 
Immunogenicity and Pharmacokinetics ........................................................... 34 
5.8.6.3 
Immunogenicity and Safety and Efficacy ........................................................ 34 
5.9 
Analysis of Pharmacokinetic Data ........................................................................ 35 
5.9.1 Descriptive Analysis of Dupilumab Concentrations in Serum ............................. 35 
5.9.2 Analysis of Concentration-Response Relationship ............................................... 35 
5.10 
Pharmacodynamic Data ........................................................................................ 36 
6 
DATA CONVENTIONS ...................................................................................... 37 
6.1 
Definition of Baseline for Efficacy/Safety Variables ........................................... 37 
6.2 
General Data Handling Conventions .................................................................... 37 
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EFC15116 - dupilumab                                                                                    Version Number: 1.0 
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6.3 
Data Handling Convention Missing Data ............................................................. 37 
6.4 
Analysis Visit Window ......................................................................................... 39 
7 
INTERIM ANALYSIS ......................................................................................... 43 
8 
SOFTWARE ......................................................................................................... 44 
9 
REFERENCES ...................................................................................................... 45 
10 
APPENDIX ........................................................................................................... 46 
10.1 
Summary of Statistical Analyses .......................................................................... 46 
10.2 
Schedule of Events ................................................................................................ 48 
10.3 
Criteria for Treatment-Emergent Potentially Clinical Significant Abnormality 
(PCSA) for Dupilumab AD studies ....................................................................... 51 
10.4 
SAS code for EQ-5D index utility scoring ........................................................... 55 
10.5 
Search Criteria for TEAE of Special Interest/TEAE Syndrome ........................... 56 
10.6 
Search Criteria for Personal history of atopic/allergic conditions ........................ 57 
10.7 
List of efficacy-related entry criteria ..................................................................... 59 
 
 
 
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EFC15116 - dupilumab                                                                                    Version Number: 1.0 
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5
List of abbreviations and definition of terms  
AD 
Atopic dermatitis 
ADA 
Anti-Drug Antibodies 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BSA 
Body surface area 
CRF 
Case report form 
CI 
Confidence interval 
Ctrough 
Trough concentration 
DLQI 
Dermatology life quality index 
CPK 
Creatine phosphokinase 
EAIR 
The exposure-adjusted incidence rate 
EASI 
Eczema area and severity index 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of treatment 
EQ-5D 
EuroQol five dimensions questionnaire 
EQVAS 
EQ visual analogue scale 
ET 
Early termination 
ETV 
Early termination visit 
HLGT 
High-level group term 
HLT 
High level term 
HR 
Hazard ratio 
ICF 
Informed consent form 
ICH 
International conference on harmonisation 
IFN-γ 
Interferon-gamma 
IGA 
Investigator global assessment 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IL-4Rα 
IL-4 receptor alpha 
IMP 
Investigational medicinal product 
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IRT 
Interactive response technology 
ITT 
Intent-to-treat 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LOCF 
Last observation carried forward 
LS 
Least-squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MMRM 
Mixed effect model with repeated measures 
NAb 
Anti-dupilumab neutralizing antibodies 
NEPY 
Number of events per 100 patient-years 
NIMP 
Noninvestigational medicinal product 
NRS 
Numerical rating scale 
PCS 
Pruritus categorical scale 
PCSA 
Potentially clinically significant abnormality 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
POEM 
Patient oriented eczema measure 
PP 
Per protocol 
PRO 
Patient reported outcome 
PT 
Preferred term 
q2w 
Every 2 weeks 
QOL 
Quality of life 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SMQ 
Standard MedDRA Query 
SOC 
System organ class 
SIT 
Allergen-specific immunotherapy 
TARC 
Thymus and activation regulated chemokine 
TCI 
Topical calcineurin inhibitors 
TCS 
Topical corticosteroids 
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EFC15116 - dupilumab                                                                                    Version Number: 1.0 
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TCM 
Traditional Chinese Medicine 
TEAE 
Treatment emergent adverse event 
Th1 
Type 1 helper T cell 
Th2 
Type 2 helper T cell 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
US 
United States 
WBC 
White blood cell 
WHODD 
World health organization drug dictionary 
WOCF 
Worst-observed-case-forward 
 
 
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EFC15116 - dupilumab                                                                                     Version number: 1.0 
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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 this study. The 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 EFC15116 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) is a chronic/relapsing inflammatory skin disease characterized by intense 
pruritus (i.e., itchiness), xerosis (skin dryness), and eczematous lesions whose features include 
erythema, infiltration/papulation, oozing with crusting, excoriations, and lichenification. It is often 
associated with other atopic disorders, such as allergic rhinitis and asthma. Severe disease can be 
extremely disabling due to several factors: major psychological problems, significant sleep loss, 
and impaired quality of life (QOL) that lead to a high socioeconomic cost. An estimated 2% to 
10% of adults worldwide are affected by AD. 
The pathophysiology of AD is influenced by a complex interplay between inflammation, 
environmental factors, genetics and skin barrier dysfunction.  
Skin-infiltrating lymphocytes are thought to play a pivotal role in the initiation and amplification 
of atopic inflammation. The key cells involved in the pathophysiologic mechanism of AD are 
classified into 4 general subgroups. First, dendritic cell subtypes including Langerhans cells and 
inflammatory dendritic epithelial cells polarize T-helper cells via Immunoglobulin E (IgE)- and 
non-IgE-mediated mechanisms. Dendritic cells in the skin take up and present allergens to 
lymphocytes, causing a Type 2 helper T cell (Th2) polarization and subsequent release of 
pro-inflammatory cytokines, which include interleukin (IL)-4, IL-5, and IL-13. The T-helper cells 
are the second group of cells. In acute exudative skin lesions, chemokine “C” receptor (CCR4+) 
Th2 cells are abundant and secrete cytokines IL-4, IL-13, and IL-5, whereas Type 1 helper T cells 
(Th1), which secrete interferon-gamma (IFN-γ), are also seen in chronic, lichenified lesions. 
Activated eosinophils are the third group of cells, causing local inflammation at lesional sites. 
Keratinocytes are the fourth cell-type involved in the pathophysiology of AD. These skin cells 
express high levels of the Th2 polarizing cytokine and thymic stromal lymphopoietin in AD 
lesions, which may amplify and sustain the allergic response. 
The goal in treating AD is reducing skin inflammation. Therapy has been focused on trying to 
control the T helper cell response. Topical corticosteroids (TCS) are overwhelmingly the most 
frequently prescribed class of drugs. However, long-term application of TCS is not recommended 
because of the risk of skin atrophy, dyspigmentation, acneiform eruptions, and risks associated 
with systemic absorption. Topical calcineurin inhibitors (TCI) are generally effective and safe as 
short-term treatments, but concerns of skin malignancies and increased risk of lymphomas have 
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EFC15116 - dupilumab                                                                                     Version number: 1.0 
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prompted regulatory authorities to require a warning regarding the long-term safety of topical 
tacrolimus and pimecrolimus in their prescribing information. Repeated application of any topical 
therapy over a long period of time or to large surface areas also leads to reduced patient 
compliance. First generation antihistamines are widely prescribed for acute symptomatic treatment 
of pruritus, although their effectiveness is limited and largely attributed to their sedating effect. 
Oral immunosuppressants and glucocorticoids are effective, but are sometimes associated with 
severe toxicity and side effects, thus limiting their use to short courses and/or intermittent therapy. 
Diabetes, hypertension, and osteoporosis are side effects associated with systemic corticosteroids 
and there is also the risk of rebound after steroid discontinuation.  
Cyclosporine, a current therapy for severe AD in some regions, is a potent immunosuppressant 
affecting both humoral and cellular immune responses. This results in increased susceptibility to 
infections and decreased cancer immunosurveillance. Other commonly recognized toxicities 
include hypertension and impaired renal and hepatic function. In addition, cyclosporine interacts 
with other commonly used medicines potentially affecting their metabolism and effect. Patients' 
disease often rebounds when the treatment is stopped, especially after the administration of 
systemic glucocorticoids. Biological agents including anti-tumor necrosis factor (TNF) α 
(infliximab, etanercept), anti-IgE (omalizumab), anti-IL-5 (mepolizumab), and anti CD11a 
(efalizumab) have generally been ineffective in clinical trials. Therefore, there exists a significant 
unmet medical need for an alternative treatment for AD.  
Up-regulation of IL-4 and IL-13 have been implicated as an important inflammatory component 
of AD disease progression. Dupilumab, a fully human monoclonal antibody, is directed against 
the IL-4 receptor alpha subunit (IL-4Rα), which is a component of IL-4 receptors Type I and Type 
II, as well as the IL 13 receptor system. The binding of dupilumab to IL-4Rα results in the blockade 
of both IL-4 and IL-13 signal transduction. 
Dupilumab is being developed for the treatment of moderate-to-severe AD in patients intolerant 
of, or not adequately controlled with, topical treatments. This population includes patients who are 
often treated with systemic corticosteroids, as well as other non-selective immunosuppressants, 
including cyclosporine, which are associated with significant toxicities. Dupilumab is being 
developed as a potential alternative to oral corticosteroids, calcineurin inhibitors, and other 
systemic immonosuppressive drugs, which are used for treatment of AD patients and have 
numerous, considerable adverse drug reactions (ADRs), and may increase the risk of serious 
infection. A more focused immunomodulatory agent such as dupilumab may have more limited 
effects on the immune system and potentially fewer ADRs. 
Data with dupilumab have, to date, demonstrated efficacy, safety, and tolerability in a patient 
population with moderate-to-severe AD. In global phase 2 and phase 3 studies, treatment with 
dupilumab monotherapy consistently and significantly cleared or reduced the extent and severity 
of AD lesions and relieved pruritus, with superior treatment effect to placebo demonstrated by an 
array of clinically relevant endpoints. 
The dupilumab safety database consists of over 3000 patients exposed to dupilumab across all 
indications, including over 2500 in AD. Dupilumab was well tolerated and generally safe when 
used in patients with moderate-to-severe AD. 
This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety in Chinese adult patients with moderate-to-severe AD whose disease cannot be adequately 
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Statistical Analysis Plan                                                                                               27-Nov-2019 
EFC15116 - dupilumab                                                                                     Version number: 1.0 
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10 
controlled with topical medications or for whom topical treatment is medically inadvisable. This 
study will generate information in Chinese AD patients regarding monotherapy with dupilumab 
compared to placebo. The choice of placebo as a control is appropriate for the objectives of this 
study, since it will provide the most robust assessment of the efficacy and safety of dupilumab. 
The dose regimen of subcutaneous (SC) dupilumab selected for this study is 300 mg every 2 weeks 
(q2w). The dose of dupilumab in this study were based on the efficacy and safety results from 
global pivotal Phase 3 studies (R668-AD-1334 and R668-AD-1416). 
1.2 
Study Objectives  
1.2.1 Primary Objective  
The primary objective of the study is to evaluate the efficacy of dupilumab monotherapy compared 
to placebo treatment in adult patients with moderate-to-severe AD. 
1.2.2 Secondary Objectives  
 To evaluate the safety of dupilumab monotherapy compared to placebo treatment in patients 
with moderate-to-severe AD. 
 To evaluate the effect of dupilumab on improving patient reported outcomes (PROs) 
 To evaluate dupilumab immunogenicity 
1.2.3 Other Objectives  
 To evaluate dupilumab systemic exposure 
 
 
1.3 
Modifications from the Statistical Section in the Final Protocol  
Modifications from the Amended protocol 1 (final protocol) 
1. concomitant medication/procedure 
Any concomitant treatment is considered from the first dose of study drug in the SAP instead of 
the time of informed consent in the protocol. 
2. Potentially clinically significant abnormality (PCSA) 
PCSA is applied to clinical laboratory evaluations and vital signs in SAP, while PCSA was applied 
to ECG as well in the protocol. 
1.4 
Modification from the Previously Approved SAP  
NA 
 
 
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EFC15116 - dupilumab                                                                                     Version number: 1.0 
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2 
INVESTIGATIONAL PLAN  
2.1 
Study Design and Randomization  
This is a randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate 
the efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe AD. The 
study period included 16-week treatment period 12-week follow-up. Eligible patients will be 
randomized in a 1:1 ratio to receive q2w SC injections of 300 mg dupilumab, or matching placebo. 
Randomization will be stratified by baseline disease severity (moderate [Investigator’s Global 
Assessment (IGA) 3] versus severe [IGA 4] AD). 
2.2 
Sample Size and Power Considerations  
A total of 160 patients (with a randomization ratio of 1:1, 80 patients in each of the dupilumab 300 
mg q2w and the placebo groups) will be enrolled in this study. 
The study will have 94% power to detect the difference between dupilumab and the placebo. It is 
based on the following assumptions: 
 The percentages of patients who achieve an IGA score of 0 to 1 and a reduction from 
baseline ≥2 points at Week 16 are 37% and 12% for dupilumab and placebo, respectively.  
 A two-sided continuity corrected Chi-square test with the significance level of 0.05. 
Calculations were made using nQuery Advisor 7.0 Software. 
2.3 
Study Plan  
The study consists of a screening period, a treatment period and a follow-up period as presented 
below: 
Screening:1-5 weeks  
 
 
Treatment1: 16 weeks 
 
Follow-up: 12 weeks 
 
 
 
1 Patients will receive a loading dose of the IMP on Day 1 and then receive the IMP every two weeks during the subsequent 14 
weeks. 
IMP = investigational medicinal product, q2w = once every 2 weeks. 
After providing informed consent, patients will be assessed for study eligibility at the screening 
visit. Patients will undergo screening for 7-35 days prior to randomization. During the screening 
period, treatments for AD will be washed out, as applicable, according to eligibility requirements. 
D-7 to D-35 
D1 (V2): Randomization 
Screening 
Dupilumab 300 mg q2w 
(80 patients) 
Placebo q2w 
(80 patients) 
Follow-up 
Primary  
Endpoint 
D113 (V7) End of treatment D197 (V10) End of Study 
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Patients may be rescreened once if they fail the screening evaluation for reasons related to 
incidental transitory conditions. Patients will be required to apply moisturizers (emollients) at least 
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 to receive q2w SC injections of 300 mg dupilumab following 
a loading dose of 600 mg on Day 1, or matching placebo (including doubling the amount of placebo 
on Day 1 to match the loading dose). Eligible patients must have a documented history of 
inadequate response or intolerance to treatment with topical AD medications. Following the initial 
dose of 600 mg, the investigational medicinal product (IMP) will be administered 300 mg at Weeks 
2, 4, 6, 8, 10, 12, and 14. Patients will remain at the study site for a minimum of 30 minutes after 
each injection at the study site. Patients will have the option to self-administer the IMP (or have a 
caregiver administer the IMP) outside the study site during weeks in which no clinic visit is 
scheduled (ie, Weeks 6, 10, and 14). Patients (and/or caregivers) will be trained on injecting the 
IMP at Visit 2 (Day 1) through Visit 4 (Week 4), or until competency has been demonstrated. 
Patients who do not want to self-inject may have the clinic staff administer all the IMP injections 
in the clinic. 
During the 16-week treatment period, patients will have study visits at Weeks 0, 2, 4, 8, 12, and 
16. Safety laboratory tests, collection of samples for dupilumab concentrations and anti-drug 
antibodies (ADA), and clinical assessments will be performed at specified clinic visits as noted in 
the Schedule of Events (Appendix 10.2). 
The end of treatment visit will occur at Week 16, 2 week after the last dose of study drug. The 
primary endpoint will be determined at Week 16. 
Follow-up visits will occur every 4 weeks from Week 20 through Week 28. The duration of the 
12-week follow-up period is based on the time expected for drug levels to reach below the lower 
limit of quantification in most patients after the last dose of dupilumab. The end of study visit will 
occur at Week 28. 
 
 
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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 
Intent-to-treat Population  
The intent-to-treat (ITT) population includes all randomized patients. Efficacy analyses will be 
based on the treatment allocated by the interactive response technology (IRT) at randomization (as 
randomized). This is the primary analysis population for efficacy analyses. 
For any patient who was randomized more than once, only the data associated with the first 
randomization will be used in any analysis population. The safety experience associated with any 
later randomization will be assessed separately. 
Patients who temporarily or permanently discontinue from the IMP and who do not withdraw from 
the study will be asked to return to the clinic for all remaining study visits and complete all study 
assessments per the study schedule. 
3.2 
Per Protocol Population  
The per protocol (PP) population includes all patients in the ITT population 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 
efficacy results. The criteria of major efficacy-related protocol deviation are defined as following: 
 Patients who did not receive treatment as randomized, which are defined as 
o patients on placebo but accidentally exposed to dupilumab,  
o patients on dupilumab receiving placebo whose compliance with the dupilumab 
injection is <80% by counting placebo injections as missing 
 Any major violations of efficacy-related entry criteria (Appendix 10.7) 
o Inclusion criteria 3, 4, 5 and 6 
o Exclusion criteria 3 ,4, 5, 6, 7, 8 and 9 
 The percentage of a patient’s compliance with the IMP injection is <80% or >120% of the 
scheduled doses during the study treatment period 
 Patients who were randomized more than once 
 Patients who were randomized but not treated 
Final determination of the PP population will be made in the blinded manner prior to the database 
lock. 
3.3 
Safety Population  
The safety population consists all randomized patients who receive any IMP. Patients will be 
analyzed according to the treatment they actually received (as treated).  
The actual treatment group is defined by the following rules: 
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 For patients on placebo but accidentally exposed to dupilumab, the treatment group 
allocation for as-treated analysis will be dupilumab 
 For patients on dupilumab but accidentally received placebo, the actual treatment group 
allocation for as-treated analysis will be the treatment as randomized if at least one dose or 
part of a dose of dupilumab was received 
 For patients on dupilumab but accidentally received placebo, the actual treatment group 
allocation for as-treated analysis will be placebo if the patient did not exposed to any 
dupilumab 
In addition:  
 Nonrandomized but treated patients will not be part of the safety population, but their safety 
data will be presented separately 
 Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
safety population. 
The pre-treatment period is defined as the time from signing the informed consent form (ICF) to 
before the first dose of IMP. The treatment emergent period is defined as the time from first dose 
of IMP (Day 1) to the end of the study. 
For safety summarizes, three analysis period are defined as follows: 
 On-treatment period is defined as day 1 to the day of last dose of IMP + 14 days or early 
termination date from study, whichever comes first 
 Follow-up period is defined as the last dose of IMP + 15 days to the date of the end of study 
 Overall study period is defined as day 1 to the date of the end of study, consisting of both 
the treatment and follow-up periods 
The safety population will be the basis for the analyses for the week 16 treatment period and overall 
study period; however, for the analyses for the follow-up period, only a subset of safety population 
will be included, which is defined as the patients who entered the follow-up and had at least one 
visit after week 16 treatment visit. 
3.4 
Pharmacokinetic (PK) Population  
The PK population consists of all patients in the safety population with at least one evaluable 
functional dupilumab concentration result following the first dose of study drug up to Week 16. 
Functional dupilumab concentration will also be reported in those patients who completed the 
study through week 28. Patients will be analyzed according to the treatment actually received. 
3.5 
Anti-Drug Antibody (ADA) Population  
The ADA population includes all patients in the safety population with at least one reportable 
ADA result (either “ADA negative” or “ADA positive”) after first dose of the IMP. 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 with grouping (year; ≥18-<40, ≥40-<65, ≥65), 
Sex, Race (Asian), Baseline weight with grouping (kilograms [kg], <70; ≥70-<100, ≥100), 
Baseline Height (centimeters [cm]), and Baseline BMI  (kg/m2; <15, ≥15-<25, ≥25-<30, 
≥30; <18.5, ≥18.5-<24, ≥24-<28, ≥28), Patients with inadequate response to topicals 
(Yes/No), Topical treatments are medically inadvisable for the patient (Yes/No) 
 Baseline disease characteristics: Duration of AD disease with grouping (years; <26 and 
≥26), Investigator’s Global Assessment (IGA) score, Eczema Area and Severity Index 
(EASI) score, Pruritus numerical rating scale (NRS) for maximum or average itch intensity, 
Pruritus categorical scale (PCS), Body Surface Area (BSA) Involvement of Atopic 
Dermatitis, Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index 
(DLQI), and EuroQol five dimensions questionnaire (EQ-5D)  
4.2 
Medical History and Atopic Disease Medical History  
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) using the version of Medical Dictionary for Regulatory Activities (MedDRA) 
currently in effect at Sanofi at the time of database lock.  
Family history of atopic/allergic conditions will be collected, including atopic dermatitis, asthma, 
allergic conjunctivitis (keratoconjunctivitis), allergic rhinitis, chronic rhinosinusitis, nasal polyps, 
eosinophilic esophagitis, food allergy, hives and other allergies (medications, animals, plants, 
mold, dust mites, etc.). 
4.3 
Pre-treatment/ Concomitant Medications and Procedures  
Medications/Procedures will be recorded from the day of informed consent until the final study 
visit (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). Patients will be counted once in all ATC categories linked to the 
medication. Procedures will be coded to a PT and associated primary SOC using the version of 
MedDRA currently in effect at Sanofi at the time of database lock. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the first IMP. Pre-treatment medications/procedures can be discontinued before 
first administration or can be ongoing during treatment period. 
Concomitant medications/procedures: medications taken or procedures performed following the 
first IMP through the EOS visit.  
Background treatment: All patients are required to apply moisturizers (emollients) at least twice 
daily for at least the 7 consecutive days immediately before randomization and to continue 
throughout the study. 
Prohibited concomitant medications/procedures during the study  
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The following treatments are prohibited during the study: 
 Treatment with a live (attenuated) vaccine 
 Treatment with immunomodulating biologics 
 Treatment with an investigational drug (other than dupilumab) 
 Treatment with TCS or TCI 
 Treatment with systemic corticosteroids or nonsteroidal systemic 
immunosuppressive/immunomodulating drugs (eg, cyclosporine, methotrexate, 
mycophenolate-mofetil, azathioprine, and Janus kinase inhibitors) 
 Initiation or uptitration of allergen-specific immunotherapy (SIT). Patients on SIT prior to 
the screening visit must be on a stable dose and remain on that dose during the study  
 Any other medications for AD that could have interfered with efficacy outcomes or affected 
the evaluation for AD severity. Examples of such medications include coal tar products, 
other staining topical products, traditional Chinese medicine (TCM), or any other 
therapeutic agents for AD that were not properly evaluated in clinical trials 
The IMP will be discontinued if the following is used through Week 16: 
 Treatment with a live (attenuated) vaccine 
 Treatment with immunomodulating biologics 
 Treatment with an investigational drug (other than dupilumab) 
 Treatment with systemic corticosteroids or nonsteroidal systemic 
immunosuppressive/immunomodulating drugs (eg, cyclosporine, methotrexate, 
mycophenolate-mofetil, azathioprine, and Janus kinase inhibitors) 
The following concomitant procedures are prohibited during study participation: 
 Major elective surgical procedures 
 Phototherapy 
 Tanning in a bed/booth 
Rescue treatments for AD: If medically necessary (ie, to control intolerable AD symptoms), rescue 
treatment for AD with otherwise prohibited medication or procedure may be provided to study 
patients at the discretion of the investigator. 
Patients who receive rescue treatment during the study treatment period will continue study 
treatment if rescue consisted of topical medications. Topical calcineurin inhibitors may be used 
for rescue, but should be reserved for problem areas only. If possible, Investigators should attempt 
to limit the first step of rescue therapy to topical medications, and escalate to systemic medications 
only for patients who do not respond adequately after at least 7 days of topical treatment. 
 If a patient receives rescue treatment with systemic corticosteroids or nonsteroidal systemic 
immunosuppressive/immunomodulating drugs (cyclosporine, methotrexate, mycophenolate 
mofetil, azathioprine, Janus kinase inhibitors, biologic agents, etc), the IMP will be immediately 
discontinued. 
After the treatment with these medications is completed, the IMP may be resumed if deemed 
appropriate by the Investigator and the sponsor, but not sooner than 5 half-lives after the last dose 
of systemic rescue medication. 
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All patients will complete the schedule of study visits and assessments whether or not they 
complete the treatment with the IMP 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 labs) 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, 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 is: 
 Proportion of patients with both IGA 0 to 1 (on a 5-point scale) and a reduction from 
baseline of ≥2 points at Week 16 
Investigator’s Global Assessment (IGA) 
The IGA is a static 5-point assessment instrument used in clinical studies to rate the severity of 
AD globally. The ratings (0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe) are an 
overall assessment of the skin lesions based on erythema and papulation/infiltration. The IGA 
score will be assessed at every scheduled and unscheduled clinic visit. 
4.4.2 Secondary Efficacy Variables  
The secondary endpoints are: 
 Proportion of patients with EASI-75 response (reduction of EASI score ≥75% from 
baseline) at Week 16 
 Proportion of patients with reduction of weekly average of peak daily pruritus NRS ≥4 from 
baseline to Week 16 
 Proportion of patients with reduction of weekly average of peak daily pruritus NRS ≥3 from 
baseline to Week 16 
 Percent change from baseline to Week 16 in weekly average of peak daily Pruritus NRS 
 Change from baseline to Week 16 in weekly average of peak daily Pruritus NRS 
 Percent change in EASI score from baseline to Week 16 
 Change from baseline to Week 16 in percent BSA of AD involvement 
 Change from baseline to Week 16 in DLQI 
 Change from baseline to Week 16 in POEM 
 Percent change from baseline to Week 2 in weekly average of peak daily Pruritus NRS 
 Absolute and percent change from baseline to Week 16 in EQ-5D 
 Proportion of patients who achieve reduction of IGA score by ≥2 from baseline to Week 16 
 The proportion of patients with EASI-50 (≥50% improvement from baseline) at Week 16 
 The proportion of patients with EASI-90 (≥90% improvement from baseline) at Week 16 
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 Proportion of patients achieving IGA 0 to 1 and a reduction of ≥2 points from baseline 
through Week 16 
 Absolute and percent changes in EASI score from baseline through Week 16 
 Absolute and percent changes in weekly average of peak daily pruritus NRS score from 
baseline through Week 16 
 The proportion of patients who responded “absence of pruritus” or “mild pruritus” in the 
pruritus categorical scale at Week 16 
 Number of days and proportion of patients with sick leave/missed school days 
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). 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%). 
For each body region (head, trunk, upper limbs, and lower limbs), EASI score = (sum of the four 
AD disease characteristics scores) multiply (area of AD involvement score). The total EASI sore 
is the weighted total of the body region EASI scores using the weights 10% = head, 20% = upper 
limbs, 30% = trunk, 40% = lower limbs. 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 AD.  
The EASI will be collected at every scheduled and unscheduled clinic visit. 
Pruritus Numeric Rating Scale (NRS) 
The Pruritus NRS is a simple assessment tool that patients will use to report the intensity of their 
pruritus (itch) during a daily recall period using a pruritus reporting system. Patients will be asked 
the following questions: 
 For average 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 overall (on average) during the 
previous 24 hours?” 
 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 pruritus reporting system to record their Pruritus NRS score 
at the screening visit. Patients will complete the rating scale daily. Clinical sites will receive alerts 
when patients do not complete the pruritus reporting system items. Sites will be expected to contact 
patients who have missed 2 consecutive entries to encourage patient compliance. The Investigator 
will check patients’ reports at each visit. 
If there are multiple NRS to the same question (average or maximum itch intensity) collected on 
the same day, average of all the scores collected will be taken. 
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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. The 
baseline NRS and mean weekly NRS will be calculated for average itch intensity and peak itch 
intensity separately. 
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. Patients will undergo this assessment at every scheduled and 
unscheduled clinic visit. 
Dermatology Life Quality Index (DLQI) 
The DLQI is a 10-item, validated questionnaire (Badia 1999) used in clinical practice and clinical 
trials to assess the impact of AD disease symptoms and treatment on Quality of Life (QOL). The 
format is a simple response to (0 to 3, where 0 = not at all; 1 = a little, 2 = a lot, 3 = very much) 10 
questions, which assess QOL over the past week, with an overall scoring system of 0 to 30; a high 
score is indicative of a poor QOL. For question 7, 0 = not relevant, 1= no + a little, 2 = no + a lot, 
3 = yes. For general inflammatory skin conditions a change in DLQI score of at least 4 points is 
considered clinically important (Basra et al, 2015).The DLQI will be assessed at every scheduled 
and unscheduled clinic visit. 
Handling missing items from DLQI: 
i. 
If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. 
ii. 
If two or more questions are left unanswered the questionnaire is not scored. 
iii. 
If question 7 is answered 'yes' this is scored 3 even if in the same question one of the 
other boxes is ticked. 
iv. 
If question 7 is answered “no” or “not relevant”, but either 'a lot' or 'a little' is ticked 
this is then scored 2 or 1. 
v. 
If two or more response options are ticked for one question, the response option with 
the highest score should be recorded. 
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 (Charman 2004). The format is a response to 7 items 
(dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency during 
the past week (ie, 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days) 
with a scoring system of 0 to 28; the total score reflects disease-related morbidity. 
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.  
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The POEM will be assessed at every scheduled and unscheduled clinic visit. 
EuroQol five dimensions questionnaire (EQ-5D) 
The EuroQoL 5-Dimension Health Questionnaire 3 Level (EQ-5D-3L) is a standardized measure 
of health status developed by the EuroQOL Group in order to provide a simple, generic measure 
of health for clinical and economic appraisal. The EQ-5D-3L is a self-administered questionnaire 
used to assess health status ‘today’ which consists of 2 parts: the descriptive system and the EQ 
visual analogue scale (EQVAS).  
The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 3 levels of perceived problems: “no 
problem” (level 1), “some problems” (level 2), “extreme problems” (level 3). The respondent is 
asked to indicate his/her health state by ticking (or placing a cross) in the box against the most 
appropriate statement (ie, no problems, some problems, or severe problems) in each of the 5 
dimensions; this results in a 1-digit number expressing the level for that dimension. The digits for 
5 dimensions can be combined in a 5-digit number describing the respondent’s health state, 
potentially producing 243 different states. Health states defined by the 5-dimensional classification 
can be converted into corresponding index scores that quantify health status, where 0 represents 
“death” and 1 represents “perfect health.” Values for the 243 theoretically possible health states 
defined by the EuroQol classification are calculated using a regression model and weighted 
according to the social preferences of the Chinese population. The minimum value for the single 
index utility score is 0.1702. Appendix 10.4 provides the SAS code to derive the index utility score 
using Chinese based population (Zhu, 2018). 
The EQVAS records the respondent’s self-rated health on a vertical, visual analogue scale where 
the endpoints are labeled “best imaginable health state (100)” and “worst imaginable health state 
(0)”. This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents.  
EQ-5D-3L will be assessed at the following visits: baseline (Day 1), Week 8, Week 16 (EOT), 
Week 28 (EOS), and early termination (ET) visit. 
Pruritus Categorical Scale (PCS) 
The PCS is a 4-point scale used to assess symptoms that has been used in 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 pruritus reporting system to complete the PCS at the 
screening visit. Patients will complete the categorical scale daily. Clinical sites will receive alerts 
when patients do not complete the pruritus reporting system items. Sites will be expected to contact 
patients who have missed 2 consecutive entries to encourage patient compliance. The Investigator 
will check patients’ reports 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 
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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 continuously for 
7 days right before and on the baseline visit (i.e. study day -6 to day 1). 
Sick Leave/Missed School Days 
Patients who are employed or enrolled in school will be asked to report the number of sick 
leave/missed school days since the last study assessment. Patients will undergo this assessment at 
the following visits: baseline (Day 1), Week 4, Week 8, Week 12, Week 16 (EOT), Week 20, 
Week 24, Week 28 (EOS), ET and unscheduled visits. 
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 
“PT”, “High Level Term (HLT)”, “High-level Group Term (HLGT)” and the associated primary 
“SOC” using the version of MedDRA currently in effect at Sanofi at the time of database lock. 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in 
death; is life-threatening; requires inpatient hospitalization or prolongation of existing 
hospitalization; results in persistent or significant disability/ incapacity; is a congenital anomaly/ 
birth defect; or is a medically important event. 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added or removed during a study by protocol amendment. 
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if 
 Symptomatic, and/or 
 Requiring either corrective treatment or consultation, and/or 
 Leading to IMP discontinuation or modification of dosing, and/or 
 Fulfilling a seriousness criterion, and/or 
 Defined as an AESI 
Pretreatment AEs are defined as AEs that developed or worsened during the pre-treatment period. 
Treatment emergent adverse events (TEAEs) are defined as AEs that developed or worsened 
during the treatment-emergent period.  
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4.5.2 Laboratory Safety Variables  
Hematology, chemistry, urinalysis, and serum pregnancy testing samples will be analyzed by a 
central laboratory. The urine pregnancy test kit will be provided to the site by the laboratory. 
Blood samples for serum chemistry and hematology testing will be collected at screening (day -7 
to day -35), baseline (Day 1), Week 8, Week 16 (EOT), Week 28 (EOS), ET and unscheduled 
visits. Total basophil and eosinophil counts are of particular interest in AD patients, due to the 
occurrence of basophil histamine release and eosinophilia in this population. Understanding the 
lymphocyte profiles of AD patients may help researchers understand disease heterogeneity. Blood 
samples should be collected after a 6 to 8 hour fast, if possible; fasting is not mandatory.  
Blood Chemistry 
Sodium 
Total protein  (serum) 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen  
Low-density lipoprotein  
Carbon dioxide 
Aspartate aminotransferase (AST) 
High-density lipoprotein 
Calcium 
alanine aminotransferase (ALT) 
Triglycerides 
Glucose 
Alkaline phosphatase 
Uric acid 
Albumin 
Lactate dehydrogenase  
Creatine phosphokinase (CPK) 
Note: Direct and indirect bilirubin will be measured when the total bilirubin is above the upper limit of normal (ULN); 
CPK isoenzymes will be reflexly measured when CPK >5 ULN 
Hematology with Differential 
Hemoglobin 
 WBCs differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Urine samples for urinalysis will be collected to measure overall patient health at screening (day -
7 to day -35), baseline (Day 1), Week 16, Week 28 (EOS), ET and unscheduled visits. 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast  
Note: Microscopic analysis will only be done in the vent of abnormal dipstick results  
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Pregnancy testing (serum or urine) will be performed for all women of childbearing potential at 
screening (day -7 to day -35), baseline (Day 1), Week 4, Week 8, Week 12, Week 16 (EOT), Week 
28 (EOS), ET and unscheduled visits. 
4.5.3 Vital Sign Variables  
The following vital signs parameters will be collected: 
 Weight (kg) and height (cm) 
 Respiratory rate (breaths/min) 
 Heart rate (beats/min) 
 Systolic and diastolic blood pressures (mmHg) 
 Body temperature (oC) 
Weight is determined at screening and baseline (Day 1), and Week 16 (EOT), Week 28 (EOS), ET 
and unscheduled visits. Height is only measure at screening. Other vital signs are collected pre-
dose at every scheduled and unscheduled clinic visit. 
4.5.4 12-Lead Electrocardiography (ECG) Variable  
The ECG interpretation variable are dichotomized to normal and abnormal. Electrocardiograms 
will be performed before blood is drawn during visits requiring blood draws. A standard 12-lead 
ECG will be performed at screening, Week 16 (EOT), and Week 28 (EOS) or ET visits. 
4.5.5 Physical Examination Variable  
The physical examination variable values are dichotomized to normal and abnormal. 
A thorough and complete physical examination will be performed at screening, Week 16 (EOT), 
and Week 28 (EOS) or ET visits. If patients have any symptom or sign of ocular surface diseases, 
eg, conjunctivitis and blepharitis, at screening or during study period, ophthalmological 
examinations should be done. 
4.5.6 Immunogenicity Variables  
The immunogenicity variables are ADA status, ADA titer and anti-dupilumab neutralizing 
antibodies (NAb) status. 
Immunogenicity will be characterized by ADA responses and titers observed in patients in the 
ADA population.  
ADA response categories are defined as follows: 
 Negative in ADA assay at all time points analyzed 
 Preexisting immunoreactivity  
Defined as either an ADA positive response in the ADA assay at baseline with all post 
first dose ADA results negative, OR a positive response at baseline in the ADA assay 
with all post first dose ADA results less than 4-fold baseline titer levels  
 Treatment emergent response in the ADA assay 
Defined as a positive response in the ADA assay post first dose when baseline results are 
negative or missing. The treatment emergent responses may be further characterized as 
Persistent, Indeterminate or Transient 
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o 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 85 days], with no ADA negative samples or any 
missing sample in between 
o Indeterminate Response - treatment-emergent response with only the last 
collected sample positive in the ADA assay 
o Transient Response - treatment emergent ADA positive response that is not 
considered persistent or indeterminate 
 Treatment boosted response in the ADA assay  
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 
ADA status are defined as follows: 
 ADA positive patients, that is patients with treatment-emergent or treatment boosted 
response.  
 ADA negative patients, that is patients with preexisting immunoreactivity or negative in 
the ADA assay at all time points. 
Titer Category (Maximum titer values): 
 Low (titer <1000) 
 Moderate (1000 ≤ titer ≤ 10 000) 
 High (titer >10 000) 
Serum samples for ADA will be collected at the clinic visits specified in Appendix 10.2. ADA 
analysis will be conducted on sample collected at baseline, Week 16 (EOT), Week 28 (EOS), and 
ET. All samples that are positive in the ADA assay will be further characterized for ADA titers 
and for the presence of NAb. Samples that tested negative for ADA are considered to be NAb 
negative and are therefore not analyzed in the NAb assay. The NAb status is categorized as 
follows: 
 Negative (samples negative in the ADA assay, and samples positive in ADA assay that 
are negative in the NAb assay) 
 Positive (samples positive in both the ADA and NAb assays) 
4.6 
Pharmacokinetic (PK) Variables  
Pharmacokinetic variables include trough concentration (Ctrough) over time until week 16. Samples 
for measurement of functional dupilumab concentration in serum will be collected before the 
injection of the IMP at baseline (Day 1), Week 12, Week 16 (EOT), Week 28 (EOS), ET and 
unscheduled visits. 
 
  
 
 
 
 
 
 
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5 
STATISTICAL METHODS  
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1 
Demographics and Baseline Characteristics  
Demographic and baseline characteristics will be summarized descriptively by treatment group 
based on ITT population.  
5.2 
Medical History and Atopic Disease Medical History  
Medical history will be summarized by primary SOC and PT for each treatment group. The table 
will be sorted by internationally agreed order of SOC followed by PT sorted in alphabetical order 
based on the overall incidence across treatment groups. 
Number and percentage of patients with personal history (current/past) of atopic/allergic 
conditions will be summarized for each treatment groups. Appendix 10.6 provides a list of personal 
history of atopic/allergic conditions search criteria. Blinded manual adjudication will be required 
by the study medical monitor, before database locks. 
Number and percentage of patients with family history of atopic/allergic conditions will be 
summarized by the categories listed on the case report form (CRF) for each treatment groups. 
5.3 
Pre-treatment/Concomitant Medications/Procedures  
Number and proportion of patients taking pre-treatment/concomitant medications and rescue 
medications will be summarized, sorted by decreasing frequency of ATC Level 2 (therapeutic 
main group) and ATC level 4 (chemical/therapeutic subgroup), based on the overall incidence 
across treatment groups. 
Procedures will be summarized by treatment group by primary SOC (sorted by internationally 
agreed order) and PT (sorted in alphabetical order), sorting are based on the overall incidence 
across treatment groups. 
The detailed information of rescue medications/procedures including duration of use and incidence 
of use will be summarized by topical and systemic groups. Kaplan Meier curves for time to first 
rescue use will be generated. Listing of rescue use will be presented. 
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. 
5.4 
Patient Disposition  
The following summaries by table will be provided: 
 The total number of screened patients: patients who signed the informed consent 
 The total number of randomized patients: patients with a treatment kit number allocated and 
recorded in the IRT database, and regardless of whether the treatment kit was used or not 
 The total number of patients in each analysis population 
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 The total number of patients who discontinued the study treatment and the reasons for the 
discontinuation 
 The total number of patients who discontinued the study, and the reasons for discontinuation 
The following listings will be provided: 
 Listing of patient disposition including: date of randomization, last visit, dosing, completed 
study drug or discontinued by reason, completed study or discontinued by reason 
 A listing of patients treated but not randomized, patients randomized but not treated, and 
patients randomized but not treated as randomized 
 Summary table with listing of protocol deviations will be provided 
5.5 
Dose administration  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. The compliance with protocol-defined study 
treatment will be calculated as follows: 
Treatment compliance= (number of IMP injections during exposure period)/(number of planned 
IMP injections during exposure period) x 100% 
Loading doses for the same patient will be counted as 1. 
Summary of study drug administration will include the number of study drug doses administered 
and treatment compliance. The treatment compliance will be summarized descriptively and will 
be presented by the following specific ranges for each treatment group: <80%, 80% - 120%, and 
>120%. 
5.6 
Treatment Exposure and Observation Period  
The duration of IMP exposure during the study will be presented by treatment and calculated as: 
(Date of last IMP injection – date of first IMP injection) + 14 days regardless of unplanned 
intermittent discontinuations. 
The duration of exposure during the study will be summarized for each 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, ≥112 days. 
The duration of observation period during the study is calculated as: 
(Date of the last study visit – date of the first IMP injection) +1. 
The duration of observation period will be summarized descriptively as a quantitative data (n, 
mean, SD, median, minimum and maximum). In addition, the number (%) of patients with 
observation periods will be presented by specific time periods. The time periods of interest is 
specified as:  
≥ 15 days, ≥ 29 days, ≥ 43 days, ≥ 57 days, ≥ 71 days, ≥ 85 days, ≥ 99 days, ≥113 days, ≥141 days, 
≥169 days, ≥197 days. 
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5.7 
Analyses of Efficacy Variables  
For all efficacy variables, the analysis will be comparisons of dupilumab and the placebo treatment 
groups. The following null and alternative hypotheses for the primary endpoint will be tested: 
H0: No treatment difference between dupilumab and placebo (𝑝𝑑𝑢𝑝𝑖𝑙𝑢𝑚𝑎𝑏 =  𝑝𝑝𝑙𝑎𝑐𝑒𝑏𝑜, where 𝑝 
stands for the proportion of responders in a treatment group) 
H1: There is a treatment difference between dupilumab and placebo (𝑝𝑑𝑢𝑝𝑖𝑙𝑢𝑚𝑎𝑏 ≠  𝑝𝑝𝑙𝑎𝑐𝑒𝑏𝑜) 
The analyses of efficacy variables are described in the subsections below and summarized in 
Appendix 10.1. 
Subgroups are defined by key baseline factors recorded on the CRF and listed to be considered 
for primary and secondary (EASI and/or Pruritus NRS) efficacy analyses: 
 Age group (≥18-<40, ≥40-<65, ≥65)  
 Sex (Male, Female) 
 Duration of AD (< 26 years, ≥26 years) 
 Baseline weight group (<70 kg, ≥70-<100 kg, ≥100 kg) 
 BMI (<15, ≥15-<25, ≥25-<30, ≥30) 
 Baseline disease severity [moderate (IGA=3) and severe (IGA=4)] 
 Baseline moderated-to-severe EASI (<20, ≥20) 
 Baseline severe EASI (<25, ≥25) 
 Baseline peak pruritus NRS (<7, ≥7) 
 Baseline Body Surface Area (BSA) (≥10%-<30%, ≥30%-<50%, ≥50%) 
 Previous use of systemic immunosuppressants (Yes, No) 
 Previous use of systemic cyclosporine (Yes, No), and/or Azathioprine (Aza) (Yes, No), 
and/or Methotrexate (MTX) (Yes, No) 
 History of asthma (Yes, No) 
 History of nasal polys (Yes, No) 
 History of allergic rhinitis (Yes, No) 
 History of food allergies (Yes, No) 
5.7.1 Analysis of Primary Efficacy Variables  
The Cochran-Mantel-Haenszel test adjusted by baseline disease severity (moderate or severe) will 
be used for the percentage of patients with both IGA 0 or 1 and a reduction from baseline of ≥2 
points at Week 16. 
Handling of dropouts or adjudicated rescue therapy 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 
endpoints after withdrawal. 
 If rescue medication or procedure is used (see Section 4.3 for rescue), the patient will be 
specified as a non-responder from the time the rescue is used. 
 Patients with missing values at Week 16 will be counted as non-responders at Week 16. 
Sensitivity analyses  
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1. Post-baseline last observation carried forward (LOCF) approach after censoring for 
rescue medication or procedure 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. For patients with only baseline value, the baseline 
value will be carried forward to Week 16.  
2. All observed data regardless of rescue medication or procedure use or data is collected 
after study withdrawal, will be included for the primary endpoint. Patients with missing 
values will be counted as non-responders. 
3. Post-baseline worst-observed-case-forward (WOCF) approach after censoring for 
rescue medication or procedure use to determine patient’s status at Week 16. For 
patients with only baseline value, the baseline value will be carried forward to Week 16. 
For the remaining missing values at Week 16 after imputation, multiple imputation (MI) 
approach following the oval pattern will be used to do the imputation.  
The primary efficacy analyses will be performed on the ITT population, as well as on the PP 
population as a supporting analysis. 
5.7.2 Analyses of Secondary Efficacy Variables  
The binary secondary efficacy endpoints will be analyzed using the same approach as that used 
for the analysis of the primary endpoints.  
The continuous endpoints will be analyzed using the multiple imputation (MI) with analysis of 
covariance (ANCOVA) model as the primary analysis. Patients’ efficacy data after rescue 
medication or procedure up to Week 16 or after study withdrawal up to Week 16 will be set to 
missing and then imputed by the MI method. Missing data from the ITT population will be imputed 
50 times to generate 50 complete data sets by using the SAS MI procedure (using Markov Chain 
Monte Carlo method) 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 group, 
randomization strata (disease severity), and relevant baseline value. 
The Week 16 data of each of the 50 complete datasets will be analyzed using an ANCOVA model 
with treatment, randomization strata (disease severity), and relevant baseline value included in the 
model, and the SAS MIANALYZE procedure will be used to generate valid statistical inferences 
by combining results from the 50 analyses using Rubin’s formula. 
The imputation model will include: 
 The variables in the ANCOVA model, including treatment group, randomization strata and 
relevant baseline value 
 Measured continuous endpoint values in each scheduled visit up to Week 16 
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Categorical variables included in above model (ie, treatment group and randomization strata) are 
not expected to be missing. 
To account for the impact of rescue medication or procedure or dropouts on the efficacy effect: 
 If a patient receives rescue medication or procedure that specifies the patient as a non-
responder according to the above rules for binary efficacy endpoints, the data collected after 
rescue medication or procedure is initiated will be treated as missing. 
 If a patient withdraws from the study, the data collected after study withdrawal 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. This sensitivity analysis will use a mixed-effect model repeated measures (MMRM). The 
model will include factors (fixed effects) for treatment, randomization strata, visit, 
treatment-by-visit interaction, and relevant baseline values. An unstructured covariance 
matrix will be used to model the within-patient errors. Denominator degrees of freedom 
will be estimated using approximation of SATTERTH. The efficacy data will be set to 
missing after rescue medication or procedure is used or after study withdrawal. Afterwards 
no imputation will be made. 
The MMRM model will provide baseline adjusted least-squares (LS) means at Week 16 
and at other time points for each treatment group with the corresponding standard error and 
the confidence interval, as well as the p values for treatment comparisons. The graph of 
LS-mean +/- SE by visit will be provided. 
2. The sensitivity analysis based on all observed data regardless if rescue treatment is used or 
if data are collected after withdrawal using MI method will be performed. 
3. This sensitivity analysis will use ANCOVA model, including the treatment group, 
randomization strata and relevant baseline value. The efficacy data will be set to missing 
after rescue medication or procedure is used or after study withdrawal. The post-baseline 
LOCF method will then be used to impute missing values. 
4. This sensitivity analysis will use ANCOVA model, including the treatment group, 
randomization strata and relevant baseline value. The efficacy data will be set to missing 
after rescue medication or procedure is used or after study withdrawal. The post-baseline 
WOCF method will then be used to impute missing values. 
Multiplicity Considerations 
If the primary endpoint is significant at the 0.05 level, the secondary endpoints will be tested 
following the hierarchical testing procedure with a pre-specified order, that is, inferential 
conclusions about successive secondary endpoints require statistical significance at the 0.05 
significance level of the prior one.  
The hierarchy for the secondary endpoints is as follows: 
 Proportion of patients with EASI-75 response (reduction of EASI score ≥75% from 
baseline) at Week 16 
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 Proportion of patients with reduction of weekly average of peak daily Pruritus NRS ≥4 from 
baseline to Week 16 
 Proportion of patients with reduction of weekly average of peak daily Pruritus NRS ≥3 from 
baseline to Week 16  
 Percent change from baseline to Week 16 in weekly average of peak daily Pruritus NRS 
 Change from baseline to Week 16 in weekly average of peak daily Pruritus NRS 
 Percent change in EASI score from baseline to Week 16 
 The proportion of patients with EASI-50 (≥50% improvement from baseline) at Week 16 
 The proportion of patients with EASI-90 (≥90% improvement from baseline) at Week 16 
 Change from baseline to Week 16 in percent BSA of AD involvement 
 Change from baseline to Week 16 in DLQI 
 Change from baseline to Week 16 in POEM  
 Percent change from baseline to Week 2 in weekly average of peak daily Pruritus NRS 
5.8 
Analysis of Safety Data  
The summary of safety and tolerance will be performed based on the safety population. 
The safety analysis will be based on the reported AEs, clinical laboratory evaluations, vital signs, 
physical examination, 12-lead ECG, and immunogenicity. 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the sponsor according to predefined criteria/thresholds 
(Appendix 10.3) based on literature review and defined by the sponsor for clinical laboratory tests, 
and vital signs.  
Treatment-emergent PCSA is any PCSA developed or worsened in severity compared to the 
baseline during the treatment-emergent period. The time interval to detect any event or 
abnormality is between the first injection of study drug and EOS. All evaluations performed during 
the time interval will be taking into account when determine which patients had at least one PCSA, 
including unscheduled or repeated evaluations. 
5.8.1 Analysis of Adverse Events  
The number and proportion of patients will be summarized separately for the week 16 treatment 
period, the follow-up period and overall study period, described in Section 3.3. The incidence 
tables will present by primary SOC (sorted by internationally agreed order for the dupilumab 
group), HLGT, HLT and PT sorted in alphabetical order for each treatment group and selected 
subgroup, including the number (n) and percentage (%) of patients experiencing a TEAE. Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment phase. The denominator for computation of percentages is the safety population within 
each treatment group. 
TEAEs will also be summarized by severity and relationship to IMP for each treatment group, 
presented by primary SOC and PT. 
The time to first TEAE of special interest (AESIs) during the week 16 treatment period will be 
assessed by Kaplan-Meier estimates (K-M plot). The time is defined as the date of first event – the 
date of first dose + 1. Patients without an event will be censored at the end of 16-week treatment 
period. Graphs of cumulative incidence rate over time will be presented by treatment group. 
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Listings will be provided for all TEAEs, SAEs, death and TEAEs leading to permanent treatment 
discontinuation by treatment group and patient. Flags will be used to indicate on-treatment death.  
The following variables will be included in the listing: 
 Patient ID 
 Treatment group 
 Age/sex/race 
 SOC 
 HLGT 
 HLT 
 PT 
 Verbatim Term 
 AE start date and end date/ongoing 
 AE Duration 
 Relationship of AE to study drug: unrelated or related 
 Action taken: drug interrupted, dose reduced, drug withdrawn, drug not changed, dose 
increased, or not applicable 
 Severity: using a 3–point scale (mild, moderate, or severe) 
 Outcome: recovered or resolved, recovered or resolved with sequelae, recovering or 
resolving, not recovered or not resolved, fatal or unknown 
Overall TEAE summary 
The overall summary of TEAEs will be provided with number and proportions of patients with 
any: 
 TEAE 
 TEAE related to study drug 
 TEAE by severity 
 Serious TEAE 
 TEAE of special interest (AESI) 
 TEAE leading to death 
 TEAE leading to permanent treatment discontinuation 
AESI: 
 Anaphylactic reactions 
 Systemic or extensive hypersensitivity reactions 
 Malignancy 
 Helminthic infections 
 Suicide-related events 
 Blepharitis (severe or serious or lasting ≥4 weeks) 
 Any type of conjunctivitis (severe or serious or lasting ≥4 weeks)  
 Pregnancy of a female patient entered in a study as well as pregnancy occurring in a female 
partner of a male patient entered in a study with IMP/NIMP 
 Symptomatic overdose (serious or nonserious) with IMP/NIMP 
Appendix 10.5 provides a list of AESIs search criteria.  
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TEAE Incidence 
Number and proportions of patients reporting TEAEs will be summarized for the following 
TEAEs: 
 TEAEs 
o TEAEs by SOC/PT 
o TEAEs by SOC/HLGT/HLT/PT 
o TEAEs by SOC/PT with PT ≥5% in any treatment groups 
o TEAEs by severity by SOC/PT 
o TEAEs by relationship to IMP assessed by the investigator by SOC/PT 
o TEAE of special interest by category and PT 
 Serious TEAEs  
o Serious TEAEs by SOC/PT 
o Serious TEAEs by SOC/HLGT/HLT/PT 
o Serious TEAEs related to study drug as assessed by the investigator by SOC/PT 
 TEAEs leading to permanent discontinuation of study treatment by SOC/HLGT/HLT/PT 
 TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
investigator) by SOC/HLGT/HLT/PT 
Death 
 Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population by treatment received 
 Death in nonrandomized patients or randomized and not treat patients 
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 baseline laboratory test results and change from baseline to each 
visit 
 Number and percentage of patients with a treatment-emergent PCSA  
 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. 
Listing of all laboratory parameters normal range, abnormal flag and treatment-emergent PCSA 
by patient and visit will be provided. 
5.8.3 Analysis of Vital Signs  
Summaries of vital sign variables will include: 
 Descriptive statistics of baseline vital sign variable and change from baseline to each visit 
 Number and percentage of patients with a treatment-emergent PCSA  
 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 will be provided with flags indicating the treatment-emergent PCSA, depending on data. 
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5.8.4 Analysis of Physical Examination  
Number and percentage of patients with abnormal physical examination 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  
Number and percentage of patients with abnormal ECG interpretation will be summarized at 
baseline, end of treatment period and end of study by treatment group. 
5.8.6 Analysis of Immunogenicity Data  
5.8.6.1 Analysis of ADA Data  
The incidence of ADA response variables will be summarized using descriptive statistics in the 
ADA population. The NAb relevant analyses will be based on all patients in the ADA population 
with at least one non-missing NAb result (either “NAb negative” or “NAb positive”) after first 
dose of the IMP.  
Frequency tables of the proportion of patients developing ADA positivity in the ADA assay, 
Neutralizing antibody status in the NAb assay, pre-existing immunoreactivity, treatment-
emergent, treatment-boosted, persistent, indeterminate and transient ADA responses and titers will 
be presented as absolute occurrence (n) and percent of patients (%), presented by treatment groups. 
Percentages are rounded to 3 significant figures; therefore, there may be slight differences between 
subgroups and overall percentages. 
Listings of anti-dupilumab antibody status, neutralizing status, and titers per time point and 
treatment group will be provided. 
The following summaries will be performed on the ADA population: 
 
Number (%) of patients ADA negative at all time points analyzed by treatment group 
 
ADA titers using descriptive statistics (mean, standard deviation, geometric mean, 
median, minimum and maximum) by treatment group  
 
Number (%) of patients with neutralizing antibody status (negative or positive) by 
treatment group  
 
Number (%) of patients with pre-existing ADA, treatment-emergent ADA, and treatment 
boosted response ADA response by treatment group  
 
Number (%) of patients with persistent, transient and indeterminate treatment-emergent 
ADA response by treatment group 
5.8.6.2 Immunogenicity and Pharmacokinetics  
Potential associations between immunogenicity and serum concentration of dupilumab will be 
explored for dupilumab dose group. Plot of serum concentration of functional dupilumab may be 
provided for analyzing the potential impact of ADA/NAb status, ADA titer on PK. 
5.8.6.3 Immunogenicity and Safety and Efficacy  
Association of ADA responses and safety events may be performed in the ADA population.  
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The safety assessment will focus on the following events: 
 Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
 Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Number (%) of patients with the above mentioned safety events will be summarized by ADA status 
(positive or negative), and presence of neutralizing antibody (positive or negative).  
In addition, the primary endpoint and key secondary efficacy endpoints will be summarized in 
patients with and without ADA (positive vs. negative) and neutralizing antibody (positive or 
negative) status if applicable. 
5.9 
Analysis of Pharmacokinetic Data  
5.9.1 Descriptive Analysis of Dupilumab Concentrations in Serum  
Serum concentrations of dupilumab will be summarized in the PK population using arithmetic and 
geometric means, SD, standard error of the mean (SEM), coefficient of variation (CV, %), median, 
minimum, first quartile, third quartile and maximum per sampling time by treatment group. If date 
and/or time of the drug injection and/or sampling is missing then the concentration will not be 
taken into account. Percentages are rounded to 3 significant figures; therefore, slight differences 
between subgroups and overall percentages may occur.   
Concentrations of functional dupilumab below the lower limit of quantification (LLOQ) are set to 
zero. Line plots of mean (SD) and median functional dupilumab concentrations will be presented 
over nominal time (weeks; linear and log scales). Individual line plots of functional dupilumab 
concentration (spaghetti plots) will be presented over actual time (weeks) on linear and log scales. 
Individual scatter plots will be presented over nominal time (weeks). When the scale is linear, 
concentrations below the LLOQ are set to zero. In the log-scaled figures, concentrations below the 
LLOQ are imputed as LLOQ/2. 
Dupilumab trough concentration on week 16 will be summarized based on baseline body weight 
categories (<70 kg, ≥70-<100 kg, ≥100 kg). 
5.9.2 Analysis of Concentration-Response Relationship  
The concentration-response (C-R) relationship will be analyzed by comparing the time course of 
mean (±SD) percent (%) change from baseline in IGA, EASI or Pruritus NRS (linear scale) with 
that of the mean (±SD) functional dupilumab concentrations in serum (linear scale). Observed 
data will be used for these analyses.  
The concentration-response relationship analyses will be implemented for patients in the PK 
population with at least one non-missing IGA, EASI, or pruritus NRS value, as applicable for the 
each concentration-response assessment. Hence, there may be modest differences from the primary 
efficacy analysis due to the differences in the analysis populations. Patients will be analyzed 
according to the treatment actually received. 
No formal statistical testing will be performed. 
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6 
DATA CONVENTIONS  
The following analysis conventions will be used in the statistical analysis. 
6.1 
Definition of Baseline for Efficacy/Safety Variables  
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the 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 by both 
date/time information: 
1. For the AE, lab (including biomarker), 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 (including biomarker), PK or ADA, only date of the measurement 
will be used to determine baseline by comparing with the first injection date (equal or less than 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 patient ID or enrolled patient ID. 
6.2 
General Data Handling Conventions  
For the laboratory safety variables and biomarker data, if the data below the lower limit of 
quantification (LLOQ) / limit of linearity, half of the lower limit value (i.e., LLOQ/2) will be used 
for quantitative analyses. For data above the upper limit of quantification (ULOQ) / limit of 
linearity, the upper limit value (i.e., ULOQ) will be used for quantitative analyses. 
6.3 
Data Handling Convention Missing Data  
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary.  
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAE. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
Adverse event start date  
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month, then impute AE 
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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 the last study 
visit 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 
last study visit date instead. 
If AE end year is missing: Impute AE end date using the end of follow up date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment medication or concomitant medication or 
both, the missing medication start date is estimated as early as possible, and the missing medication 
end date is estimated as late as possible. If the medication start date is missing, the onset day will 
not be calculated in medication listings. 
Prior medication start date  
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’; 
If start month is missing, and start year is not missing: Impute the day and month using 01 January. 
Imputation flag is ‘M’. 
If start year is missing: Impute start date using 2 years before inform consent date. Imputation flag 
is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However in 
order to simplify the programming flow, the imputation is proposed to align 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.  
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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 the last visit study 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 last study visit date 
instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of last study visit 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. 
PCSA 
Patients who had post-baseline PCSA but missing baseline value will be regarded as having 
treatment emergent PCSA. 
6.4 
Analysis Visit Window  
Data analyzed by-visit-analysis (including efficacy, laboratory data, visit sign, ECG, ADA) will 
be summarized by the study scheduled visits described Appendix 10.2, “Schedule of Event”. The 
analysis visit windows will be exhaustive so that all available values obtained from unscheduled 
visits, early termination visit (ETV) 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.  
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The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT/EOS visits, based on the study day: 
Time window for efficacy variables 
 
 
 
Analysis Window in Study Days 
Visit 
No. 
Visit 
Targeted Study 
Days* 
IGA, EASI, BSA, 
POEM, DLQI 
EQ-5D 
Sick-Leave/Missed 
School Days 
1 
Screening 
<1 
<1 
 
 
2 
Baseline 
1 
1 
≤1 
≤1 
3 
Week 2 
15 
[2,22] 
 
 
4 
Week 4 
29 
[23, 43] 
 
[2, 43] 
5 
Week 8 
57 
[44, 71] 
[2, 85] 
[44, 71] 
6 
Week 12 
85 
[72, 99] 
 
[72, 99] 
7 
Week 16  
(End of 
Treatment) 
113 
[100, 127] 
[86, 155] 
[100, 127] 
8 
Week 20 
141 
[128, 155] 
 
[128, 155] 
9 
Week 24 
169 
[156, 183] 
 
[156, 183] 
10 
Week 28 
(End of Study) 
197 
≥184 
≥156 
≥184 
*Study days are calculated from 1st day of dupilumab injection (1st day of randomization if the patient is not treated) 
Time window for safety variables 
 
 
 
Analysis Window in Study Days 
Visit 
No. 
Visit 
Targeted 
Study Days* 
Vital 
Signs 
Weight 
ECG 
Hematology 
and 
Chemistry 
Urinalysis 
Serum 
Pregnancy 
Test 
Urine 
Pregnancy 
Test 
1 
Screening 
<1 
<1 
<1 
<1 
<1 
<1 
<1 
 
2 
Baseline 
1 
1 
1 
 
1 
1 
 
≤1 
3 
Week 2 
15 
[2,22] 
 
 
 
 
 
 
4 
Week 4 
29 
[23, 43] 
 
 
 
 
 
[2, 43] 
5 
Week 8 
57 
[44, 71] 
 
 
[2, 85] 
 
 
[44, 71] 
6 
Week 12 
85 
[72, 99] 
 
 
 
 
 
≥72 
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7 
Week 16  
(End of 
Treatment) 
113 
[100, 127] 
[86, 155] 
[86, 155] 
[86, 155] 
[2, 155] 
[2, 155] 
 
8 
Week 20 
141 
[128, 155] 
 
 
 
 
 
 
9 
Week 24 
169 
[156, 183] 
 
 
 
 
 
 
10 
Week 28 
(End of 
Study) 
197 
≥184 
≥156 
≥156 
≥156 
≥156 
≥156 
 
*Study days are calculated from 1st day of dupilumab injection (1st day of randomization if the patient is not treated) 
Time window for other variables 
 
 
 
Analysis Window in Study Days 
Visit 
No. 
Visit 
Targeted Study 
Days* 
 
PK/Drug Concentration, ADA 
1 
Screening 
<1 
<1 
 
2 
Baseline 
1 
1 
≤1 
3 
Week 2 
15 
 
 
4 
Week 4 
29 
 
 
5 
Week 8 
57 
 
 
6 
Week 12 
85 
 
[2, 99] 
7 
Week 16  
(End of 
Treatment) 
113 
[2, 155] 
[2, 155] 
8 
Week 20 
141 
 
 
9 
Week 24 
169 
 
 
10 
Week 28 
(End of Study) 
197 
≥156 
≥156 
*Study days are calculated from 1st day of dupilumab injection (1st day of randomization if the patient is not treated) 
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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 ETV/EOT/EOS are not available 
For the multiple measurements of the same test in the same window, the following rules will be 
used to pick up the analysis value: 
 If multiple valid values of a variable within an analysis visit window, the closest from 
the target study day will be selected.  
 If the difference is a tie, the value after the targeted study day will be used.  
 If multiple available values of a variable exist within a same day, then the first value of 
the day will be selected. 
Both scheduled and unscheduled measurements will be considered for determining 
abnormal/PCSA values from laboratory, vital sign or ECG as well as the baseline values.  
For the ePRO data collected daily, the analysis visit windows will be implemented following the 
procedures 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 
Randomization date will be used instead of 1st injection date for patients randomized but 
not treated. 
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. 
 
 
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7 
INTERIM ANALYSIS  
No interim analysis is planned. 
Sponsor may run a first step analysis when all patients complete their 16-week treatment period. 
 
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8 
SOFTWARE  
All analyses will be done using SAS Version 9.4 or above. 
 
 
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9 
REFERENCES  
Badia X, Mascaro JM, Lozano R.. Measuring health-related quality of life in patients with mild to 
moderate eczema and psoriasis: clinical validity, reliability and sensitivity to change of the DLQI. 
Br J Dermatol. 1999;141:698-702. 
Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the Minimal Clinically 
Important Difference and Responsiveness of the Dermatology Life Quality Index (DLQI): Further 
Data. Dermatology. 2015;230(1):27-33. 
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. 
Arch Dermatol. 2004;140:1513-9. 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity 
index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 
2001;10:11-18. 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. 
Kaufmann R, Bieber T, Helgesen AL, Andersen BL, Luger T, Poulin Y, et al. Onset of pruritus 
relief with pimecrolimus cream 1% in adult patients with atopic dermatitis: a randomized trial. 
Allergy. 2006;61:375-81. 
Zhuo L, Xu L, Ye J, Sun S, Zhang Y, Burstrom K, et al. Time Trade-Off Value Set for EQ-5D-3L 
Based on a Nationally Representative Chinese Population Survey. Value in Health. 
2018;21(11):1330-7. 
 
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46 
10 APPENDIX  
10.1 Summary of Statistical Analyses  
Efficacy Analysis: 
Endpoint 
Analysis 
Population 
Primary Statistical Method  
Supportive/Sensitive 
Statistical 
Method 
Subgroup Analysis 
Other 
Analyses 
Proportion of patients with both IGA 
0 to 1 (on a 5-point scale) and a 
reduction from 
baseline of ≥2 points at Week 16 
ITT 
population 
Cochran-Mantel-Haenszel 
test / define missing as 
treatment failure 
Cochran-Mantel-Haenszel test on 
observed value or LOCF, and on PP 
population 
Yes 
Line 
plot, 
forest plot 
Secondary continuous variables 
ITT 
population  
MI  
MMRM, ANCOVA with LOCF 
Yes for EASI and 
NRS endpoints 
Line plot 
Secondary categorical variables 
ITT 
population 
Cochran-Mantel-Haenszel 
test / define missing as 
treatment failure 
Cochran-Mantel-Haenszel 
test 
/ 
LOCF 
Yes for EASI and 
NRS endpoints 
Line 
plot, 
forest plot 
 
 
 
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Safety Analyses: 
Endpoint 
Analysis Populations 
Statistical Method 
Supportive Analysis 
Subgroup Analysis 
Other Analyses 
Adverse Events 
Safety population 
Descriptive statistics 
No 
No 
No 
Laboratory Measures 
Safety population 
Descriptive Statistics 
No 
No 
No 
Vital sign 
Safety population 
Descriptive Statistics 
No 
No 
No 
Physical Examination 
Safety population 
Descriptive Statistics 
No 
No 
No 
ECG 
Safety population 
Descriptive Statistics 
No 
No 
No 
 
 
 
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10.2 Schedule of Events  
 
Study Procedure 
SCR 
RND 
Treatment 
EOT 
Follow-up 
EOS 
Unscheduled 
visita (if 
applicable) 
Early 
termination 
(if 
applicable) 
VISIT(V) 
V1 
V2 
V3 
V4 
 
V5 
 
V6 
 
V7 
V8 
V9 
V10 
Week(W) 
 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
Day (D) 
D-7 to D-35 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
Visit Window (d) 
 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
Screening/baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training on pruritus reporting 
systemb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection training/observation 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Administer IMPc 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Dispense/review patient dosing 
diaryd 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
IMP dispensation/accounte 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Con meds/procedures 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Efficacyf,g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus NRS (daily)b 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Pruritus categorical scale (daily)b 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
POEM, DLQIh 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
EQ-5Dh 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
IGA, EASI, BSA 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Assess sick-leave/missed school 
days 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Photograph AD area (selected 
sites)i 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
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Study Procedure 
SCR 
RND 
Treatment 
EOT 
Follow-up 
EOS 
Unscheduled 
visita (if 
applicable) 
Early 
termination 
(if 
applicable) 
VISIT(V) 
V1 
V2 
V3 
V4 
 
V5 
 
V6 
 
V7 
V8 
V9 
V10 
Week(W) 
 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
Day (D) 
D-7 to D-35 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
Visit Window (d) 
 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
Safetyf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Physical examinationj 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Adverse events 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Laboratory Testingf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV ab, HBsAg, HbsAb, HBcAbk, 
and Hep C Abk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistry 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
Pregnancy test (WOCBP only) 
Serum 
Urine 
 
Urine 
 
Urine 
 
Urine 
 
Serum 
 
 
Serum 
Urine 
Serum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, anti-dsDNA (if ANA positive) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/Drug Concentration and ADA Samplesf 
Functional dupilumab PK sample 
 
X 
  
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
Anti-dupilumab antibody sample 
 
X 
  
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
Abbreviations: AD = atopic dermatitis, ADA = anti-drug antibody, ANA = anti-nuclear antibody, anti-dsDNA = anti-double-strand DNA, BSA = body surface area, DLQI = Dermatology Life Quality 
Index, EASI = Eczema Area and Severity Index, EQ-5D = EuroQol five dimensions questionnaire, EOS = end-of-study, EOT = end-of-treatment, HBcAb = hepatitis B core antibody, HBsAb = hepatitis 
B surface antibody, HBsAg = hepatitis B surface antigen, Hep C Ab = hepatitis C antibody, HIV ab = human immunodeficiency virus antibody, IGA = investigator global assessment, 
 
, IMP = investigational medicinal product,  
NRS = numerical rating scale, PK = pharmacokinetics, POEM = Patient Oriented Eczema Measure, RND = randomization, SCR = screening, 
, 
WOCBP = woman of child bearing potential. 
a During an unscheduled visit, any of the study procedures noted may be performed, but not all are required. 
b Patients will be trained at the screening visit on using the appropriate diary system to report pruritus daily and provide other information as required. Investigators will check patients’ reports at 
each visit.  
c Patients will be monitored at the study site for a minimum of 30 minutes after the IMP administration for any signs or symptoms of a hypersensitivity reaction. Adverse event assessments will be 
done at 30 minutes (±10 minutes) post-injection. 
d For patients who choose to self-administer the IMP at Weeks 6, 10, and 14, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of 
the clinic. 
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e For patients who choose to self-administer the IMP, the IMP will be dispensed to the patient for the dose that will be administered before the next clinic visit. Patients will return the original kit box 
for the prefilled syringe at each clinic visit. 
f 
To be collected before the injection of the IMP. 
g Assessments/procedures should be conducted in the following order: patient reported outcomes (PROs), Investigator assessments, safety and laboratory assessments, and then administration of 
the IMP. 
h All questionnaires will be administered before any invasive procedures (blood draws, IMP injection, etc). 
i 
Selected sites only - photograph AD area 
j 
If patients have any symptom or sign of ocular surface diseases, eg, conjunctivitis and blepharitis, at screening or during study period, ophthalmological examinations should be done. 
k Heptitis B virus (HBV) DNA testing should be performed during screening period for patients presenting with HBsAg (-) and HBcAb (+). In case of results showing HCV Ab positive, an HCV RNA 
testing may be performed to rule out a false positivity, if the Investigator believes the patient is a false positive. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.3 Criteria for Treatment-Emergent Potentially Clinical Significant Abnormality 
(PCSA) for Dupilumab AD studies  
Parameter 
Treatment Emergent PCSA 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzyme activity must be expressed in ULN, 
not in IU/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution across the 
different PCSA levels, additional shift table 
on ≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and > 
20 category for baseline vs. post baseline may 
be provided  
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. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution across the 
different PCSA levels, additional shift table 
on ≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and > 
20 category for baseline vs. post baseline may 
be provided 
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* 
>1.5 and ≤ 2 ULN and baseline ≤ 1.5 ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not in µmol/L or 
mg/L. Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution of 
significant level, additional shift table on 
≤1.5, >1.5 to ≤2.0 and > 2.0 category for 
baseline vs. post baseline may be provided 
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Parameter 
Treatment Emergent PCSA 
Comments 
Conjugated 
Bilirubin 
(Direct Bilirubin >35% Total Bilirubin and 
Total Bilirubin >1.5 ULN) and (Direct Bilirubin 
<=35% Total Bilirubin or Total Bilirubin <=1.5 
ULN) at baseline 
Conjugated bilirubin dosed on a case-by-case 
basis. 
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 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤ 10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution of 
significant level, additional shift table on ≤3, 
>3 to ≤10, and > 10 category for baseline vs. 
post baseline may be provided 
Creatinine 
≥150 μmol/L (Adults) and baseline < 150 
μmol/L 
>=30% change from baseline and <100% 
change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
3 independent criteria  
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L and <=408 μmol/L at baseline 
<120 μmol/L and >= 120 μmol/L at baseline 
Harrison- Principles of internal Medicine 17th 
Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L and <17 mmol/L at baseline 
Two independent criteria 
Chloride 
Hypochloremia 
Hyperchloremia 
 
<80 mmol/L and baseline ≥ 80 mmol/L  
>115 mmol/L and baseline ≤ 115 mmol/L  
Two independent criteria  
Sodium 
Hyponatremia 
Hypernatremia 
 
≤129 mmol/L and baseline > 129 mmol/L  
≥160 mmol/L and baseline <160 mmol/L  
Two independent criteria 
Potassium 
Hypokalemia 
Hyperkalemia 
 
<3 mmol/L and baseline ≥ 3 mmol/L  
≥5.5 mmol/L and baseline <5.5 mmol/L  
FDA Feb 2005. 
Two independent criteria 
Total Cholesterol ≥7.74 mmol/L and < 7.74 mmol/L at baseline 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L and < 4.6 mmol/L at baseline 
Threshold for therapeutic intervention. 
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Parameter 
Treatment Emergent PCSA 
Comments 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
(≤3.9 mmol/L and <LLN) and (>3.9 mmol/L or 
>=LLN) at baseline 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
and < 11.1 mmol/L (unfasted); <7 mmol/L 
(fasted) at baseline 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% and <= 8% at baseline 
 
Albumin 
≤25 g/L and >25 g/L at baseline 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) and 
<=2 ULN or <=10 mg/L (if ULN not provided) 
at baseline 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L and >=3.0 Giga/L at baseline (Non-
Black);  
<2.0 Giga/L and >=2.0 Giga/L at baseline 
(Black) 
≥16.0 Giga/L and < 16 Giga/L at baseline 
Increase in WBC: not relevant. 
 
 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L and <= 4.0 Giga/L at baseline 
 
Neutrophils 
<1.5 Giga/L and >=1.5 Giga/L at baseline (Non-
Black);  
<1.0 Giga/L and >=1.0 Giga/L at baseline 
(Black) 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at baseline 
 
Basophils 
>0.1 Giga/L <= 0.1 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 
≤115 g/L and > 115 g/L at baseline for male; 
 ≤95 g/L and> 95 g/L at baseline for Female. 
 
≥185 g/L and <185 g/L at baseline for Male; 
 ≥165 g/L and < 165 g/L at baseline for Female 
 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
 
Criteria based upon decrease from baseline 
are more relevant than based on absolute 
value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
Hematocrit 
≤0.37 v/v and > 0.37 v/v at baseline for Male; 
≤0.32 v/v and > 0.32 v/v at baseline forFemale 
≥0.55 v/v and < 0.55 v/v at baseline for Male; 
≥0.5 v/v and < 0.5 v/v at baseline for Female 
Two Criteria are independent 
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EFC15116 - dupilumab                                                                                        Version number: 1.0 
 
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Parameter 
Treatment Emergent PCSA 
Comments 
RBC 
Female 
<3 Tera/L and baseline ≥3 Tera/L 
≥6 Tera/L and baseline < 6 Tera/L  
Male 
<4 Tera/L and baseline ≥4 Tera/L 
≥7 Tera/L and baseline < 7 Tera/L 
Unless specifically required for particular 
drug development, the analysis is redundant 
with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L and >=100 Giga/L at baseline 
≥700 Giga/L and < 700 Giga/L at baseline 
International Consensus meeting on drug-
induced blood cytopenias, 1991. 
Two independent criteria 
Urinalysis 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
Two independent criteria 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline ≥20 
mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 
mmHg 
≥110 mmHg and increase from baseline ≥10 
mmHg 
To be applied for all positions (including 
missing) except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
 
 
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10.4 SAS code for EQ-5D index utility scoring  
/*==================================================================*/; 
/*  Aim                      : Derive the EQ5-D index (utility)            */; 
/*  Source for the algorithm : scoring EQ-5D health states (Rosalind Rabin */; 
/*            (cf. G:\_HE\PRO questionnaire\EQ5D\scoring\YorkTariffx.doc)  */; 
/*  Note                     : UK based population (Dolan, 1997)           */; 
/*  Author                   : Elisheva Smadja                             */; 
/*==================================================================*/; 
 
data EUROQOL; set temp; 
   profil= (10000*eqq1cd)+(1000*eqq2cd)+(100*eqq3cd)+(10*eqq4cd)+eqq5cd; 
   eq5d=1; 
**********Mobility*********; 
if eqq1cd=2     then eq5d=eq5d-0.0766; 
if eqq1cd=3     then eq5d=eq5d-0.2668; 
********Self-care**********; 
if eqq2cd=2     then eq5d=eq5d-0.0441; 
if eqq2cd=3     then eq5d=eq5d-0.2912; 
******Usual activities*****; 
if eqq3cd=2     then eq5d=eq5d-0.0370; 
if eqq3cd=3     then eq5d=eq5d-0.0538; 
*****Pain/discomfort******; 
if eqq4cd=2     then eq5d=eq5d-0.0274; 
if eqq4cd=3     then eq5d=eq5d-0.0409; 
*****Anxiety/depression*****; 
if eqq5cd=2    
then eq5d=eq5d-0.0359; 
if eqq5cd=3    
then eq5d=eq5d-0.1771; 
 
if (eqq1cd=. or eqq2cd=. or eqq3cd=. or eqq4cd=. or eqq5cd=.)  
 
 
 
 
then eq5d=.; 
run;  
 
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10.5 Search Criteria for TEAE of Special Interest/TEAE Syndrome  
AESI 
Search Criteria 
Anaphylactic reactions  
Narrow SMQ for “anaphylactic reaction” 
Note: CMQsn00021 
Systemic or extensive 
hypersensitivity reaction 
Narrow SMQ for “hypersensitivity”  
Note: CMQsn00214 
Malignancy 
Narrow SMQ for “Malignancy” 
Note:CMQsn00090 
Helminthic infections 
HLGT as “Helminthic disorder” 
Note: CMQ10544 
Suicide-related events 
Narrow SMQ for “Depression and suicide/self-injury” 
Note: CMQsn00035 
Blepharitis (severe or serious or 
lasting ≥4 weeks) 
HLT as “Lid, lash and lacrimal infections, irritations and 
inflammations” and “Severe” ticked in Adverse Events CRF page or 
lasting ≥28 days  
Note: CMQ10497 
Any type of conjunctivitis 
(severe or serious or lasting ≥4 
weeks) 
Selected PTs and  “Severe” ticked in Adverse Events CRF page or 
lasting ≥28 days 
Note: CMQ10498 
Pregnancy of a female patient 
entered in a study as well as 
pregnancy occurring in a female 
partner of a male patient entered 
in a study with IMP/NIMP 
“Pregnancy” or “Partner Pregnancy” checked on the Pregnancy CRF 
page as reported by the investigator 
Symptomatic overdose (serious 
or nonserious) with IMP/NIMP 
“Symptomatic overdose” checked as “Yes” on the Overdose CRF 
page as reported by the investigator 
 
 
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10.6 Search Criteria for Personal history of atopic/allergic conditions  
Atopic/allergic conditions 
Search Criteria 
Atopic Dermatitis 
PT as “Dermatitis atopic” 
Asthma 
Include the following PTs: 
-Asthma 
-Asthma exercise induced 
-Bronchospasm 
-Status asthmaticus 
-Asthmatic crisis 
-Bronchial hyperreactivity 
-Reactive airways dysfunction syndrome 
-Aspirin-exacerbated respiratory disease 
-Childhood asthma 
Note: CMQ10424 
Allergic Conjunctivitis 
Include the following PTs: 
-Conjunctival irritation 
-Conjunctival oedema 
-Conjunctival ulcer 
-Conjunctivitis 
-Conjunctivitis allergic 
-Giant papillary conjunctivitis 
-Inclusion conjunctivitis 
-Ophthalmia neonatorum 
-Seasonal allergy 
-Conjunctival hyperaemia 
-Inclusion conjunctivitis neonatal 
-Pingueculitis 
-Acute haemorrhagic conjunctivitis 
-Ligneous conjunctivitis 
-Noninfective conjunctivitis 
Note: CMQ10539 
Atopic Keratoconjunctivitis 
PT as “Atopic Keratoconjunctivitis” and “Keratoconjunctivitis” 
Note: CMQ10538 
Allergic Rhinitis 
HLT= “Nasal congestion and inflammations” exclude PT= 
“Radiation rhinitis” 
Note: CMQ10540 
Chronic Rhinosinusitis 
Include the following PTs: 
-Chronic sinusitis 
-Chronic hyperplastic eosinophilic sinusitis 
-Chronic eosinophilic rhinosinusitis 
-Chronic rhinosinusitis with nasal polyps 
Note: CMQ10440 
Nasal Polyps 
Include the following PTs: 
-Nasal polyps 
-Sinus polyp 
-Sinus polyp degeneration 
-Chronic rhinosinusitis with nasal polyps 
Note: CMQ10522 
Eosinophilic Esophagitis 
PT as “Eosinophilic oesophagitis” 
Note: CMQ10541 
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Food Allergy 
Include the following PTs: 
-Flour sensitivity 
-Food allergy 
-Milk allergy 
-Reaction to food additive 
-Allergy to fermented products 
-Caffeine allergy 
-Transplantation associated food allergy 
-Gluten sensitivity 
Note: CMQ10537 
Hives 
HLT as “Urticarias” 
Note: CMQ10458 
Other Allergies 
HLGT as “Allergic conditions” exclude above allergic conditions 
Note: CMQ10523 exclude above allergic conditions 
 
 
 
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10.7 List of efficacy-related entry criteria  
I 03. EASI score ≥16 at the screening and baseline visits 
I 04. IGA score ≥3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at the screening and 
baseline visits 
I 05. ≥10% BSA of AD involvement at the screening and baseline visits 
I 06. Baseline Pruritus 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 
E 03. 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: 
- 
Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, cyclosporine, 
mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, and methotrexate) 
- 
Phototherapy for AD 
E 04. Treatment with TCS or TCI within 1 week before the baseline visit 
E 05. Treatment with systemic TCM within 4 weeks before the baseline visit or treatment with topical 
TCM within 1 week before the baseline visit 
E 06. Treatment with biologics as follows: 
- 
Any cell-depleting agents including but not limited to rituximab: within 6 months before the 
baseline visit or until lymphocyte count returns to normal, whichever islonger 
- 
Other biologics: within 5 half-lives (if known) or 16 weeks prior to baseline visit, whichever is 
longer 
E 07. 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) 
E 08. Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the baseline 
visit 
E 09. Planned or anticipated use of any prohibited medications (see protocol Section 8.8.1) and procedures 
during study treatment 
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