Clinical trial NCT01949311
Conditions: Atopic Dermatitis
Sponsor: Regeneron Pharmaceuticals
Start date: 2013-10-10; Completion date: 2022-06-27
Enrollment: 2733 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective is to assess the long-term safety of dupilumab administered in adult participants with atopic dermatitis (AD).

The secondary objective of the study is to assess the immunogenicity of dupilumab in adult participants with AD, in the context of re-treatment, and to monitor efficacy parameters associated with long-term treatment.

Optional Sub-Study:

The primary objective of the sub-study is to assess the safety of the new dupilumab drug product in adult patients with AD after switching from the current dupilumab drug product.

The secondary objectives of the sub-study are to evaluate systemic exposure and immunogenicity of the new dupilumab drug product in adult patients with AD.

Detailed description:

Arms: arm 1: Participants will receive repeat doses of dupilumab
Interventions: intervention 1: Dupilumab
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
R668-AD-1225 Amendment 10 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 124 
CONFIDENTIAL 
EUDRACT: 2013-001449-15, IND: 107969 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
AN OPEN-LABEL STUDY OF DUPILUMAB IN PATIENTS WITH 
ATOPIC DERMATITIS WHO PARTICIPATED IN PREVIOUS 
DUPILUMAB CLINICAL TRIALS 
Compound: 
Dupilumab 
Clinical Phase: 
3 
Protocol Number: 
R668-AD-1225 
Protocol Version: 
R668-AD-1225 Amendment 10 
Amendment 10 Date of Issue: 
See appended electronic signature page 
Amendment 9 Date of Issue: 
12 November 2019 
Amendment 8 Date of Issue: 
08 Jan 2018 (FI); 04 Jan 2019 (PL) 
Amendment 7 Date of Issue: 
02 June 2017 (FI); 05 June 2017 (PL) 
Amendment 6 Date of Issue: 
28 June 2016 
Amendment 5 Date of Issue: 
No date of issue as Amendment 5 was skipped 
Amendment 4 Date of Issue: 
26 July 2015 
Amendment 3 Date of Issue: 
12 January 2015 
Amendment 2 Date of Issue: 
12 June 2014 
Amendment 1 Date of Issue: 
12 December 2013 
Original Date of Issue: 
12 June 2013 
Scientific/Medical Monitor: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
 
 
.  
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NCT01949311


Clinical Study Protocol 
R668-AD-1225 Amendment 10 
Regeneron Pharmaceuticals, Inc. 
Page 2 of 124 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 10 
Primary Rationale for Amendment 10: The purpose of this amendment is to include a sub-study to 
assess the safety, pharmacokinetics (PK), and immunogenicity of dupilumab derived from a new 
manufacturing process in adults with atopic dermatitis (AD).  The following table outlines the 
changes made to the protocol and the rationale.  
Change 
Rationale 
Section Title and Number 
Approximately 50 patients who are 
participating in the current study 
will be asked to participate in a 
sub-study using the new dupilumab 
drug product.  Patients who provide 
informed consent to participate will 
enter the sub-study at either visit 41, 
43, or 44 of the main study and have 
study treatment switched from 
current dupilumab drug product to 
new dupilumab drug product at 
sub-study visit 1a.  Patients will be 
treated with new dupilumab drug 
product for at least 12 weeks.   
Serious or severe injection site 
reactions (ISRs) or ISRs lasting 
>24 hours were added as adverse 
events of special interest (AESIs) for 
the sub-study. 
A primary analysis of the sub-study 
will be conducted after all patients 
who enter the sub-study complete 12 
weeks of treatment with the new 
dupilumab drug product. 
The new sub-study was added to 
assess 
the 
safety, 
PK, 
and 
immunogenicity of dupilumab made 
from a new manufacturing process 
(new dupilumab drug product). 
 
Clinical Study Protocol Synopsis: 
Sub-Study Objectives (new); Study 
Design; Treatments; Sub-Study 
Endpoints (new)  
Section 1.2.3 Rationale for the 
Sub-Study (new) 
Section 2.3 Sub-Study Objectives 
(new) 
Section 3.1 Study Description and 
Duration 
Figure 1 Study Flow Diagram, 
footnote i (new) 
Figure 2 Sub-Study Flow Diagram 
(new) 
Figure 3 Relationship Between 
Visit Schedules in Main OLE Study 
and Sub-Study (new) 
Section 4.1 Number of Patients 
Planned 
Section 4.2.1 Inclusion Criteria 
Section 4.2.2 Exclusion Criteria 
Section 4.2.4 Entry Criteria for 
Sub-Study (new) 
Section 4.2.4.1 Sub-Study Inclusion 
Criteria (new) 
Section 4.2.4.2 Sub-Study 
Exclusion Criteria (new) 
Section 5.1 Investigational 
Treatment 
Section 6.1 Schedule of Events 
Table 6 Schedule of Events – 
Visits 37 (Week 204) through 
Visits 43 (Week 252), footnote j 
(new) 
Table 7 Schedule of Events – End 
of Treatment, End of Study, Early 
Termination, Unscheduled Visit, 
and Re-entry Visit, footnote s (new) 
Table 8 Sub-Study Schedule of 
Events (new) 
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CONFIDENTIAL 
Change 
Rationale 
Section Title and Number 
Section 6.2.4 Visit 31/Day 
1093/Week 156 through Visit 
43/Day 1765/Week 252 (+/-3 Days) 
Section 6.2.5 End of Treatment 
Visit/Day 1821/Visit 44/Week 260 
(+/-3 Days) 
Section 6.2.6 Sub-Study Treatment 
Period (new) 
Section 6.2.6.1 Sub-Study Visit 1a/ 
Day 1a/Week 0a (±3 days) (new) 
Section 6.2.6.2 Sub-Study Visit 
2a/Day 29a/Week 4a (±3 days) 
(new) 
Section 6.2.6.3 Sub-Study Visit 
3a/Day 85a/Week 12a (±3 days) 
(new) 
Section 6.2.6.4 Sub-Study Visit 
4a/Day 169a/Week 24a (±3 days) 
(new) 
Section 6.2.6.5 End of Study Visit 
(Last Dose+12 weeks), Early 
Termination Visit, and 
Unscheduled Visits (new) 
Section 6.2.7 End of Study Visit 
(84 Days After Last Dose or 
12 Weeks After Last Dose) 
Section 6.2.8 Early Termination 
Visit 
Section 6.2.10 Re-entry Visit (Main 
Study Only) 
Section 7.2.3 Other Events that 
Require Accelerated Reporting to 
Sponsor 
Section 8.2.3 Sub-Study Endpoints 
(new) 
Section 8.3 Pharmacokinetic 
variable 
Section 9.5.6 Analysis of the 
Sub-Study (new) 
Section 9.5.6.1 Statistical 
Hypothesis for the Sub-Study (new) 
Section 9.5.6.2 Justification of the 
Sub-Study Sample Size (new) 
Section 9.5.6.3 Analysis Sets for 
the Sub-Study (new) 
Section 9.5.6.4 Statistical Methods 
for the Sub-Study (new) 
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CONFIDENTIAL 
Change 
Rationale 
Section Title and Number 
The protocol was updated to remove 
the Kaplan-Meier survival curve 
from the primary analysis and the 
secondary endpoint of time to event.  
The time to event endpoints were 
used in the first-step analysis to 
support a regulatory submission.  As 
the first-step analysis has been 
completed, 
the 
time-to-event 
endpoints and the Kaplan-Meier 
estimates are no longer needed and 
have been removed from statistical 
analysis. 
For consistency with the statistical 
analysis plan (version 2.0).   
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 8.2.2 Secondary Endpoints 
Section 9.5.3 Efficacy Analysis 
Language was added to clarify 
general changes in study conduct in 
the context of the COVID-19 
pandemic.  This is in addition to 
information previously provided 
directly to sites prior to amendment. 
To address guidance from health 
authorities. 
Section 6.1 Study Schedule of 
Events and Visit Descriptions 
Section 9 Statistical Plan 
Residuals samples will be stored for 
up to 15 years for exploratory 
research.  Leftover samples may be 
used to investigate unexpected AEs.  
Clarification of storage 
requirements 
Section 6.3.5 Research Testing 
Editorial revisions, including update 
name of the Scientific/Medical 
Monitor for the study; and update of 
confidentiality statement on cover 
page.  
For clarity, as needed. 
Throughout the protocol 
 
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CONFIDENTIAL 
Amendment 9 
The purpose of this amendment is to align the dosing regimen of dupilumab with the dosing 
regimen approved by various regulatory agencies, globally, for this patient population. Criteria 
for the events that require accelerated reporting to the sponsor were updated to align with current 
standards for the dupilumab clinical development program. Additionally, the Finland 
country-specific amendments and Poland country-specific amendments were merged into one 
global protocol. The following table outlines the changes made to the protocol and the rationale.  
Change 
Section Changed 
The dosing regimen of dupilumab 300 mg was 
changed from weekly (qw) to every 2 weeks (q2w) 
starting from visit 25 until the end of the treatment 
period to match the dosing regimen approved by 
various regulatory agencies, globally, for this 
patient population.  
As dosing of study drug will be less frequent, 
several in-clinic visits for supplying study drug for 
at-home administration (V26, 28, 32, 34, 36, 38, 40, 
and 42) were removed since these visits are no 
longer needed.  
Synopsis: Study Design; Treatments 
Section 1.2.1 Rationale for Study Design 
Section 1.2.2 Rationale for Dose Selection 
Section 3.1 Study Description and Duration 
Figure 1: Study Flow Diagram; footnote b; 
footnote h (added) 
Section 5.1 Investigational Treatment 
Table 1: Schedule of Events – Visits 1 through 8 
(Week 12); footnotes c and l; footnote m (added) 
Table 2: Schedule of Events – Visits 9 (Week 16) 
through 18 (Week 52); footnotes a and h; 
footnote j (added) 
Table 3: Schedule of Events – Visit 19 (Week 60) 
through 24 (Week 100); footnotes a and h 
Table 4: Schedule of Events – Visits 25 (Week 
108) through Visit 30 (Week 148); footnotes a and 
g; footnote i (added) 
Table 5: Schedule of Events – Visits 31 (Week 
156) through Visit 36 (Week 196); footnotes a and 
g; footnote i (added) 
Table 6: Schedule of Events – Visits 37 (Week 
204) through Visit 43 (Week 252); footnotes a and 
g; footnote i (added) 
Table 7: Schedule of Events – End of Treatment, 
End of Study, Early Termination and Unscheduled 
Visit; footnotes a and g 
Section 6.2.2.25 Visit 26/Day 813/Week 116 
(+/-3 Days) 
Section 6.2.2.27 Visit 28/Day 925/Week 132 
(+/-3 Days) 
Section 9.5.2.3 Treatment Exposure 
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CONFIDENTIAL 
Change 
Section Changed 
Clarified/updated list of adverse events of special 
interest (AESIs) including addition of clinically 
symptomatic 
eosinophilia 
and 
removal 
of 
malignancy and suicide-related events per health 
authority request. The AESI definition for 
conjunctivitis and blepharitis was revised to remove 
the criteria for events lasting ≥4 weeks. This change 
was made because in previous dupilumab trials for 
the treatment of atopic dermatitis, events of mild to 
moderate severity were not found to be clinically 
meaningful, even when lasting >28 days during the 
study, as they did not result in sequelae or treatment 
discontinuation. 
This 
will 
enable 
better 
characterization of a known adverse event with 
dupilumab and it also complies with a health 
authority request.  
Section 7.2.3 Other Events that Require 
Accelerated Reporting to Sponsor 
The requirement for reporting pregnancy of a 
female partner of a male patient during the study or 
within 12 weeks of the last study drug dose was 
removed. This requirement was removed from all 
guidance to investigators in the most current version 
of the Investigator’s Brochure as there has been no 
evidence of adverse changes to spermatogenesis.  
Section 7.2.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Changes outlined in previously issued country-
specific amendments for Finland and Poland have 
been merged.  
Section 3.1 Study Description and Duration 
(includes text that was previously in the 
PL-specific protocol but not the FI-specific 
protocol) 
Section 4.2.3 Entry Criteria for Patients Re-
Entering the Study (this section was previously in 
the PL-specific protocol but not the FI-specific 
protocol) 
Section 5.1 Investigational Treatment (includes 
text that was previously in the PL-specific protocol 
but not the FI-specific protocol) 
Table 7: Schedule of Events – End of Treatment, 
End of Study, Early Termination, Unscheduled 
Visit and Re-entry Visit (table title, column for re-
entry visit, rows, and footnotes pertaining to the 
re-entry visit were previously in the PL-specific 
protocol but not the FI-specific protocol) 
Section 6.2.10 Re-entry Visit (this section was 
previously in the PL-specific protocol but not the 
FI-specific protocol) 
Minor changes were made to improve clarity, 
accuracy, and readability.  
Throughout the protocol.  
 
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CONFIDENTIAL 
Amendment 8 (Poland) 
The table that follows outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
The purpose of this amendment is to extend the 
duration of the treatment period to up to 5 years in 
order to collect longer term safety data. 
This amendment is notification that as of the date 
of issue of amendment 8, this study is closed to 
further enrollment. 
Synopsis:  Study Design and Study Duration  
Section 3.1: Study Description and Duration 
Figure 1: Study Flow Diagram 
Section 3.2:  End of Study Definition (added) 
Section 4.2.3:  Entry Criteria for Patients 
Re-Entering the Study  
Section 5.1: Investigational Treatment 
Table 3: Schedule of Events – Visit 19 (Week 60) 
through 24 (Week 100) 
Table 4: Schedule of Events – Visits 25 
(Week 108) through Visit 30 (Week 148) 
Table 5: Schedule of Events – Visits 31 
(Week 156) through Visit 36 (Week 196) 
Table 6: Schedule of Events – Visits 37 (Week 
204) through Visit 43 (Week 252) 
Table 7: Schedule of Events – End of Treatment, 
End of Study, Early Termination and Unscheduled 
Visit 
Section 6.2.4: Visit 31/Day 1093/Week 156 
through Visit 43/Day 1765/Week 252 (+/-3 Days)  
Section 6.2.5:  End of Treatment Visit/Day 
1821/Visit 44/Week 26 (+/-3 Days) 
Section 6.2.8: Unscheduled Visits  
Section 6.2.9: Re-entry Visit 
 
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Clinical Study Protocol 
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Regeneron Pharmaceuticals, Inc. 
Page 8 of 124 
CONFIDENTIAL 
Amendment 8 (Finland) 
The table that follows outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
The purpose of this amendment is to extend the 
duration of the treatment period to up to 5 years in 
order to collect longer term safety data. 
This amendment is notification that as of the date 
of issue of amendment 8, this study is closed to 
further enrollment. 
Synopsis:  Study Design and Study Duration  
Section 3.1 Study Description and Duration 
Figure 1 Study Flow Diagram 
Section 3.2 End of Study Definition (added) 
Table 3 Schedule of Events – Visit 19 (Week 60) 
through 24 (Week 100) 
Table 4 Schedule of Events – Visits 25 
(Week 108) through Visit 30 (Week 148) 
Table 5 Schedule of Events – Visits 31 
(Week 156) through Visit 36 (Week 196) (added) 
Table 6 Schedule of Events – Visits 37 (Week 
204) through Visit 43 (Week 252) (added) 
Table 7 Schedule of Events – End of Treatment, 
End of Study, Early Termination and Unscheduled 
Visit (added) 
Section 6.2.3 Visit 30/Day 1037/Week 148 (+/-3 
Days) (added) 
Section 6.2.4 Visit 31/Day 1093/Week 156 
through Visit 43/Day1765/Week 252 (added) 
Section 6.2.5 End of Treatment Visit/Day 
1821/Visit 44/week 260 (section updated) 
Section 6.2.6 End of Study Visit (84 Days After 
Last Dose or 12 Weeks After Last Dose) (section 
updated) 
Section 6.2.8 Unscheduled Visits 
 
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CONFIDENTIAL 
Amendment 7 (Poland) 
The table that follows outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Allow patients who are expected to complete 
3 years of treatment prior to regulatory approval to 
continue treatment through approximately 
31 December 2017.  Patients who have already 
completed the End of Treatment visit will be 
permitted to resume treatment with study drug.  
Patients who have already completed the End of 
Study visit will be permitted to re-enter the study.   
The treatment period will end for all patients on or 
about 31 December 2017. 
Add entry criteria for patients who re-enter the 
study 
Synopsis:  Study Design and Study Duration  
Section 3.1:  Study Description and Duration 
Figure 1: Study Flow Diagram 
Section 4.2.3:  Entry Criteria for Patients Re-
Entering the Study (section added) 
Section 5.1:  Investigational Treatment 
Table 4:  Schedule of Events – Visits 25 
(Week 108) through End of Study (Last Dose + 
12 Weeks/84 Days) 
Section 6.2.3:  Visit 30/Day 1037/Week 148 (+/-
3 Days) 
Section 6.2.4:  Visit 31 through Visit 33 
(section added) 
Section 6.2.5:  End of Treatment Visit 
Section 6.2.6:  End of Study Visit (84 Days after 
Last Dose or 12 Weeks after Last Dose) 
Section 6.2.9:  Re-entry Visit (section added) 
Update the list of adverse events of special interest 
(AESIs).  Dupilumab has now been studied in 
more than 4000 patients, with more than 
2000 patients exposed for more than 52 weeks.  
Dupilumab has been approved by the U.S. Food 
and Drug Administration for the treatment of adult 
patients with moderate-to-severe atopic dermatitis 
(AD).  There is no evidence of an 
immunosuppressant effect of dupilumab and no 
increased risk of serious, severe, or opportunistic 
infections.  Nor is there any evidence of an 
increased risk of cutaneous T-cell lymphoma.  
Nearly all injection site reactions (ISRs) are of 
mild or moderate severity without causing 
treatment discontinuation and do not warrant 
increased surveillance.  Conjunctivitis will 
continue to be reported as an adverse event (AE), 
but only serious, severe, and/or prolonged events 
of conjunctivitis will require reporting as AESIs.  
Systemic or extensive hypersensitivity reactions, 
malignancy (except basal cell carcinoma), and 
serious, severe, and/or prolonged events of 
blepharitis and keratitis have been added as AESIs. 
Section 7.2.3:  Other Events that Require 
Accelerated Reporting to Sponsor 
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CONFIDENTIAL 
Change 
Section Changed 
Modify the criteria for which study drug may be 
temporarily discontinued 
Section 5.2.2.2:  Reasons for Temporary 
Discontinuation of Study Drug 
Remove “treatment with systemic corticosteroids” 
as a reason for temporary discontinuation of study 
drug and from the List of Prohibited and Restricted 
Medications.  Patients are no longer required to 
temporarily discontinue study drug if they are also 
treated concomitantly with systemic 
corticosteroids.  As there is no evidence that 
dupilumab is an immunosuppressant, the 
theoretical basis for avoiding combined treatment 
with dupilumab and systemic corticosteroids is no 
longer valid. 
Section 5.2.2.2:  Reasons for Temporary 
Discontinuation of Study Drug 
Section 5.5.1:  Permitted Medications and 
Procedures 
Section 5.5.2:  Prohibited and Restricted 
Medications 
Reduce the duration of the End of Study visit from 
16 weeks to 12 weeks after the last dose of 
dupilumab.  Pharmacokinetic (PK) analysis of the 
once every week (qw) dosing regimen 
demonstrates that the median time to non-
detectable concentrations after the last steady-state 
dose is approximately 12 weeks. 
Synopsis:  Study Design 
Section 3.1:  Study Description and Duration 
Figure 1: Study Flow Diagram 
Section 4.2.2:  Exclusion Criteria, exclusion 
criterion 23 
Table 4:  Schedule of Events – Visits 25 
(Week 108) through End of Study (Week 160) 
Section 6.2.6:  End of Study Visit/ 
Visit 31/Day 1121 (or 84 Days after 
Last Dose)/Week 160 (or 12 Weeks after 
Last Dose) 
Section 6.2.7:  Early Termination Visit 
Section 7.2.3:  Other Events that Require 
Accelerated Reporting to Sponsor 
Update the sample size since no new patients are 
expected to be enrolled in this trial 
Synopsis:  Sample Size 
Section 4.1:  Number of Patients Planned 
 
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CONFIDENTIAL 
Amendment 7 (Finland) 
The table that follows outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Update the list of adverse events of special interest 
(AESIs).  Dupilumab has now been studied in 
more than 4000 patients, with more than 
2000 patients exposed for more than 52 weeks.  
Dupilumab has been approved by the U.S. Food 
and Drug Administration for the treatment of adult 
patients with moderate-to-severe atopic dermatitis 
(AD).  There is no evidence of an 
immunosuppressant effect of dupilumab and no 
increased risk of serious, severe, or opportunistic 
infections.  Nor is there any evidence of an 
increased risk of cutaneous T-cell lymphoma.  
Nearly all injection site reactions (ISRs) are of 
mild or moderate severity without causing 
treatment discontinuation and do not warrant 
increased surveillance.  Conjunctivitis will 
continue to be reported as an adverse event (AE), 
but only serious, severe, and/or prolonged events 
of conjunctivitis will require reporting as AESIs.  
Systemic or extensive hypersensitivity reactions, 
malignancy (except basal cell carcinoma), and 
serious, severe, and/or prolonged events of 
blepharitis and keratitis have been added as AESIs.  
Section 7.2.3 : Other Events that Require 
Accelerated Reporting to Sponsor 
Modify the criteria for which study drug may be 
temporarily discontinued 
Section 5.2.2.2 :Reasons for Temporary 
Discontinuation of Study Drug 
Remove “treatment with systemic corticosteroids” 
as a reason for temporary discontinuation of study 
drug and from the List of Prohibited and Restricted 
Medications.  Patients are no longer required to 
temporarily discontinue study drug if they are also 
treated concomitantly with systemic 
corticosteroids.  As there is no evidence that 
dupilumab is an immunosuppressant, the 
theoretical basis for avoiding combined treatment 
with dupilumab and systemic corticosteroids is no 
longer valid. 
Section 5.2.2.2 :  Reasons for Temporary 
Discontinuation of Study Drug 
Section 5.5.1 :Permitted Medications and 
Procedures 
Section 5.5.2 :  Prohibited and Restricted 
Medications 
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Change 
Section Changed 
Reduce the duration of the end-of-study visit from 
16 weeks to 12 weeks after the last dose of 
dupilumab.  Pharmacokinetic (PK) analysis of the 
once every week (qw) dosing regimen 
demonstrates that the median time to non-
detectable concentrations after the last steady-state 
dose is approximately 12 weeks. 
Synopsis:  Study Design 
Section 3.1 :  Study Description and Duration 
Figure 1 :Study Flow Diagram 
Section 4.2.2:  Exclusion Criteria, exclusion 
criterion 23 
Table 4 : Schedule of Events – Visits 25 
(Week 108) through End of Study (Week 160) 
Section 6.2.3 :  End of Study Visit/Visit 31/Day 
1121 (or 84 Days after Last Dose)/Week 160 (or 
12 Weeks after Last Dose) 
Section  6.2.5 :  Early Termination Visit 
Section  7.2.3 :  Other Events that Require 
Accelerated Reporting to Sponsor 
Update the sample size since no new patients are 
expected to be enrolled in this trial 
Synopsis:  Sample Size 
Section 4.1 :  Number of Patients Planned 
Amendment 6 (28 June 2016) 
The main purpose of this amendment is to streamline and simplify the schedule of study visits and 
procedures.  This is expected to facilitate the implementation of the protocol at participating study 
centers, decrease the burden for study patients, and improve their compliance.  At the time of 
implementing this amendment, data has been generated from more than 1400 patients who have 
followed a more intensive schedule of visits and assessments.  More than 400 patients have 
completed one year in the study.  Consequently, at this stage, it has become possible to remove the 
non-essential visits and assessments.   
Specific changes in this amendment include:  
• To align the Global, Great Britain (GB), and Japan (JP) protocol amendment numbers 
for ease of operation 
• Update rationale for dose selection to indicate that the dose ranging study 
R668-AD-1021 is now complete and to provide rationale for 300 mg QW dose 
• Update study description to justify abbreviation of visits in this amendment  
• Remove the following visits at the following weeks from the Schedule of Events and 
throughout the protocol:  week 1, week 2, week 3, week 8, week 20, week 28, week 
36, and week 44.  This was deemed acceptable from a patient safety standpoint based 
on data from completed phase 3 studies 
• Remove the genomic sub-study DNA sample (optional) from the Schedule of Events 
and throughout the protocol 
• Remove the informed consent form (ICF) for optional assessments from the Schedule 
of Events as it is no longer needed because the optional sample for DNA analysis has 
also been removed 
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• Remove the concomitant medications/procedures assessment from visits at week 12, 
week 24, week 40, week 52, week 68, week 84, week 100, week 116, week 132, and 
week 148 
• Remove the Patient Oriented Eczema Measure (POEM), Dermatology Quality of Life 
Index (DLQI), and EQ-5D assessments from visits at screening, week 12, week 24, 
week 76, week 124, End of Treatment, End of Study, Early Termination, and 
Unscheduled visit to simplify study conduct 
• Remove patient global assessment of disease from the Schedule of Events and 
throughout the protocol.  This was deemed appropriate from a patient safety 
standpoint based on data from completed studies. 
• Remove patient global assessment of treatment effect from the Schedule of Events 
and throughout the protocol.  This was deemed appropriate from a patient safety 
standpoint based on data from completed studies. 
• Remove research samples (serum/plasma) from the Schedule of Events and 
throughout the protocol.  It is non-essential and this was deemed appropriate from a 
safety standpoint based on data from completed studies. 
• Remove electrocardiogram from the Schedule of Events and throughout the protocol.  
This was deemed appropriate from a patient safety standpoint based on data from 
completed studies. 
• Remove urinalysis from the Schedule of Events and throughout the protocol.  This 
was deemed appropriate from a patient safety standpoint based on data from 
completed studies. 
• Remove the thymus and activation-regulated chemokine (CCL17 [TARC]) 
assessment from the Schedule of Events and throughout the protocol. 
• Remove the total serum IgE assessment from the Schedule of Events and throughout 
the protocol. 
• Remove high-sensitivity C-reactive protein (hs-CRP), anti-nuclear antibody (ANA), 
anti-dsDNA, and anti-thyroid peroxidase antibody (anti-TPO) assessments from the 
Schedule of Events and throughout the protocol. 
• Remove all physical exams except for at baseline.  This was deemed appropriate from 
a patient safety standpoint based on data from completed studies. 
• Remove hematology and chemistry from all visits except visit 1 (screening), visit 2 
(baseline), week 16, week 48, week 100, week 148, and unscheduled visits 
• Remove Investigator’s Global Assessment (IGA) and Eczema Area and Severity 
Index (EASI) from visits at week 12, week 24, 32, week 40, week 68, week 76, week 
84, week 92, week 108, week 116, week 132, week 140, and week 148 (End of 
Treatment visit) 
• Remove vital signs assessments from visits at week 12, week 24, week 40, week 52, 
and week 68 
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• Remove weight assessment from the visit at week 24 
• Remove drug concentration samples from visits at week 4, week 12, week 52, week 
60, week 68, and week 116. Add drug concentration samples to week 48 and week 
100. 
• Update the Schedule of Events to clarify that patients will be provided with a 
pregnancy test kit to take home for monthly testing in between clinic visits, or may 
choose to have the testing done at the study site 
• Remove anti-drug antibody (ADA) samples from the visits at week 4, week 12, 
week 52, week 68, week 92, and week 116.  Add ADA at week 48, week 100, week 
124, and End of Treatment visit 
• Addition of an ophthalmological examination to the Schedule of Events at baseline, 
week 4, week 12, week 16, week 32, week 48, week 60, week 76, week 92, week 108, 
week 124, week 140, end of study visit, and unscheduled visits 
• Remove the 3 day window for the End of Study visit and indicate that a late visit is 
acceptable and preferable to foregoing the assessments altogether 
• Update the number of global study sites and patients planned 
• Clarify dosing language 
• Clarify how long patients treated with a prohibited or restricted medication must 
temporarily discontinue from study drug 
• Clarify inclusion criterion 1b to allow enrollment of patients who participated in any 
dupilumab atopic dermatitis (AD) study that has undergone last visit 
• Change the wording in exclusion criterion 3 to allow enrollment of patients who met 
conditions for permanent study drug discontinuation in a prior study if such 
conditions were considered resolved and of no further consequence – subject to 
medical monitor review and approval 
• Update exclusion criterion 12 to add that patients with positive hepatitis C antibody 
may undergo additional tests and consultations 
• Update exclusion criterion 23 to state that use of effective and accepted contraception 
applies only when patients engage in heterosexual intercourse and to add double 
barrier methods as accepted method of contraception 
• Remove severe laboratory abnormalities as reason for permanent discontinuation of 
study drug.  This event is now listed as a reason for temporary discontinuation of 
study drug. 
• Clarify that “Pregnancy at any time during the study” is a reason for permanent 
discontinuation of study drug 
• Clarify when elevated creatine phosphokinase (CPK) should be considered a reason 
for temporary discontinuation of study drug 
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• Align the text describing severe infection as a reason for temporary discontinuation of 
study drug with the AESI criteria 
• Add suicide-related events and conjunctivitis to AESI 
• Remove the section Restricted Concomitant Medications and Procedures to 
consolidate information under “Prohibited and Restricted Medications” 
• Update secondary endpoints to reflect removal of some assessments 
Amendment 5 
This amendment number was skipped to align the Global, GB, and Japan protocol amendment 
numbers for ease of operation. 
Amendment 4 (26 July 2015) 
The purposes of this amendment are to: 
• Extend the study duration for each patient to up to 3 years or until the product is 
commercially available in the geographic region of the patient (whichever comes 
first) to allow patients to continue treatment with dupilumab in the study prior to 
product becoming available. 
• Update the estimated planned enrollment to approximately 2000 to reflect patients in 
the phase 3 studies expected to roll over into this study and the number of study sites 
to approximately 550 globally to reflect the number of study sites in the phase 3 
studies expected to participate in this study. 
• Revise inclusion criterion 1 to allow enrollment of patients in this open-label study 
who have been screened for a phase 3 study (R668-AD-1334 and -1416), but could 
not be randomized in the phase 3 studies due to randomization closure, to provide 
these patients (who meet the eligibility criteria for this open-label study) the 
opportunity for dupilumab treatment; and to make edits for clarity 
• In exclusion criterion 5, change the washout period for prohibited medications from 
1 week to 5 half-lives to be consistent with the parent studies, such as the phase 3 
studies. 
• Clarify and simplify exclusion criterion 9 regarding infections indicating a patient 
with any infection requiring systemic treatment that is not resolved within 1 week 
before baseline will not be eligible to enroll in the study. 
• Clarify exclusion criterion 12 to indicate that a given hepatitis virus, antigen, or 
antibody test is not required for patients with a negative result of that test documented 
within 1 year prior to baseline, and to clarify serology tests necessary to rule out 
active hepatitis B infection and carrier status. 
• Add ECG at week 100 visit (end of year 2) and change ECG at the end of study visit 
to end of treatment visit. 
• Add additional laboratory tests at the unscheduled visit, and a note that not all listed 
procedures and tests are required at the visit. 
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• Change “electrocardiograms will be performed before blood is drawn during visits 
requiring blood draws” to “electrocardiograms should be performed before blood is 
drawn during visits requiring blood draws” to allow slight flexibility in this long-term 
study. 
• Add a note in the Other Laboratory Tests section indicating that HIV testing is not 
required at screening for patients with a negative test result in the parent study within 
1 year of baseline to be consistent with exclusion criterion 11; and to add a note to 
clarify policy and procedure for unplanned laboratory tests. 
• Add the following footnote for laboratory tests to be consistent with the phase 3 
studies:  “direct and indirect bilirubin will be measured when the total bilirubin is 
above the upper limit of normal (ULN); CPK isoenzymes will be measured when 
CPK >5X the ULN”. 
• Remove the requirement to have some patients who are negative for anti-drug 
(dupilumab) antibody (ADA) at their last study visit to have additional ADA samples 
collected for analysis (which was intended to maintain blind) because maintaining 
blind is not necessary in this open-label study, and to revise the criteria for additional 
ADA follow-up for patients with an positive ADA titer at their last study visit to 
provide flexibility as the criteria may be adjusted according to new ADA data and 
knowledge accumulated. 
• Specify that research samples may be stored for up to 10 years. 
• Remove “by telephone” for pregnancy reporting to allow reporting by other means 
(eg, filling out and faxing the pregnancy form). 
• In the statistical methods for efficacy analysis section, remove censoring of efficacy 
data during data analysis based on use of prohibited concomitant treatment because it 
is inappropriate or not practical in this long-term study where study treatment is 
allowed to resume after certain period following completion of prohibited 
concomitant medications; and to add a statement that subgroup analyses for key 
efficacy endpoints will be performed. 
• Revise the definition of EASI-75 to be consistent with that in the phase 3 dupilumab 
protocols. 
• Add Pruritus NRS related endpoints to the secondary endpoint section to be 
consistent with the phase 3 dupilumab protocols. 
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Amendment 3 (12 January 2015) 
The purposes of this amendment are to: 
• Update information about study drug formulation to indicate availability of prefilled 
syringes (PFS) and to remove mention of glass vials. 
• Clarify that assessments in the screening visit in this study that coincide with 
assessments in the last visit in the previous study will be performed only once 
• Clarify that it is currently anticipated that approximately 800 patients who 
participated in controlled and/or short-term dupilumab studies will enroll in this 
study, but the actual size of the study population will depend on the number of 
patients transitioning from prior dupilumab studies, so the anticipated number is not 
proposed as a fixed enrollment goal. 
• Add a statement that patients who fail screening or who fail to complete the baseline 
visit within 28 days of screening may be rescreened. 
• Add study R668-AD-1021 to the list of completed studies excepted from the specific 
compliance requirements. 
• Clarify that patients who discontinued from the previous dupilumab study due to 
protocol-defined criteria for permanent discontinuation are not eligible to participate 
in this study. 
• State that patients with active chronic or acute infection requiring systemic treatment 
with antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 
2 weeks before day 1 are not eligible to participate in this study. 
• Add hepatitis B core antibody (HBcAb) to the list of tests in exclusion #12, that are 
not required at screening if patients had a negative test result within 1 year prior to 
baseline. 
• Delete history of nonmalignant lymphoproliferative disorders as an exclusion 
criterion to harmonize with other dupilumab protocols, as this exclusion is implicitly 
covered under other criteria. 
• Delete the redundant statement that if necessary, study staff will train the patient or 
caregivers who are willing to administer study drug outside of the clinic, on 
preparation and administration of study drug. 
• Add the upper arms as an optional site for administration of study drug. 
• Add a note to state that patients who discontinue the study because of a laboratory 
abnormality may resume study treatment when the laboratory abnormality is 
sufficiently normalized if a causal relationship to study drug can be reasonably 
excluded, and that the decision to resume study treatment will be made jointly by the 
investigator and medical monitor. 
• State that a review of efficacy will be triggered whenever patients fail to achieve 
and/or maintain Eczema Area and Severity Index (EASI)-25 at week 12. 
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• Remove the redundant statement that treatment with any prohibited concomitant 
medication or procedure may lead to temporary discontinuation from the study. 
• Delete the statement that study drug dosing could be temporarily discontinued in the 
event of confirmed alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) values >3 x upper limit of normal (ULN), total bilirubin >2 x ULN excluding 
confirmed Gilbert’s Syndrome, or confirmed AST and/or ALT >5 x ULN (for more 
than 2 weeks) from Section 5.2.2.2, as these criteria are noted in Section 5.2.2.1 as 
reasons for permanent discontinuation. 
• Add treatment with systemic corticosteroids or nonsteroidal 
immunosuppressive/immunomodulating medications (eg, cyclosporine, methotrexate, 
azathioprine, mycophenolate-mofetil, Janus kinase inhibitors, biologic agents) as a 
reason for temporary discontinuation of study drug. 
• Delete phototherapy as a reason for temporary discontinuation of study drug. 
• Clarify that study drug dosing may resume at the discretion of the principal 
investigator in consultation with the medical monitor after the laboratory abnormality 
leading to suspension of dosing normalizes sufficiently, and/or the medication leading 
to suspension of dosing has been discontinued. 
• Confirm that the investigator may discontinue study drug dosing at any time if 
necessary to ensure the safety of study patients. 
• Add basic skin care, emollients, topical anesthetics, antihistamines, topical and 
systemic anti-infective medications, topical calcineurin inhibitors, and topical 
corticosteroids to the list of permitted medications. 
• Add systemic corticosteroids and nonsteroidal systemic medications as prohibited 
medications. 
• Delete nonsteroidal systemic immunomodulating medications as prohibited 
medications. 
• Clarify that patients who receive prohibited medications will be discontinued from 
study drug for the duration of treatment with these prohibited medications plus 5 
half-lives. 
• Add HIV screening, and hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HBcAb), and hepatitis C antibody assessments at screening. 
• Specify the preferred order of assessments prior to injection of study drug. 
• Clarify the purpose of collection of research samples. 
• Add that a pregnancy occurring in a female partner of a male patient participating in 
the study during the study or within 16 weeks of the last dose of study drug must be 
reported by the investigator to the sponsor (or designee) by telephone within 24 hours 
of identification. 
• Add mycosis fungoides and other forms of cutaneous T cell lymphoma as an adverse 
event of special interest (AESI). 
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Amendment 2 (12 June 2014) 
The purposes of this amendment are: 
• To change the weekly dose of dupilumab from 200 mg to 300 mg and the loading 
dose from 400 mg to 600 mg based on the interim results from the dose ranging study 
(R668-AD-1021). 
• To revise inclusion criterion #1, removing the requirement of 4-week study treatment 
in a parent study to allow more patients to become eligible, especially those who may 
have discontinued the parent study sooner than 4 weeks of treatment due to being on 
placebo; clarifying visits/assessments required to be completed in the parent study for 
a patient to be eligible to participate in this study to prevent accelerated entry into this 
study. 
• To add an inclusion criterion to clarify that only adult patients (≥18 years of age) are 
eligible to participate in this study. 
• To revise exclusion criteria #1, 2, and 3 for clarity and consistency. 
• To revise exclusion criterion #5, reducing washout period for the listed prior 
medications from 4 weeks to 1 week. 
• To revise exclusion criteria #9, 10, and 11 for clarity or accuracy. 
• To remove hepatitis B core antibody (HBcAb) from exclusion criterion #12 and 
schedule of assessments. 
• To change the requirement for adequate birth control from up to 16 weeks to up to 
120 days after the last dose of study drug in exclusion criterion #24. 
• To revise Section 5.2.2.1 Reasons for Permanent Discontinuation of Study Drug and 
Section 5.2.2.2 Reasons for Temporary Discontinuation of Study Drug for clarity and 
to be consistent with other dupilumab clinical studies where appropriate. 
• To remove ultraviolet procedures from the list of restricted concomitant medications 
and procedures. 
• To change the 1-hour postdose close monitoring to be a minimum of 30 minutes at 
visits 2 to 4, and to remove the 1-hour postdose close monitoring from visits 5 and 6. 
• To add Patient Assessment of Pruritus Intensity via IVRS/IWRS (weekly) at the end 
of study visit. 
• To specify that the pregnancy test will be performed with urine sample at visits 2, 6 to 
23, as well as at the end of treatment, end of study, early termination, and 
unscheduled visits. 
• To correct that the Investigator’s Global Assessment (IGA) is a 5-point scale (instead 
of 6-point). 
• To correct that the Pruritus Numerical Rating Scale will be completed weekly 
(instead of daily). 
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• To revise the description of anti-drug (dupilumab) antibody (ADA) measurements 
and samples to be clear on how patients with an ADA titer ≥240 at the last study visit 
will be monitored. 
• To add the following statement “Unused samples collected for drug concentration or 
ADA analyses may also be used for research purposes”. 
• To change the secondary endpoint of “proportion of patients with EASI-50” to 
“proportion of patients with EASI-75” to be consistent with phase 3 studies and to 
clarify that the change in EASI is in reference to baseline of the parent study. 
• To clarify the observation periods for analyses of safety variables. 
• To clarify that summarization of potentially clinically significant values (PCSVs) for 
laboratory results will be performed for treatment-emergent PCSVs. 
• To revise the calculation of duration of exposure during the study from “(date of last 
study drug injection – date of first study drug injection) + 14 days” to “(date of last 
study drug injection – date of first study drug injection) + 7 days”. 
Amendment 1 (12 December 2013) 
Purpose: 
The purposes of this amendment are: 
• To add the monitoring of efficacy associated with long-term treatment to the 
secondary objective of the study, as efficacy procedures are performed in this study. 
• To add the use of “systemic corticosteroids” and “systemic immunosuppressive 
drugs” to the list of other secondary endpoints, to allow for more specific analyses. 
• To specify the requirements for patients to assess the overall (average) intensity of 
their pruritus using a 10-point numerical rating scale (NRS) on a weekly basis, which 
was inadvertently omitted in the original version of the protocol. 
• To move the IVRS/IRWS training from screening to baseline, and to add a second 
IVRS/IWRS training time point at week 4 (visit 6), to be proximate to the time at 
which the patient is eligible to take drug home for self-injection; the IVRS/IWRS will 
be used to capture dosing diary information when patients dose from home. 
• To change the dosing window for visits with windows of “± 4” and “± 7 days” to 
“± 3 days.”  Visit windows have been defined as “± 3 days” to avoid overlapping 
windows for weekly dosing. 
• To add measurement of “height” to the list of procedures and assessments performed 
in the study (inadvertently omitted in the original version). 
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• To clarify that in order to become eligible for the open-label extension study, patients 
enrolled in previous AD studies must adequately complete the assessments required 
for both the treatment and follow-up periods of those particular studies; to further 
clarify that adequate completion of these assessments includes undergoing at least 
2 landmark visits, as defined in each study protocol:  (1) primary endpoint visit, 
which is usually the end of treatment visit, and (2) end of study visit as defined in 
each study protocol, as well as completing all other assessments during the treatment 
and follow-up periods for at least 50% of the timepoints allocated to each assessment, 
unless the protocol of the previous study allows earlier transition into the open-label 
extension, in which case these requirements apply up to the point when this transition 
is permitted. 
• To remove systemic corticosteroids (including topical and oral) as a prohibited and 
restricted medication.  Since this is a long-term study, it is anticipated that some 
patients may use systemic corticosteroids for the treatment of concurrent atopic 
conditions, such as asthma, which are commonly associated with AD. 
• To clarify that resumption of study treatment after temporary discontinuation will 
require written approval from the medical monitor. 
• To add inadequate efficacy as a reason for permanent discontinuation from the study 
drug, and from the study in response to the German Ethics Committee request. 
• To remove the requirement to administer 400 mg SC dupilumab as a loading dose 
(ie, 200 mg initial dose, and 200 mg loading dose) for patients treated in a previous 
AD study unless the last dose administered is less than 4 weeks before their first dose 
in the current study.  These patients will only receive 200 mg as their first dose in the 
current study, as their dupilumab plasma concentration may be high as a result of 
their participation in their previous study. 
• To clarify that training on self- injection or injection administered by a caregiver will 
not be required if training occurred in the previous study; to remove the requirement 
that patients will be monitored at the study site for 1 hour after each of the first 5 
injections. 
• To remove inclusion criterion #2 requiring IGA ≥2 at baseline in the current study to 
account for patients who may transition into the study directly from the dosing phase 
in the previous study.  Many of these patients may have low disease severity scores. 
• To more clearly define the basis on which a patient will be excluded from the 
open-label extension study. 
• To modify exclusion criterion #6 prohibiting treatment with biologics other than 
dupilumab in the past 12 months for any indication, or 5 years for dermatological 
indications, to the new requirement of within 5 half-lives (if known), or 16 weeks, 
whichever is longer, before the first dose in the open-label extension study.  Because 
patients were already screened for this exclusion criteria in their previous studies, this 
criteria was modified so as not to screen out patients who participated in clinical trials 
with biologics for AD (eg, Stelara) in the past 5 years. 
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Regeneron Pharmaceuticals, Inc. 
Page 22 of 124 
CONFIDENTIAL 
• To clarify that any history of HIV and/or hepatitis seropositivity, if known at the time 
of the screening visit, will render the patient ineligible for the study, and to remove all 
requirements for human immunodeficiency virus (HIV) and hepatitis B testing at 
screening.  This change was made because patients in this study already underwent 
similar screening in their previous study. 
• To clarify that the screening visit in this study may coincide with the last visit in the 
previous study.  Assessments that are common to both studies will be performed only 
once. 
• To remove the HbA1C testing requirement from the study, which was erroneously 
included among the laboratory tests to be performed.  
• To add the performance of a physical examination to the end of treatment visit. 
• To permanently discontinue from the study patients who received prohibited 
medications.  These patients will be asked to complete the assessments of the early 
termination and end of study visits, as described in the protocol. 
• To remove the requirement that efficacy measurements be collected prior to 
administering prohibited medications or procedures which are not critical in an 
open-label safety study. 
• To clarify that patients will document/report compliance in a patient dosing diary via 
IVRS/IWRS. 
• During year 1, to change the requirement for performance of a urine pregnancy test in 
the clinic from every 12 weeks to every month.  During year 2, to distribute 
pregnancy test kits at clinic visits for monthly pregnancy testing in between clinic 
visits. 
• To allow a local physician, qualified by training and experience, to review ECGs, to 
accommodate those sites that do not have access to a cardiologist. 
• To require SAEs be entered into the EDC within 24 hours. 
• To remove the pregnancy reporting requirement for a female partner of a male 
patient, and the requirement to follow-up on the pregnancy of a female partner of a 
male patient enrolled in the study. 
• To remove the key secondary endpoint of “number of disease-free days per patient 
year” from the protocol.  As assessments are not conducted on a daily basis, these 
cannot be assessed. 
• To add language regarding the impact of dupilumab on cytochrome P450 (CYP) 
enzyme activity. 
• To correct typographical errors, clarifications to wording of key secondary endpoints, 
statistical plan, rational for study design and dose selection, several 
inclusion/exclusion criteria, clarification of definition of on-treatment, and post-
treatment period for the analysis of TEAEs, clarification of time period for 
calculation of treatment exposure, and to reorder the presentation of safety and 
efficacy.  As this is a safety study, safety is presented first. 
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CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
AN OPEN-LABEL STUDY OF DUPILUMAB IN PATIENTS WITH 
ATOPIC DERMATITIS WHO PARTICIPATED IN PREVIOUS 
DUPILUMAB CLINICAL TRIALS 
Site Locations 
Principal Investigator 
Approximately 500 global study sites. 
Objectives 
The primary objective is to assess the long-term safety of dupilumab 
administered in adult patients with atopic dermatitis (AD). 
The secondary objective of the study is to assess the immunogenicity of 
dupilumab in adult patients with AD, in the context of re-treatment, and 
to monitor efficacy parameters associated with long-term treatment. 
Sub-Study Objectives: 
The primary objective of the sub-study is to assess the safety of the new 
dupilumab drug product in adult patients with AD after switching from 
current dupilumab drug product. 
The secondary objectives of the sub-study are to evaluate systemic 
exposure and immunogenicity of the new dupilumab drug product in 
patients with AD. 
Study Design 
This is a multicenter, open-label extension (OLE) study to assess the 
long-term safety and efficacy of repeat doses of dupilumab in adults 
with moderate-to-severe AD who have previously participated in 
controlled studies of dupilumab or have been screened for a phase 3 
study (R668-AD-1334 or R668-AD-1416), but could not be 
randomized due to randomization closure. 
Enrollment will take place at approximately 500 global study sites.  
After providing informed consent, patients will be assessed for study 
eligibility at the screening visit.  The screening visit in this study may 
coincide with the last visit in the previous study, in which case 
assessments that are common to both studies will be performed only 
once.   
A loading dose of 600 mg SC (two 300 mg doses administered on the 
same day) dupilumab will be administered on day 1 unless the patient 
has received a dose of dupilumab in the 4 weeks prior to baseline.  If 
the patient has received a dose of dupilumab in the past 4 weeks, then 
they will receive a single 300 mg dose at baseline.  The first dose 
should be at least 1 week after the last dose in the previous study, and 
then 300 mg SC dupilumab weekly (qw) starting on day 8. For patients 
who have not completed the study prior to the implementation of 
amendment 9, study drug dosing will change from dupilumab 300 mg 
qw to every 2 weeks (q2w). 
Patients will return for visits that are spaced 4 to 16 weeks apart, as 
specified in the protocol.  The study treatment duration will be up to 
5 years.  The end of study visit occurs 12 weeks after the end of 
treatment visit.  As of the date of issue of amendment 8, this study is 
closed to further enrollment. 
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Regeneron Pharmaceuticals, Inc. 
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CONFIDENTIAL 
Approximately 50 patients who are participating in the current ongoing 
OLE study (R668-AD-1225) and have not completed the end of 
treatment visit (ie, visit 44) prior to the implementation of 
amendment 10 will be asked to participate in the sub-study.  After 
providing informed consent, eligible patients who agree to participate 
will enter the sub-study at either visit 41, 43, or 44 of the main study 
and have study treatment switched from the current dupilumab drug 
product to the new dupilumab drug product at sub-study visit 1a.  
Dupilumab dosing will remain 300 mg SC q2w, and patients will be 
treated with the new dupilumab drug product 300 mg SC q2w for at 
least 12 weeks (some patients may be treated for 24 weeks).  The end 
of study visit for patients participating in the sub-study under 
amendment 10 will be 84 days (12 weeks) after the last dose using the 
new dupilumab drug product.  Patients who enter the sub-study from 
either visit 43 or visit 44 of the main study will have the duration of 
their study treatment increased by 4 or 12 weeks, respectively. 
Patients and/or caregivers who are willing and able to administer 
dupilumab doses outside the clinic will be trained on injecting study 
drug unless they had already been trained during their participation in 
the previous study.  These patients will self-inject study drug (or have 
the drug administered by a caregiver) during weeks in which no clinic 
visit is scheduled.  Safety, laboratory, and clinical assessments will be 
performed at specified clinic visits. 
Patients who receive treatment with a prohibited or restricted 
medication will be discontinued from study drug for the duration of the 
prohibited treatment (plus 5 half-lives as applicable).  Study treatment 
may be resumed only if approved by the medical monitor. 
Patients who test positive for anti-drug antibody (ADA) at their last 
study visit (early termination or end of study) may, based on the 
benchmark ADA titer in effect at the time, be asked to return to the 
clinic to have additional ADA samples collected for analysis within 6 
to 12 months after their last dose of study drug, and thereafter at 
intervals of approximately 3 to 6 months until their titers fall below the 
benchmark titer. 
Study Duration 
The study treatment duration will be up to 5 years. 
Population 
 
Sample Size: 
The study is open to patients who participated in controlled and/or 
short-term dupilumab clinical trials or have been screened for a phase 3 
study (R668-AD-1334 or R668-AD-1416), but could not be 
randomized because of randomization closure.  Based on the numbers 
of patients enrolled or screened in the antecedent dupilumab studies, it 
is currently anticipated that approximately 2500 patients will be 
enrolled.  Institutional Review Boards (IRBs)/Ethics Committees (ECs) 
will be notified if there is more than 25% greater participation than 
currently anticipated. 
Target Population: 
The target population includes adult (≥18 years of age) patients with 
AD who participated in a prior dupilumab clinical study. 
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Regeneron Pharmaceuticals, Inc. 
Page 25 of 124 
CONFIDENTIAL 
Treatments 
 
Study Drug 
Dose/Route/Schedule 
Dupilumab 
300 mg SC qw for patients who complete the study prior to the 
implementation of amendment 9 
300 mg SC q2w after implementation of amendment 9 
For the sub-study: new dupilumab drug product 300 mg SC q2w (after 
implementation of amendment 10) 
A loading dose of 600 mg SC (two 300 mg doses administered on the 
same day) dupilumab will be administered on day 1 unless the patient 
has received a dose of dupilumab in the 4 weeks prior to baseline.  If 
the patient has received a dose of dupilumab in the past 4 weeks, then 
they will receive a single 300 mg dose at baseline.  The first dose 
should be at least 1 week after the last dose in the previous study. 
Endpoints 
 
Primary: 
The primary endpoint in the study is the incidence and rate (events per 
patient-year) of treatment-emergent adverse events (TEAEs) through 
the last study visit. 
Secondary: 
The key secondary endpoints are: 
• 
Incidence and rate (events per patient-year) of serious adverse 
events (SAEs) and adverse events (AEs) of special interest 
(AESIs) 
• 
Proportion of patients with Investigator’s Global Assessment 
(IGA) = 0-1 at each visit 
• 
Proportion of patients with Eczema Area and Severity Index 
(EASI) -75 (≥75% reduction from baseline in EASI scores) at 
each visit 
Sub-Study Endpoints 
 
Primary: 
The primary endpoint in the sub-study is the incidence of AESIs 
through the last study visit after switching to the new dupilumab drug 
product. 
Secondary: 
Secondary endpoints of the sub-study are: 
• 
Trough concentrations of functional dupilumab in serum before 
and after switching to the new dupilumab drug product 
• 
Incidence of treatment-emergent ADA response in patients 
receiving the new dupilumab drug product 
Procedures and 
Assessments 
The safety of dupilumab in this population will be assessed by 
evaluating TEAEs, detailed medical history, vital signs, and clinical 
laboratory testing.  Concomitant medications and procedures will be 
collected at time points specified in the protocol. 
Blood samples will be collected for drug concentration and ADA levels 
at predetermined time points. 
The efficacy of dupilumab in this population will be assessed by AD 
disease severity scores and quality of life (QOL) questionnaires. 
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Statistical Plan 
The safety analysis set (SAF) will include all patients who received any 
study drug; it is based on the treatment received (as treated).  Efficacy, 
treatment compliance/administration, and all clinical safety variables 
will be analyzed using the SAF, as treated. 
Descriptive statistics of the efficacy endpoints will be summarized for 
this open-label study.  These include the proportions for category 
endpoints and basic statistics of original, absolute, and percentage 
change from baseline for continuous endpoints.  All observed data will 
be used for analysis. 
A summary of safety results (reported TEAEs and clinical laboratory 
evaluations) will be presented. 
The following drug concentration analyses will be conducted: 
descriptive statistics at each sampling time and least square mean 
analysis for concentration at steady-state.  No formal statistical analysis 
will be performed. 
Listings of ADA positivity and titers presented by patient and time 
point will be provided.  Prevalence of ADA will be assessed as absolute 
occurrence (N) and percent of patients (%), grouped by titer level. 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................23 
1. 
INTRODUCTION AND RATIONALE .....................................................................37 
1.1. 
Introduction .................................................................................................................37 
1.2. 
Rationale .....................................................................................................................38 
1.2.1. 
Rationale for Study Design .........................................................................................38 
1.2.2. 
Rationale for Dose Selection ......................................................................................39 
1.2.3. 
Rationale for the Sub-Study ........................................................................................39 
2. 
STUDY OBJECTIVES ..............................................................................................40 
2.1. 
Primary Objective .......................................................................................................40 
2.2. 
Secondary Objective ...................................................................................................40 
2.3. 
Sub-Study Objectives .................................................................................................40 
3. 
STUDY DESIGN .......................................................................................................40 
3.1. 
Study Description and Duration .................................................................................40 
3.2. 
End of Study Definition ..............................................................................................43 
3.3. 
Planned Interim Analysis ............................................................................................43 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............44 
4.1. 
Number of Patients Planned .......................................................................................44 
4.2. 
Study Population .........................................................................................................44 
4.2.1. 
Inclusion Criteria ........................................................................................................44 
4.2.2. 
Exclusion Criteria .......................................................................................................46 
4.2.3. 
Entry Criteria for Patients Re-Entering the Study ......................................................48 
4.2.4. 
Entry Criteria for Sub-Study .......................................................................................49 
4.2.4.1. 
Sub-Study Inclusion Criteria ......................................................................................50 
4.2.4.2. 
Sub-Study Exclusion Criteria .....................................................................................50 
4.3. 
Premature Withdrawal from the Study .......................................................................50 
4.4. 
Replacement of Patients .............................................................................................50 
5. 
STUDY TREATMENTS............................................................................................51 
5.1. 
Investigational Treatment ...........................................................................................51 
5.2. 
Dose Modification and Study Drug Discontinuation Rules .......................................52 
5.2.1. 
Dose Modification ......................................................................................................52 
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5.2.2. 
Study Drug Discontinuation .......................................................................................52 
5.2.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................52 
5.2.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................53 
5.3. 
Method of Treatment Assignment ..............................................................................54 
5.4. 
Treatment Logistics and Accountability .....................................................................54 
5.4.1. 
Packaging, Labeling, and Storage ..............................................................................54 
5.4.2. 
Supply and Disposition of Treatments .......................................................................54 
5.4.3. 
Treatment Accountability ...........................................................................................54 
5.4.4. 
Treatment Compliance ................................................................................................54 
5.5. 
Concomitant Medications and Procedures .................................................................55 
5.5.1. 
Permitted Medications and Procedures ......................................................................55 
5.5.2. 
Prohibited and Restricted Medications .......................................................................55 
6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS.........................57 
6.1. 
Schedule of Events .....................................................................................................57 
6.2. 
Study Visit Descriptions .............................................................................................74 
6.2.1. 
Visit 1/Screening/Day –28 to Day -1..........................................................................74 
6.2.2. 
Treatment Period ........................................................................................................75 
6.2.2.1. 
Visit 2/Baseline/Day 1 ................................................................................................75 
6.2.2.2. 
Visit 3/Day 8/Week 1 (+/-2 Days) ..............................................................................76 
6.2.2.3. 
Visit 4/Day 15/Week 2 (+/-2 Days) ............................................................................76 
6.2.2.4. 
Visit 5/Day 22/Week 3 (+/-2 Days) ............................................................................76 
6.2.2.5. 
Visit 6/Day 29/Week 4 (+/-3 Days) ............................................................................76 
6.2.2.6. 
Visit 7/Day 57/Week 8 (+/-3 Days) ............................................................................77 
6.2.2.7. 
Visit 8/Day 85/Week 12 (+/-3 Days) ..........................................................................77 
6.2.2.8. 
Visit 9/Day 113/Week 16 (+/-3 Days) ........................................................................77 
6.2.2.9. 
Visit 10/Day 141/Week 20 (+/-3 Days) ......................................................................78 
6.2.2.10. 
Visit 11/Day 169/Week 24 (+/-3 Days) ......................................................................78 
6.2.2.11. 
Visit 12/Day 197/Week 28 (+/-3 Days) ......................................................................78 
6.2.2.12. 
Visit 13/Day 225/Week 32 (+/-3 Days) ......................................................................78 
6.2.2.13. 
Visit 14/Day 253/Week 36 (+/-3 Days) ......................................................................79 
6.2.2.14. 
Visit 15/Day 281/Week 40 (+/-3 Days) ......................................................................79 
6.2.2.15. 
Visit 16/Day 309/Week 44 (+/-3 Days) ......................................................................79 
6.2.2.16. 
Visit 17/Day 337/Week 48 (+/-3 Days) ......................................................................79 
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6.2.2.17. 
Visit 18/Day 365/Week 52 (+/-3 Days) ......................................................................80 
6.2.2.18. 
Visit 19/Day 421/Week 60 (+/-3 Days) ......................................................................80 
6.2.2.19. 
Visit 20/Day 477/Week 68 (+/-3 Days) ......................................................................81 
6.2.2.20. 
Visit 21/Day 533/Week 76 (+/-3 Days) ......................................................................81 
6.2.2.21. 
Visit 22/Day 589/Week 84 (+/-3 Days) ......................................................................82 
6.2.2.22. 
Visit 23/Day 645/Week 92 (+/-3 Days) ......................................................................82 
6.2.2.23. 
Visit 24/Day 701/Week 100 (+/-3 Days) ....................................................................83 
6.2.2.24. 
Visit 25/Day 757/Week 108 (+/-3 Days) ....................................................................83 
6.2.2.25. 
Visit 26/Day 813/Week 116 (+/-3 Days) ....................................................................84 
6.2.2.26. 
Visit 27/Day 869/Week 124 (+/-3 Days) ....................................................................84 
6.2.2.27. 
Visit 28/Day 925/Week 132 (+/-3 Days) ....................................................................84 
6.2.2.28. 
Visit 29/Day 981/Week 140 (+/-3 Days) ....................................................................85 
6.2.3. 
Visit 30/Day 1037/Week 148 (+/-3 Days) ..................................................................85 
6.2.4. 
Visit 31/Day 1093/Week 156 through Visit 43/Day 1765/Week 252 (+/-3 
Days) ...........................................................................................................................86 
6.2.5. 
End of Treatment Visit/Day 1821/Visit 44/Week 260 (+/-3 Days) ............................87 
6.2.6. 
Sub-Study Treatment Period.......................................................................................87 
6.2.6.1. 
Sub-Study Visit 1a/Day 1a/Week 0a (±3 days) ..........................................................88 
6.2.6.2. 
Sub-Study Visit 2a/Day 29a/Week 4a (±3 days) ........................................................89 
6.2.6.3. 
Sub-Study Visit 3a/Day 85a/Week 12a (±3 days) ......................................................89 
6.2.6.4. 
Sub-Study Visit 4a/Day 169a/Week 24a (±3 days) ....................................................90 
6.2.6.5. 
End of Study Visit (Last Dose+12 Weeks), Early Termination Visit, and 
Unscheduled Visits .....................................................................................................90 
6.2.7. 
End of Study Visit (84 Days After Last Dose or 12 Weeks After Last Dose) ...........91 
6.2.8. 
Early Termination Visit ..............................................................................................91 
6.2.9. 
Unscheduled Visits .....................................................................................................92 
6.2.10. 
Re-entry Visit (Main Study Only) ..............................................................................93 
6.3. 
Study Procedures ........................................................................................................93 
6.3.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................93 
6.3.1.1. 
Patient Training on the Interactive Voice Response System ......................................93 
6.3.1.2. 
Physical Examination .................................................................................................94 
6.3.2. 
Safety Procedures .......................................................................................................94 
6.3.2.1. 
Vital Signs ..................................................................................................................94 
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6.3.2.2. 
Ophthalmological Examination ..................................................................................94 
6.3.2.3. 
Injection Site Reaction ................................................................................................94 
6.3.2.4. 
Laboratory Testing ......................................................................................................94 
6.3.3. 
Efficacy Procedures ....................................................................................................96 
6.3.3.1. 
Investigator’s Global Assessment ...............................................................................96 
6.3.3.2. 
Eczema Area and Severity Index ................................................................................96 
6.3.3.3. 
Patient Oriented Eczema Measure ..............................................................................96 
6.3.3.4. 
Dermatology Life Quality Index ................................................................................96 
6.3.3.5. 
EQ-5D .........................................................................................................................96 
6.3.3.6. 
Pruritus Numerical Rating Scale ................................................................................97 
6.3.4. 
Pharmacokinetic and Antibody Procedures ................................................................97 
6.3.4.1. 
Drug Concentration Measurements and Samples .......................................................97 
6.3.4.2. 
Antibody Measurements and Samples ........................................................................97 
6.3.5. 
Research Testing .........................................................................................................97 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................98 
7.1. 
Definitions ..................................................................................................................98 
7.1.1. 
Adverse Event .............................................................................................................98 
7.1.2. 
Serious Adverse Event ................................................................................................98 
7.2. 
Recording and Reporting Adverse Events ..................................................................99 
7.2.1. 
Adverse Events ...........................................................................................................99 
7.2.2. 
Serious Adverse Events ..............................................................................................99 
7.2.3. 
Other Events that Require Accelerated Reporting to Sponsor .................................100 
7.2.4. 
Reporting Adverse Events Leading to Withdrawal from the Study .........................100 
7.2.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results ...........................101 
7.2.6. 
Follow-up ..................................................................................................................101 
7.3. 
Evaluation of Severity and Causality .......................................................................101 
7.3.1. 
Evaluation of Severity ..............................................................................................101 
7.3.2. 
Evaluation of Causality .............................................................................................102 
7.3.2.1 
Causality Evaluation Factors ....................................................................................102 
7.4. 
Safety Monitoring .....................................................................................................103 
7.5. 
Investigator Alert Notification ..................................................................................103 
8. 
STUDY VARIABLES..............................................................................................104 
8.1. 
Demographic and Baseline Characteristics ..............................................................104 
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8.2. 
Primary and Secondary Endpoints............................................................................104 
8.2.1. 
Primary Endpoint ......................................................................................................104 
8.2.2. 
Secondary Endpoints ................................................................................................104 
8.2.3. 
Sub-Study Endpoints ................................................................................................105 
8.3. 
Pharmacokinetic Variables .......................................................................................105 
8.4. 
Anti-Drug Antibody Variables .................................................................................106 
9. 
STATISTICAL PLAN..............................................................................................107 
9.1. 
Statistical Hypothesis ................................................................................................107 
9.2. 
Justification of Sample Size......................................................................................107 
9.3. 
Analysis Sets .............................................................................................................107 
9.3.1. 
Safety Analysis Set ...................................................................................................107 
9.3.2. 
Pharmacokinetic Analysis Set ..................................................................................107 
9.3.3. 
Analysis Set for Anti-Drug Antibody Data ..............................................................107 
9.4. 
Patient Disposition ....................................................................................................108 
9.5. 
Statistical Methods ....................................................................................................108 
9.5.1. 
Demography and Baseline Characteristics ...............................................................108 
9.5.2. 
Safety Analysis .........................................................................................................108 
9.5.2.1. 
Adverse Events .........................................................................................................108 
9.5.2.2. 
Other Safety ..............................................................................................................109 
9.5.2.3. 
Treatment Exposure ..................................................................................................109 
9.5.2.4. 
Treatment Compliance ..............................................................................................110 
9.5.3. 
Efficacy Analyses .....................................................................................................110 
9.5.4. 
Analysis of Drug Concentration Data .......................................................................110 
9.5.5. 
Analysis of Anti-Drug Antibody Data ......................................................................110 
9.5.6. 
Analysis of the Sub-Study ........................................................................................110 
9.5.6.1. 
Statistical Hypothesis for the Sub-Study ..................................................................111 
9.5.6.2. 
Justification of the Sub-Study Sample Size ..............................................................111 
9.5.6.3. 
Analysis Sets for the Sub-Study ...............................................................................111 
9.5.6.4. 
Statistical Methods for Sub-Study ............................................................................111 
9.6. 
Additional Statistical Data Handling Conventions ...................................................112 
9.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .......113 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................114 
10.1. 
Data Management .....................................................................................................114 
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10.2. 
Electronic Systems ....................................................................................................114 
11. 
STUDY MONITORING ..........................................................................................115 
11.1. 
Monitoring of Study Sites .........................................................................................115 
11.2. 
Source Document Requirements ..............................................................................115 
11.3. 
Case Report Form Requirements ..............................................................................115 
12. 
AUDITS AND INSPECTIONS ...............................................................................116 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................117 
13.1. 
Good Clinical Practice Statement .............................................................................117 
13.2. 
Informed Consent .....................................................................................................117 
13.3. 
Patient Confidentiality and Data Protection .............................................................117 
13.4. 
Institutional Review Board/Ethics Committee .........................................................118 
14. 
PROTOCOL AMENDMENTS ................................................................................119 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................120 
15.1. 
Premature Termination of the Study .........................................................................120 
15.2. 
Close-out of a Site ....................................................................................................120 
16. 
STUDY DOCUMENTATION .................................................................................121 
16.1. 
Certification of Accuracy of Data .............................................................................121 
16.2. 
Retention of Records ................................................................................................121 
17. 
CONFIDENTIALITY ..............................................................................................121 
18. 
FINANCING AND INSURANCE ...........................................................................121 
19. 
PUBLICATION POLICY ........................................................................................121 
20. 
REFERENCES .........................................................................................................122 
21. 
INVESTIGATOR’S AGREEMENT ........................................................................123 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................124 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events – Visits 1 through 8 (Week 12) ...................................................58 
Table 2: 
Schedule of Events – Visits 9 (Week 16) through 18 (Week 52) ...............................60 
Table 3: 
Schedule of Events – Visits 19 (Week 60) through 24 (Week 100) ...........................62 
Table 4: 
Schedule of Events – Visits 25 (Week 108) through Visit 30 (Week 148) ................64 
Table 5: 
Schedule of Events – Visits 31 (Week 156) through Visit 36 (Week 196) ................66 
Table 6: 
Schedule of Events – Visits 37 (Week 204) through Visit 43 (Week 252) ................68 
Table 7: 
Schedule of Events – End of Treatment, End of Study, Early Termination, 
Unscheduled Visit, and Re-entry Visit .......................................................................70 
Table 8: 
Sub-Study Schedule of Events ....................................................................................72 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................41 
Figure 2: 
Sub-Study Flow Diagram ...........................................................................................42 
Figure 3: 
Relationship Between Visit Schedules in Main OLE Study and Sub-Study ..............43 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
Definition of Terms 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANA 
Anti-nuclear antibody 
ARISg 
A pharmacovigilance and clinical safety software system 
AST 
Aspartate aminotransferase 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CPK 
Creatine phosphokinase 
CRF 
Paper or electronic case report form 
CRO 
Contract research organization 
Ctrough 
Trough concentration 
Ctrough,ss 
Trough concentration at steady state 
CYP 
Cytochrome P450 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EC 
Ethics committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IFN-γ 
Interferon-gamma 
IGA 
Investigator’s Global Assessment 
IgE 
Immunoglobulin E 
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Abbreviations 
Definition of Terms 
IL 
Interleukin 
IL-4Rα 
Interleukin-4 receptor alpha 
IRB 
Institutional review board 
ISR 
Injection site reaction 
IVRS 
Interactive voice response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numerical rating scale 
OLE 
Open-label extension 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PFS 
Prefilled syringe 
PK 
Pharmacokinetic 
POEM 
Patient Oriented Eczema Measure 
PT 
Preferred term 
q2w 
Once every 2 weeks 
q4w 
Once every 4 weeks 
QOL 
Quality of life 
qw 
Once every week 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SOC 
System organ class 
SOE 
Schedule of events 
TEAE 
Treatment-emergent adverse event 
Th1 
Type 1 helper T cell 
Th2 
Type 2 helper T cell 
TNF 
Tumor necrosis factor 
TPO 
Anti-thyroid peroxidase antibody 
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Abbreviations 
Definition of Terms 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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1. 
INTRODUCTION AND RATIONALE 
1.1. 
Introduction 
Atopic dermatitis (AD) is a chronic/relapsing inflammatory skin disease characterized by intense 
pruritus (eg, itchiness), and by scaly and dry eczematous lesions.  It is often associated with other 
atopic disorders, such as allergic rhinitis and asthma.  Severe disease can be extremely disabling 
due to major psychological problems, significant sleep loss, and impaired quality of life (QOL) 
that leads to high socioeconomic costs.  An estimated 15% to 30% of children and 2% to 10% of 
adults are affected by AD (Beiber 2008). 
The pathophysiology of AD is influenced by a complex interplay between immunoglobulin 
E (IgE)-mediated sensitization, the immune system, and environmental factors.  The primary skin 
defect may be an immunologic disturbance that causes IgE-mediated sensitization, with 
epithelial-barrier dysfunction that could be the consequence of both genetic mutations and local 
inflammation. 
Skin-infiltrating lymphocytes are thought to play a pivotal role in the initiation and amplification 
of atopic inflammation.  The key cells involved in the patho-physiologic 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 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, thymic stromal lymphopoietin, in AD lesions which may amplify and sustain 
the allergic response. 
Dupilumab, a fully human monoclonal antibody, is directed against the IL-4 receptor alpha 
(IL-4Rα) subunit, 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 blockade of the function of 
both IL-4 and IL-13 signal transduction.  Dupilumab is under development as a potential novel 
treatment for AD and asthma. 
The goal in treating AD is reducing skin inflammation and controlling the symptoms.  Therapy 
has been focused on trying to control the T helper cell response.  Topical corticosteroids are 
overwhelmingly the most frequently prescribed class of drugs; however, long term application of 
topical corticosteroids is not recommended because of the risk of skin atrophy, dyspigmentation, 
acneiform eruptions, and risks associated with systemic absorption (eg, growth retardation, 
hypothalamic-pituitary axis effects, etc.).  Topical calcineurin inhibitors 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 in the prescribing 
information of topical tacrolimus and pimecrolimus.  Repeated application of any topical therapy 
over a long period of time leads to reduced patient compliance.  Antihistamines, which are 
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primarily sedating, are widely prescribed for acute symptomatic treatment of pruritus, although 
their effectiveness is limited.  Oral immunosuppressants (Schmitt 2007) 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.  Patients' disease often rebounds when the treatment 
is stopped, especially after the administration of systemic glucocorticoids (Schmitt 2009, 
Schram 2012, Akhavan 2008).  Biological agents including anti-tumor necrosis factor (TNF) α, 
anti-IgE (omalizumab), anti-IL-5 (mepolizumab), and anti-CD11a (efalizumab) have generally 
been ineffective in clinical trials. 
Up-regulation of IL-4 and IL-13 has been implicated as an important inflammatory component of 
AD disease progression.  Dupilumab targets the IL-4Rα and thus interferes with the signaling 
cascade.  Inhibition of this Th2 inflammatory pathway is currently or has previously been 
evaluated with other agents.   
Dupilumab is being developed as a potentially safer alternative to oral corticosteroids, calcineurin 
inhibitors, and other systemic immunosuppressive drugs such as methotrexate, cyclosporine, and 
azathioprine, which have numerous and considerable side effects including diabetes, hypertension, 
and osteoporosis for corticosteroids (as well as the risk of rebound after steroid discontinuation), 
myelosuppression and hepatotoxicity for methotrexate, nephrotoxicity and hypertension for 
cyclosporine, and gastrointestinal disturbances and leucopenia for azathioprine.  In addition, the 
broad immunosuppression caused by these drugs carries an increased risk of developing serious 
bacterial, fungal, viral, and mycobacterial infections, compared with the targeted Th2 inhibition. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
1.2. 
Rationale 
1.2.1. 
Rationale for Study Design 
The primary purpose of the study is to collect long-term safety data on patients treated with 
dupilumab to better understand the safety profile and help fulfill the anticipated safety database 
requirements for long-term exposure.  
This study may be an incentive to patients enrolling in placebo-controlled trials (eg, phase 2b and 
phase 3), as patients are eventually provided with the opportunity to receive dupilumab treatment 
in this study even if previously randomized to placebo. 
Eligible patients must have received any study treatment and completed the specified assessments 
in the prior dupilumab controlled study or have been screened for a phase 3 study (R668-AD-1334 
or R668-AD-1416), but could not be randomized because of randomization closure.  This study 
will provide useful information on re-exposure to dupilumab, particularly regarding the potential 
for immunogenicity associated with a new course of treatment, as well as the relationships between 
anti-dupilumab antibodies, dupilumab serum (trough) concentration, and clinical parameters. 
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1.2.2. 
Rationale for Dose Selection 
Patients enrolled in this study initially received weekly (qw) doses of 300 mg subcutaneous (SC) 
dupilumab. 
A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will 
be administered on day 1 unless the patient has received a dose of dupilumab in the 4 weeks prior 
to baseline.  If the patient has received a dose of dupilumab in the past 4 weeks, then they will 
receive a single 300 mg dose at baseline.  The first dose should be at least 1 week after the last 
dose in the previous study, and then 300 mg dupilumab qw starting on day 8.  
A phase 2b dose-ranging study (R668-AD-1021) evaluated dupilumab dose regimens of 
300 mg qw, 300 mg once every 2 weeks (q2w), 300 mg q4w, 200 mg q2w, and 100 mg q4w versus 
placebo administered for 16 weeks.  This study indicated that dupilumab 100 mg q4w had 
suboptimal efficacy, whereas the 300 mg qw dupilumab regimen demonstrated the highest 
efficacy and was comparable to other dupilumab dosing regimens with respect to safety 
parameters.  Therefore the 300 mg qw dose will be the highest dose regimen studied in the phase 
3 program, and was the original dosing regimen selected for this phase 3, long-term safety study. 
Since initiation of this trial, multiple AD, placebo-controlled, phase 3 studies of dupilumab 
compared with placebo have been unblinded. In those studies, 300 mg dupilumab qw and q2w 
dose regimens were shown to have superior efficacy compared with control, as well as an 
acceptable safety profile. There were no statistically significant differences in efficacy between 
300 mg qw and 300 mg q2w. The dose used in this Open-Label Extension (OLE) study remained 
300 mg qw as this was the highest dose for which we planned to seek registration. The dosing 
regimen of dupilumab 300 mg qw was changed to q2w to match the dosing regimen approved by 
various regulatory agencies, globally, for this patient population.  
1.2.3. 
Rationale for the Sub-Study 
The sponsor is implementing an improved manufacturing process for the dupilumab drug product.  
Analysis of data obtained via quality testing and extended protein characterization demonstrate 
that dupilumab obtained from the new process is comparable to dupilumab obtained from the 
current process.  This clinical sub-study is designed to demonstrate clinical evidence of the safe 
use in patients with AD when switched from the current dupilumab drug product to the new 
dupilumab drug product. 
As part of the sub-study, safety, pharmacokinetics (PK), and immunogenicity endpoints before 
and after switching to the new dupilumab drug product will be summarized and listed.  
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to assess the long-term safety of dupilumab administered in adult patients 
with AD. 
2.2. 
Secondary Objective 
The secondary objective of the study is to assess the immunogenicity of dupilumab in adult patients 
with AD, in the context of re-treatment, and to monitor efficacy parameters associated with 
long-term treatment. 
2.3. 
Sub-Study Objectives 
The primary objective of the sub-study is to assess the safety of the new dupilumab drug product 
in adult patients with AD after switching from the current dupilumab drug product. 
The secondary objectives of the sub-study are to evaluate systemic exposure and immunogenicity 
of the new dupilumab drug product in adult patients with AD. 
3. 
STUDY DESIGN 
3.1. 
Study Description and Duration 
This is a multicenter, open-label extension study to assess the long-term safety and efficacy of 
repeat doses of dupilumab in adults with moderate-to-severe AD who have previously participated 
in controlled studies of dupilumab or have been screened for a phase 3 study (R668-AD-1334 or 
R668-AD-1416), but could not be randomized because of randomization closure. 
Enrollment will take place at approximately 500 global study sites.  After providing informed 
consent, patients will be assessed for study eligibility at the screening visit.  The screening visit in 
this study may coincide with the last visit in the previous study, in which case assessments that are 
common to both studies will be performed only once. 
A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will 
be administered on day 1 unless the patient has received a dose of dupilumab in the 4 weeks prior 
to baseline.  If the patient has received a dose of dupilumab in the past 4 weeks, then they will 
receive a single 300 mg dose at baseline.  The first dose should be at least 1 week after the last 
dose in the previous study, and then 300 mg SC dupilumab qw starting on day 8. For patients who 
have not completed the study prior to the implementation of amendment 9, study drug dosing will 
change from dupilumab 300 mg weekly to every 2 weeks.  
Patients will return for visits as specified in Section 6.  In order to minimize the amount of drug 
that patients need to store in their home between visits, some visits will be abbreviated for the 
primary purpose to receive additional drug supply.  The study treatment duration will be up to 
5 years.  The end of study visit occurs at 84 days/12 weeks after the last dose. Patients who have 
completed their end of treatment visit as per amendment 7 will be permitted to resume treatment 
with study drug.  Eligible patients who have completed the end of study visit as per amendment 7 
will be permitted to re-enter the study if no more than 12 weeks have elapsed since their end of 
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study visit.  The entry criteria for patients who re-enter the study are listed in Section 4.2.3. As of 
the date of issue of amendment 8, this study is closed to further enrollment. 
Patients and/or caregivers who are willing and able to administer dupilumab doses outside the 
clinic will be trained on injecting study drug unless they had already been trained during their 
participation in the previous study.  These patients will self-inject study drug (or have the drug 
administered by a caregiver) during weeks in which no clinic visit is scheduled.  Safety, laboratory, 
and clinical assessments will be performed at specified clinic visits. 
Patients who receive treatment with a prohibited or restricted medication will be discontinued from 
study drug for the duration of the prohibited treatment (plus 5 half-lives as applicable).  Study 
treatment may be resumed only if approved by the medical monitor. 
Patients who test positive for anti-drug antibodies (ADAs) at their last study visit (early 
termination or end of study) may be asked to return to the clinic to have additional ADA samples 
collected for analysis (see Section 6.3.4.2 for details and time points). 
The study flow diagram for the main study is provided in Figure 1. 
Figure 1: 
Study Flow Diagram 
  Screening 
Treatment Periodb, c 
  
 Baseline 
  
  
  
  
  
  
  
  
  
  
V1 
V2 
V3e 
V4e 
V5e 
V6 
V7e 
V8 
V9-V30d 
V31f g-
V43h,i 
V44/EOTg,i 
EOS 
D-28 
to D-1a 
D1 
W1 
W2 
W3 
W4 
W8 
W12 
W16-W148   
(every 8 
weeks) 
(every 8  
to 16 
weeks) 
12 
weeks 
after 
last 
dose 
 a Patients who fail screening or who fail to complete the baseline visit within 28 days of screening may be 
rescreened upon approval by the medical monitor.   
b A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will be administered 
on day 1 unless the patient has received a dose of dupilumab in the 4 weeks prior to baseline.  If the patient has 
received a dose of dupilumab in the past 4 weeks, then they will receive a single 300 mg dose at baseline.  The 
first dose should be at least 1 week after the last dose in the previous study, and then 300 mg dupilumab qw 
starting on day 8.  For patients who have not completed the study prior to the implementation of amendment 9, 
study drug dosing will change from dupilumab 300 mg weekly to every 2 weeks. 
c Patients will be monitored at the study site for a minimum of 30 minutes at the baseline visit. 
d Visits 10, 12, 14, and 16 have been removed per amendment 6.  This yields a schedule in which visits are 8 weeks 
apart from week 16 through week 48.  The week 48 visit is followed by a visit at 52 weeks; then visits occur every 
8 weeks thereafter up to and including the end of treatment [EOT] visit). 
e Visits 3, 4, 5, and 7 were removed per amendment 6.  
f Patients who have completed their EOT visit as per amendment 7 may resume treatment with study drug at the next 
scheduled visit they would have attended if they had not had an EOT visit.   
g Patients who have completed their end of study (EOS) visit as per amendment 7 will be re-evaluated for eligibility 
at a trial Re-Entry visit.  Patients eligible to re-enter the trial may resume treatment at the next scheduled visit they 
would have attended if they had not completed the study.  Patients are not eligible to re-enter the trial if more than 
12 weeks have elapsed since their EOS visit. 
h Visits 26, 28, 32, 34, 36, 38, 40, and 42 were removed per amendment 9.  
i Approximately 50 patients who have not completed visit 44 (EOT) prior to implementation of amendment 10 will 
be asked to participate in a sub-study using the new dupilumab product.  Eligible patients will enter the sub-study at 
either visit 41, 43, or 44 of the main study.  This optional sub-study requires a separate consent. 
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Sub-Study: 
Approximately 50 patients who are participating in the current OLE study and have not completed 
the end of treatment visit (visit 44) prior to the implementation of amendment 10 will be asked to 
participate in the sub-study.  After providing informed consent, eligible patients will enter the 
sub-study at either visit 41, 43, or 44 of the main study and have study treatment switched from 
the current dupilumab drug product to the new dupilumab drug product at sub-study visit 1a.  
Dupilumab dosing will remain 300 mg SC q2w, and patients will be treated with the new 
dupilumab drug product 300 mg SC q2w for at least 12 weeks (some patients may be treated for 
24 weeks).  The end of study visit for patients participating in the sub-study will be 84 days 
(12 weeks) after the last dose using the new dupilumab drug product.  Patients who enter the 
sub-study from either visit 43 or visit 44 of the main study will have the duration of their study 
treatment increased by 4 or 12 weeks, respectively. 
The study flow diagram for patients in the sub-study is provided in Figure 2. 
Figure 2: 
Sub-Study Flow Diagram 
Study Procedures 
Sub-Study Treatment Period 
End of Study4 
Sub-Study Visit (V) 
V1a1,2 
V2a 
V3a 
V4a3 
 
Sub-Study Week (Wk) 
Wk 0 
Wk4 
Wk12 
Wk 24 
Last Dose + 12Wk 
Abbreviations: V=visit; Wk=week. 
1 This optional sub-study requires a separate consent. 
2 Any redundant procedures with the main study visit will only be performed once. 
3 Applies only to patients in the sub-study who switched to the new dupilumab drug product at visit 41 of the main 
study.  All other patients in the sub-study complete the new dupilumab drug product treatment period at sub-study 
visit 3a. 
4 The end of study (EOS) visit occurs 12 weeks after the last dose of dupilumab.   
The relationship between the study visit schedules in main OLE study and the sub-study is shown 
in Figure 3. 
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Figure 3: 
Relationship Between Visit Schedules in Main OLE Study and Sub-Study 
 
Abbreviations: D=day; EOS=end of study; EOT=end of treatment; SOE=schedule of events; V=visit; W=week. 
1 Patients will enter the sub-study at various time points during participation in the main OLE study (V41, V43, or 
V44).  At V41, V43, or V44 (which will vary from patient to patient but should be a scheduled in-clinic visit), 
patients who are willing to participate in the sub-study and who are eligible, will enter V1a of the sub-study.  At 
V1a, patients should have assessments and procedures performed as per both the SOE of the OLE study (V41, 
V43, or V44) as well as the sub-study (V1a) (any redundant procedures will only be performed once).  This 
optional sub-study requires a separate consent.  Patients who do not enter the sub-study will continue to follow the 
SOE for the main study. 
2 The first new dupilumab drug product administration should occur 14 days (±3 days; preferably ±1 day) after the 
previous administration of the current dupilumab drug product in the main study.  
3 For patients who began treatment with the new dupilumab drug product at V43 or V44 of the main study, the last 
dose of the new dupilumab drug product will be administered at sub-study V3a. 
4 V4a only applies to patients who switched to the new dupilumab drug product at V41 of the main study.  The last 
dose for these patients will be administered at sub-study V4a. 
5 The EOS visit occurs 12 weeks after the last dose of dupilumab in either the main OLE study or the sub-study. The 
same EOS assessments are performed for patients receiving the current dupilumab drug product or the new 
dupilumab drug product. 
3.2. 
End of Study Definition 
The end of study is defined as the last visit for the last patient. 
3.3. 
Planned Interim Analysis 
No interim analysis is planned for this open-label study.  Summaries of the data may be provided 
for regulatory agency interactions and for other clinical program purposes. 
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4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
4.1. 
Number of Patients Planned 
The study is open to patients who participated in controlled and/or short term dupilumab clinical 
trials or patients who have been screened for a phase 3 study (R668-AD-1334 or R668-AD-1416), 
but could not be randomized due to randomization closure.  Based on the numbers of patients 
enrolled or screened in the antecedent dupilumab studies, it is currently anticipated that 
approximately 2500 patients will be enrolled in this global study.  Institutional Review Boards 
(IRBs)/Ethics Committees (ECs) will be notified if there is more than 25% greater participation 
than currently anticipated. 
Sub-Study: 
Approximately 50 patients who are participating in the current study and have not completed the 
end of treatment visit (ie, visit 44) prior to the implementation of amendment 10 will be invited to 
participate in the sub-study.  After providing signed informed consent, eligible patients will enter 
the sub-study at either visit 41, 43, or 44 of the main study and have study treatment switched from 
the current dupilumab drug product to the new dupilumab drug product at sub-study visit 1a.   
4.2. 
Study Population 
The target population includes adult patients (≥18 years of age) with AD who participated in a 
prior dupilumab clinical study. 
4.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Participation in a prior clinical trial of dupilumab for AD and met one of the following: 
a. Received study treatment and adequately completed the assessments required for both 
the treatment and follow-up periods of the parent studies (except studies listed in b) as 
defined in the parent protocols; specifically, patients must complete the primary 
endpoint visit and at least 50% of the scheduled in-clinic visits and at-home 
assessments*).  Additionally, patients who discontinued a parent study prematurely (ie, 
patients who did not complete the protocol-defined end-of-study visit) cannot enroll 
into this open-label extension study before the date when the end-of-study visit would 
have normally occurred.  Completion of the entire follow-up period is not required for 
parent studies where the protocol specifically allows for an earlier transition into the 
open-label extension, in which case these requirements apply up to the point of this 
early transition. 
* For at-home assessments (eg, patient reported outcomes by interactive voice 
response system [IVRS] calls), patients who completed less than 50% of the 
assessments may be eligible if technical issues (eg, IVRS system malfunction) or 
other documented objective circumstances contributed to missing assessments, 
subject to approval by the medical monitor. 
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b. Received study treatment in any dupilumab AD study that has completed last patient 
last visit irrespective of duration of participation, provided that patients complied with 
the instructions received during the study, as assessed by the investigator.   
c. Underwent screening in R668-AD-1334 (Liberty AD SOLO 1) or R668-AD-1416 
(Liberty AD SOLO 2), but could not be randomized due to randomization closure.   
These patients must have met the inclusion criteria for the Liberty AD SOLO studies 
that were applicable at the screening visit, specifically: 
• Chronic AD, (according to American Academy of Dermatology Consensus 
Criteria [Eichenfield 2014]), that has been present for at least 3 years before the 
screening visit 
• Eczema Area and Severity Index (EASI) score ≥16 at the screening visit 
• 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 visit 
• ≥10% body surface area (BSA) of AD involvement at the screening visit 
• 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)* 
* With the clarification notes provided in the SOLO protocols.  
For these patients, the following criteria must also apply at the baseline visit in 
this open-label study: 
• EASI score ≥16  
• IGA score ≥3  
• ≥10% BSA of AD involvement  
2. Must be ≥18 years of age at screening 
3. Willing and able to comply with all clinic visits and study-related procedures 
4. Able to understand and complete study-related questionnaires 
5. Provide signed informed consent 
Sub-Study: 
Additional inclusion criteria that must be met before a patient can enter the sub-study and switch 
to the new dupilumab drug product (per amendment 10) are provided in Section 4.2.4.1. 
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4.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Patients who, during their participation in a previous dupilumab clinical trial, developed a 
serious adverse event (SAE) deemed related to dupilumab*, which in the opinion of the 
investigator or of the medical monitor could indicate that continued treatment with 
dupilumab may present an unreasonable risk for the patient. 
2. Patients who, during their participation in a previous dupilumab clinical trial, developed 
an AE that was deemed related to dupilumab* and led to study treatment discontinuation, 
which in the opinion of the investigator or of the medical monitor could indicate that 
continued treatment with dupilumab may present an unreasonable risk for the patient. 
3. Conditions in the previous dupilumab study consistent with protocol-defined criteria for 
permanent study drug discontinuation, if deemed related to dupilumab* or led to 
investigator - or 
sponsor-initiated 
withdrawal 
of 
patient 
from 
the 
study 
(eg, non-compliance, inability to complete study assessments, etc.), unless such conditions 
are considered resolved and of no further consequence – subject to medical monitor review 
and approval. 
* Note for exclusion criteria # 1, 2, and 3:  In studies that are still blinded, conditions 
deemed related to the study treatment will be considered related to dupilumab. 
4. Treatment with an investigational drug, other than dupilumab, within 8 weeks or within 
5 half-lives (if known), whichever is longer, before the baseline visit. 
5. Treatment with immunosuppressive/immunomodulating drugs (eg, cyclosporine, 
mycophenolate-mofetil, IFN-γ, azathioprine, methotrexate, JAK inhibitors) within 
5 half-lives 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 in the current study. 
6. Treatment with immunomodulating biologics, other than dupilumab, within 5 half-lives (if 
known) or 16 weeks (whichever is longer) before the first dose in the open-label extension 
study. 
7. Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit. 
8. Planned or anticipated use of any prohibited medications and procedures during study 
treatment. 
9. Any active infection requiring systemic treatment; patients with such infection must have 
their infection resolved at least 1 week before baseline to be eligible to enroll in the study. 
10. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections 
(eg, 
tuberculosis, 
histoplasmosis, 
listeriosis, 
coccidioidomycosis, 
pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent 
infections of abnormal frequency as judged by the investigator. 
11. Known history of human immunodeficiency virus (HIV) infection or HIV seropositivity 
(HIV testing is not required at screening for patients with a negative HIV result within the 
past 1 year prior to baseline). 
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12. Known history of positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), or hepatitis C antibody.  If a patient has a documented negative result for any of 
these tests within 1 year of baseline, that particular test is not required at screening.  Patients 
with isolated positive HBcAb or with positive hepatitis C antibody may undergo additional 
tests and consultations, and may enter the study only if active hepatitis B infection or carrier 
status has been definitively ruled out, subject to medical monitor’s written approval. 
13. History of clinical endoparasite infection within 12 months of the baseline visit, other than 
treated vaginal trichomoniasis. 
14. Presence of skin comorbidities that may interfere with study assessments. 
15. History of malignancy within 5 years before the baseline visit, except completely treated 
in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous 
or basal cell carcinoma of the skin. 
16. 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), 
neurological conditions (eg, demyelinating diseases), active major autoimmune diseases 
(eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe 
endocrinological, gastrointestinal, hepato-biliary, metabolic, pulmonary or lymphatic 
diseases.  The specific justification for patients excluded under this criterion will be noted 
in study documents. 
17. 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. 
18. High risk of parasite infection, such as residence within or recent travel (within 12 months 
before the baseline visit) to areas endemic for endoparasitoses, where the circumstances 
are consistent with parasite exposure (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, etc.), unless subsequent medical assessments 
(eg, stool exam, blood tests, etc.) have ruled out the possibility of parasite 
infection/infestation. 
19. History of alcohol or drug abuse within 2 years before the screening visit. 
20. Planned major surgical procedure during the patient’s participation in this study. 
21. Patient is a member of the investigational team or his/her immediate family. 
22. Pregnant or breastfeeding women, or planning to become pregnant or breastfeed during the 
patient’s participation in this study. 
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23. Women unwilling to use adequate birth control, if of reproductive potential* and sexually 
active.  Adequate birth control is defined as agreement to consistently practice an effective 
and accepted method of contraception whenever engaging in heterosexual intercourse 
throughout the duration of the study and for 12 weeks after last dose of study drug.  These 
include:  hormonal contraceptives, intrauterine device (IUD), a double barrier method 
(eg, condom + diaphragm), or male partner with documented vasectomy.  Additional 
requirements for acceptable contraception may apply in certain countries, based on local 
regulations. Investigators in these countries will be notified accordingly in a protocol 
clarification letter. Investigators who are uncertain about the acceptability of a specific 
contraceptive method should seek advice and approval from the medical monitor. 
* For females, menopause is defined as at least 12 consecutive months without menses; if 
in question, a follicle stimulating hormone (FSH) of ≥25 mU/mL must be documented.  
Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be documented, 
as applicable; if documented, women with these conditions are not required to use 
additional contraception.  
Sub-Study: 
Additional exclusion criteria that must be met before a patient can enter the sub-study and be 
switched to the new dupilumab drug product (per amendment 10) are provided in Section 4.2.4.2.  
4.2.3. 
Entry Criteria for Patients Re-Entering the Study 
A patient who meets any of the following criteria will not be permitted to re-enter the study: 
1. Patients who, during their previous participation in this clinical trial, developed an SAE 
deemed related to dupilumab, which in the opinion of the investigator or of the medical 
monitor could indicate that continued treatment with dupilumab may present an 
unreasonable risk for the patient. 
2. Patients who, during their previous participation in this dupilumab clinical trial, developed 
an AE that was deemed related to dupilumab and led to study treatment discontinuation, 
which in the opinion of the investigator or of the medical monitor could indicate that 
continued treatment with dupilumab may present an unreasonable risk for the patient. 
3. Patients who became pregnant during their previous participation in this dupilumab clinical 
trial. 
4. Patients who, during their previous participation in this trial, were prematurely withdrawn 
because of a protocol violation, poor compliance, or inability to complete required study 
assessments. 
5. Known history of HIV infection or HIV seropositivity.  HIV testing is required at re-entry 
for patients who have not been tested within 12 months prior to re-entry. 
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6. Known history of positive HBsAg, HBcAb, or hepatitis C antibody.  Hepatitis testing is 
required at re-entry for patients who have not been tested within 12 months prior to 
re-entry.  NOTE: Patients who are HBsAg negative and HBsAb positive are considered 
immune after a natural infection has cleared or they have been vaccinated against hepatitis 
B.  Therefore, they are acceptable for the study.  These patients will be allowed to re-enter 
the study, but will be followed using routine clinical and liver function tests, as well as 
periodic hepatitis B viral load testing during study treatment. 
7. Treatment interruption for >12 months. 
8. Treatment with an investigational drug other than dupilumab, within 8 weeks or within 
5 half-lives (if known), whichever is longer, prior to the re-entry visit. 
9. Treatment with immunosuppressive/immunomodulating drugs (eg, cyclosporine, 
mycophenolate-mofetil, IFN-γ, azathioprine, methotrexate, JAK inhibitors) within 
5 half-lives before the re-entry visit. 
10. Treatment with immunomodulating biologics, other than dupilumab, within 5 half-lives (if 
known) or 16 weeks (whichever is longer) before the re-entry visit. 
11. Treatment with a live (attenuated) vaccine within 12 weeks before the re-entry visit. 
12. Any active infection requiring systemic treatment; patients with such infection must have 
their infection resolved at least 1 week before the re-entry visit. 
13. Pregnant or breastfeeding women. 
14. Women unwilling to use adequate birth control, if of reproductive potential and sexually 
active (see Exclusion Criterion 23 above for applicable definitions). 
15. Any medical or psychological condition that, in the opinion of the investigator, may 
suggest a new and/or insufficiently understood disease, may present an unreasonable risk 
to the patient as a result of his/her participation in the trial, may make the patient’s 
participation unreliable, or may interfere with study assessments. The specific justification 
for patients excluded under this criterion will be noted in the source documents. 
16. More than 12 weeks have elapsed since the patient’s end of study visit. 
4.2.4. 
Entry Criteria for Sub-Study 
Patients who are ongoing in the main study and who have not completed the end of treatment visit 
(ie, visit 44) and who meet the sub-study eligibility criteria below may enter the sub-study at their 
next scheduled visit (ie, visits 41, 43, or 44).  This optional sub-study requires a separate consent. 
Patients who fail eligibility criteria for participating in the sub-study under amendment 10 may not 
be rescreened. 
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4.2.4.1. 
Sub-Study Inclusion Criteria 
1. Continuing in the treatment period of the main OLE study. 
2. Demonstrated compliance with dupilumab therapy defined as having received at least 
5 out of 6 injections of the current dupilumab drug product in the 12 weeks prior to 
switching to the new dupilumab drug product, and not missing the last 3 dupilumab 
Q2W SC injections prior to the week 0a visit of the sub-study. 
3. The last current dupilumab drug product administration occurred on day -14 (±3 days) 
prior to the scheduled day for the switch to the new dupilumab drug product (sub-study 
week 0a visit).  Note: The protocol allows a window of ±3 days, but recommends a 
window ±1 day. 
4. Provide signed informed consent for participation in the sub-study using dupilumab 
derived from the improved manufacturing process. 
4.2.4.2. 
Sub-Study Exclusion Criteria 
1. Patients who have already completed the end of treatment visit (ie, visit 44) for the main 
study R668-AD-1225. 
4.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and sponsor have the right to withdraw a patient from the study in the event of an 
intercurrent illness, AE, treatment failure, protocol violation, cure, and for administrative, or other 
reasons.  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who withdraw prematurely from the study will be asked to complete study assessments 
per Section 6.2.8. 
4.4. 
Replacement of Patients 
Patients will not be replaced. 
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5. 
STUDY TREATMENTS 
5.1. 
Investigational Treatment 
Dupilumab will be supplied in ready to use prefilled syringes (PFS) for SC administration of 
300 mg at a concentration of 150 mg/mL. 
Study treatment will begin on day 1 (baseline).  Patients and/or caregivers who are willing and 
able to self-administer some dupilumab doses outside of the clinic will be trained on injecting 
study drug unless they had already been trained during their participation in the previous study.  
These patients will self-inject study drug (or have the study drug administered by a caregiver) 
during weeks in which no clinic visit is scheduled. 
Patients who prefer to have the clinic staff administer each dose of study drug may have all 
injections administered in the clinic. 
A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will 
be administered on day 1 unless the patient has received a dose of dupilumab in the 4 weeks prior 
to baseline.  If the patient has received a dose of dupilumab in the past 4 weeks, then they will 
receive a single 300 mg dose at baseline).  The first dose should be at least 1 week after the last 
dose in the previous study, and then 300 mg dupilumab qw starting on day 8. For patients who 
have not completed the study prior to the implementation of amendment 9, study drug dosing will 
change from dupilumab 300 mg weekly to every 2 weeks. If these patients (or their caregivers) 
require injection training, a study staff member can administer the first of the 2 injections and the 
patient (or caregiver) can subsequently administer the second injection under the supervision of 
the clinic staff. 
Patients who have either previously completed treatment or completed the study as per 
amendment 7 and who resume treatment under amendment 7 or 8 will receive a loading dose of 
600 mg SC (two 300 mg doses administered on the same day) if more than 4 weeks has elapsed 
since their last dose of study drug. 
In the sub-study, patients will receive the new dupilumab drug product 300 mg SC q2w. 
The procedure for preparing and administering dupilumab 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 optionally upper arms, so that the 
same site is not injected for 2 consecutive weeks.  To allow for adequate assessment of possible 
injection site reactions (ISRs), study drug should be administered only into areas of 
normal-looking skin.  Instructions for recording and reporting ISRs will be provided in the study 
reference manual. 
Detailed instructions for transport, storage, preparation, and administration of study drug will be 
provided by the site to the patient (or caregiver).  Patients will document/report compliance with 
self-injection of study drug in a patient dosing diary via IVRS/interactive web response system 
(IWRS). 
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5.2. 
Dose Modification and Study Drug Discontinuation Rules 
5.2.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
5.2.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug will be asked to return to the clinic for early 
termination assessments, per Section 6.2.8. 
5.2.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Patients will be permanently discontinued from study drug dosing in the event of: 
• Anaphylactic reaction or other severe systemic reaction to study drug 
• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin 
• Pregnancy at any time during the study 
• Any infection that is opportunistic, such as active tuberculosis and other infections 
whose nature or course may suggest an immuno-compromised status 
• Severe laboratory abnormalities that are judged to be related to dupilumab per criteria 
described in Section 7.3.2, such as: 
− Neutrophil count ≤0.5 x 103/µL 
− Platelet count ≤50 x 103/µL 
− Confirmed (by 2 separate tests at least 2 weeks apart) alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) values >3 x upper limit of normal 
(ULN) and total bilirubin >2 x ULN, excluding confirmed Gilbert’s Syndrome 
− Confirmed AST and/or ALT >5 x ULN (for more than 2 weeks) 
• Inadequate efficacy: 
− Patients who show inadequate therapeutic response after at least 12 weeks of 
treatment with dupilumab will be discontinued from the study treatment based 
upon review of the case and joint decision by the investigator and medical 
monitor.  For the purpose of this assessment, a review of efficacy will be triggered 
whenever patients fail to achieve and/or maintain EASI-25 (at least 
25% improvement in the EASI score) at week 16, compared to the baseline score 
in the previous controlled and/or short-term study.  Patients may also withdraw 
from the study at any time if they are not satisfied with the study treatment (see 
Section 4.3) 
• Other reasons that may lead to the permanent discontinuation of study drug include: 
− Certain AEs deemed related to the study drug (eg, severe and prolonged ISRs) 
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5.2.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug must be discontinued in case of: 
• Severe laboratory abnormalities (as noted in Section 5.2.2.1) where a causal 
relationship to dupilumab can be reasonably excluded (ie, an alternative cause is 
evident).  In these cases, study treatment will be discontinued (at least 1 dose while the 
clinical circumstances are being assessed), but it may be resumed when the laboratory 
parameters normalize sufficiently.  A decision to resume study treatment will be made 
jointly by the investigator and the medical monitor. 
Study drug dosing may be temporarily discontinued in the event of: 
• Clinically important laboratory abnormalities, such as: 
− Neutrophil count ≤1.0 x 103/µL but >0.5 x 103/µL 
− Platelet count ≤100 x 103/µL but >50 x 103/µL 
− Creatine phosphokinase (CPK) >10 x ULN, unless the increase can be clearly 
attributed to physical exertion and considered clinically inconsequential. 
• Other intercurrent illnesses or major surgery 
• Any severe infection; any bacterial or viral infection requiring systemic treatment and 
remaining unresolved after 2 weeks of appropriate treatment; any clinical helminth 
endoparasitosis; any opportunistic infection 
• Treatment with a live (attenuated) vaccine.  Study drug dosing will be suspended for at 
least 12 weeks.  NOTE:  If the need for live vaccination is known in advance, to the 
extent possible, stop study drug for 12 weeks prior to vaccination 
• Treatment with systemic nonsteroidal immunosuppressive/immunomodulating 
medications (eg, cyclosporine, methotrexate, azathioprine, mycophenolate-mofetil, 
Janus kinase inhibitors, biologic agents, etc) 
After the condition leading to temporary discontinuation of study drug resolves and/or the 
laboratory abnormality leading to suspension of dosing normalizes sufficiently, study drug dosing 
may resume at the discretion of the principal investigator in consultation with the medical monitor.  
Similarly, study treatment may resume after the medication leading to suspension of dosing has 
been discontinued.  A decision to temporarily discontinue study drug and/or to resume study drug 
dosing should be discussed with the medical monitor.  Resumption of study drug will require the 
medical monitor’s written approval.  The investigator may discontinue study drug dosing at any 
time, even without consultation with the medical monitor if the urgency of the situation requires 
immediate action and if this is determined to be in the patient’s best interest.  However, the medical 
monitor should be contacted as soon as possible in any case of study drug discontinuation.  
Resumption of study treatment after temporary discontinuation should always be discussed with 
the medical monitor and will require the medical monitor’s written approval. 
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5.3. 
Method of Treatment Assignment 
Not applicable for this single-arm, open-label study. 
5.4. 
Treatment Logistics and Accountability 
5.4.1. 
Packaging, Labeling, and Storage 
Study drug will be shipped open label and labeled with a unique reference number in accordance 
with local regulations.  Study drug will be refrigerated at the site at a temperature of 2°C to 8ºC.  
Storage instructions will be provided in the pharmacy manual. 
5.4.2. 
Supply and Disposition of Treatments 
Study drug will be shipped to the site at regular intervals or as needed during the study via the 
IVRS/IWRS. Drug accountability will be performed at specified time points during the study by 
the site monitor (ie, interim site monitoring visits) and at the site close-out visit.  Following drug 
reconciliation and documentation by the site monitor, all opened and unopened prefilled syringes 
(PFS) of study drug will be destroyed or returned to the sponsor or designee. 
5.4.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
• dispensed to each patient, 
• returned from each patient (if applicable), and 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
5.4.4. 
Treatment Compliance 
All drug compliance records must be kept current and must be made available for inspection by 
the sponsor and regulatory agency inspectors. 
Patients will document/report compliance with self-injection of study drug in a patient dosing diary 
via IVRS/IWRS. 
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5.5. 
Concomitant Medications and Procedures 
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. 
5.5.1. 
Permitted Medications and Procedures 
Other than the prohibited medications listed in Section 5.5.2, treatment with concomitant 
medications are permitted during the study.  This includes treatment with contraceptives, basic 
skin care (cleansing and bathing including bleach baths), emollients, topical anesthetics, 
antihistamines, topical and systemic anti-infective medications for any duration, topical 
calcineurin inhibitors, topical corticosteroids, and systemic corticosteroids.   
Cytochrome P450:  The impact of dupilumab on cytochrome P450 (CYP) enzyme activity has 
not been studied and the effect of dupilumab on levels of IL-4 and IL-13 has not been fully 
characterized.   
However, IL-4 was reported to upregulate CYP2E1, 2B6, 3A4 mRNA expression or downregulate 
CYP1A2 mRNA (Abdel-Razzak 1993, Christensen 2012).  Human peripheral blood mononuclear 
cells incubated with various Th2 cytokines showed that IL-4 and IL-13 increased mRNA 
expression of CYP2B6 and CYP3A4 (Liptrott 2009). 
Since the clinical significance of the limited in vitro findings for IL-4 and IL-13 involvement in 
CYP regulation and the impact of dupilumab on CYP enzymes is not fully understood, during the 
study treatment and at least up to the end of follow-up, investigators are cautioned to monitor 
clinical and laboratory signs that might indicate a potential drug-drug interaction in all patients 
receiving dupilumab concomitantly with narrow therapeutic index medications that are 
metabolized by CYP450.  This means that close clinical observation and/or laboratory monitoring 
as applicable are required in order to enable early detection of toxic manifestations or lack of 
activity/efficacy of these drugs, followed by dose adjustment or their withdrawal, if needed. 
5.5.2. 
Prohibited and Restricted Medications 
Concomitant treatment with the following medications is prohibited during the study.  These 
medications should generally be avoided, but if they are medically necessary (eg, as a rescue 
treatment for intolerable AD symptoms or to manage serious intercurrent conditions), they may be 
administered while the study drug is discontinued. 
• Treatment with nonsteroidal systemic immunosuppressive medications (including, 
but not limited to, cyclosporine, mycophenolate-mofetil, IFN-γ, azathioprine, 
methotrexate, or other immunomodulating biologics*) 
• Treatment with an investigational drug* (other than dupilumab) 
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• Live (attenuated) vaccines** 
Chickenpox (Varicella) 
FluMist-Influenza 
Intranasal influenza 
Measles (Rubeola) 
Measles-mumps-rubella (MMR) combination 
Measles-mumps-rubella-varicella (MMRV) 
combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rubella 
Smallpox (Vaccinia) 
Yellow fever 
Bacillus-Calmette–Guérin (BCG) 
Rotavirus 
Varicella Zoster (shingles) 
* Patients who receive an immunomodulating biologic or investigational drug will be 
discontinued from study drug for the duration of treatment with these medications, plus 
5 half-lives (if known) or 16 weeks, whichever is longer. 
** In the case of live vaccines, study treatment should optimally be stopped 12 weeks before 
vaccine administration and may not resume sooner than 12 weeks after vaccine 
administration. 
In all cases, the resumption of study treatment must be approved by the medical monitor. 
Patients who discontinue study treatment permanently will be asked to complete the assessments 
of the early termination and end of study visits. 
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6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
6.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit for the main study in 
Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7.  After providing informed 
consent for the sub-study, which is using the new dupilumab drug product, eligible patients are to 
follow the assessments and procedures in Table 8. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms.  
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff.  Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted.  All 
temporary mechanisms utilized, and deviations from planned study procedures in response to 
COVID-19, are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency. 
 
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Table 1: 
Schedule of Events – Visits 1 through 8 (Week 12) 
Study Procedures 
Screening* 
Baseline 
Treatment Period 
Visit (V) 
V 1 
V 2 
V 3m 
V 4 m 
V 5 m 
V 6  
V 7 m 
V 8 
Week (Wk) 
 
 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Day (D) 
Visit Window (d) 
-28 to -1 a 
D 1 
D 8 
+/-2d 
D 15 
+/-2d 
D 22 
+/-2d 
D 29 
+/-3d 
D 57 
+/-3d 
D 85 
+/-3d 
Screening/Baseline: 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Medical History/Demographics 
X 
X 
 
 
 
 
 
 
Training on IVRS/IWRS 
 
X 
 
 
 
 
 
 
Treatment: 
Injection training/observation 
 
X 
 
 
 
X 
 
 
Administer study drugc 
 
Xb 
 
 
 
 
 
 
Patient dosing diary d 
 
X 
 
 
 
X 
 
X 
Study drug dispensation/accounte 
 
X 
 
 
 
X 
 
X 
Con meds/procedures 
X 
X 
 
 
 
X 
 
 
Efficacy: f 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS 
(weekly)i 
 
X 
 
 
 
X 
 
 
IGA, EASI 
X 
X 
 
 
 
X 
 
 
POEM, DLQI, EQ-5Dg 
 
X 
 
 
 
 
 
 
Safety: f 
Weight 
X 
X 
 
 
 
 
 
 
Height 
X 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
 
 
 
X 
 
 
Physical examination 
 
X 
 
 
 
 
 
 
Ophthalmology examk (select 
sites and patients) 
 
X 
 
 
 
X 
 
X 
Adverse eventsh 
X 
X 
 
 
 
X 
 
X 
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Study Procedures 
Screening* 
Baseline 
Treatment Period 
Visit (V) 
V 1 
V 2 
V 3m 
V 4 m 
V 5 m 
V 6  
V 7 m 
V 8 
Week (Wk) 
 
 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Day (D) 
Visit Window (d) 
-28 to -1 a 
D 1 
D 8 
+/-2d 
D 15 
+/-2d 
D 22 
+/-2d 
D 29 
+/-3d 
D 57 
+/-3d 
D 85 
+/-3d 
Laboratory Testing:f 
Hematology, Chemistry 
X 
X 
 
 
 
 
 
 
Pregnancy test, WOCBP only 
Serum 
Urinel 
 
 
 
Urinel 
 
Urinel 
HIV screening j 
X 
 
 
 
 
 
 
 
HBsAg, HBcAb, hepatitis C 
antibody j 
X 
 
 
 
 
 
 
 
Drug Concentration/PK and Anti-drug Antibody Testing: f 
Drug concentration/PK sample 
 
X 
 
 
 
 
 
 
ADA sample 
 
X 
 
 
 
 
 
 
*Note:  The screening visit in this study may coincide with the last visit in the previous study.  Assessments that are common to both studies will be performed 
only once. 
a. Patients who fail screening or who fail to complete the baseline visit within 28 days of screening may be rescreened upon approval by the medical monitor. 
b. A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will be administered on day 1 unless the patient has received a 
dose of dupilumab in the 4 weeks prior to baseline.  If the patient has received a dose of dupilumab in the past 4 weeks, then they will receive a single 300 mg 
dose at baseline.  The first dose should be at least 1 week after the last dose in the previous study, and then 300 mg dupilumab qw starting on day 8.  In 
addition to the predose assessments, vital signs and AEs will be assessed at 30 (+/- 10) minutes postdose. 
c. Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). For patients who 
have not completed the study prior to the implementation of amendment 9, study drug dosing will change from dupilumab 300 mg weekly to every 2 weeks. 
d. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic  
e. Starting at visit 2, study drug will be dispensed to the patient for all doses that will be administered before the next clinic visit.  Patients will be instructed to 
return all study drug at each clinic visit. 
f. To be collected before the injection of study drug.  The order of the assessment should be questionnaires first, followed by laboratory evaluations.   
g. The questionnaires will be administered only to the subset of patients who fluently speak the language for which a validated translation of the questionnaire is 
available. 
h. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.   
i. Patients will be trained on using the IVRS/IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
j. Any of these tests is required only for patients who have not had a documented negative result for the respective test within 1 year prior to baseline (the 
negative HIV result must be from a parent study).  
k. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit, which can take place at any time between the screening and baseline visits, inclusive. 
l. Patients will be provided with a pregnancy test kit to take home for monthly urine sample testing in between clinic visits, or may choose to have the testing 
done at the study site.  
m. Visits 3, 4, 5, and 7 were removed per amendment 6. 
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Table 2: 
Schedule of Events – Visits 9 (Week 16) through 18 (Week 52) 
Study Procedures 
Treatment Period 
Visit (V) 
V 9 
V 10 j 
V 11 
V 12 j 
V 13 
V 14 j 
V 15 
V 16 j 
V 17 
V 18 
Week (Wk) 
Wk 16 
Wk 20 
Wk 24 
Wk 28 
Wk 32 
Wk 36 
Wk 40 
Wk 44 
Wk 48 
Wk 52 
Day (D) 
Visit Window (d) 
D 113 
+/-3d 
D 141 
+/-3d 
D 169 
+/-3d 
D 197 
+/-3d 
D 225 
+/-3d 
D 253 
+/-3d 
D 281 
+/-3d 
D 309 
+/-3d 
D 337 
+/-3d 
D 365 
+/-3d 
Treatment: 
 
Administer study drug a 
X 
 
 
 
 
 
 
 
 
 
Patient dosing diary b 
X 
 
X 
 
X 
 
X 
 
X 
X 
Study drug dispensation/account c 
X 
 
X 
 
X 
 
X 
 
X 
X 
Con meds/procedures 
X 
 
 
 
X 
 
 
 
X 
 
Efficacy: d 
 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS 
(weekly)g 
X 
 
 
 
 
 
 
 
X 
 
IGA, EASI  
X 
 
 
 
 
 
 
 
X 
 
POEM, DLQI, EQ-5D e 
 
 
 
 
 
 
 
 
X 
 
Safety: d 
 
Weight 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
X 
 
 
 
X 
 
 
 
X 
 
Ophthalmology exam i (select 
sites and patients) 
X 
 
 
 
X 
 
 
 
X 
 
Adverse events f 
X 
 
 
 
 
 
 
 
 
X 
Laboratory Testing: d 
 
Hematology, Chemistry 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy test, WOCBP onlyh 
  
 
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Study Procedures 
Treatment Period 
Visit (V) 
V 9 
V 10 j 
V 11 
V 12 j 
V 13 
V 14 j 
V 15 
V 16 j 
V 17 
V 18 
Week (Wk) 
Wk 16 
Wk 20 
Wk 24 
Wk 28 
Wk 32 
Wk 36 
Wk 40 
Wk 44 
Wk 48 
Wk 52 
Day (D) 
Visit Window (d) 
D 113 
+/-3d 
D 141 
+/-3d 
D 169 
+/-3d 
D 197 
+/-3d 
D 225 
+/-3d 
D 253 
+/-3d 
D 281 
+/-3d 
D 309 
+/-3d 
D 337 
+/-3d 
D 365 
+/-3d 
Drug Concentration and Antibody Testing:d 
Drug Concentration sample 
 
 
 
 
 
 
 
 
X 
 
ADA sample 
 
 
 
 
 
 
 
 
X 
 
a. Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). For patients who 
have not completed the study prior to the implementation of amendment 9, study drug dosing will change from dupilumab 300 mg weekly to every 2 weeks. 
b. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic.   
c. Study drug will be dispensed to the patient for all doses that will be administered before the next clinic visit.  Patients will be instructed to return all study drug 
at each clinic visit. 
d. To be collected before the injection of study drug.  The order of the assessment should be questionnaires first, followed by laboratory evaluations.   
e. The questionnaires will be administered only to the subset of patients who fluently speak the language for which a validated translation of the questionnaire is 
available. 
f. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet. 
g. Patients will be trained on using the IVRS/IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
h. Patients will be provided with a pregnancy test kit to take home for monthly urine sample testing in between clinic visits, or may choose to have the testing 
done at the study site. 
i. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit. 
j. Visits 10, 12, 14, and 16 have been removed per amendment 6.  
 
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Table 3: 
Schedule of Events – Visits 19 (Week 60) through 24 (Week 100) 
Study Procedures 
Treatment Period 
Visit (V) 
V 19 
V 20 
V 21 
V 22 
V 23 
V 24 
Week (Wk) 
Wk 60 
Wk 68 
Wk 76 
Wk 84 
Wk 92 
Wk 100 
Day (D) 
Visit Window (d) 
D 421 
+/-3d 
D 477 
+/-3d 
D 533 
+/-3d 
D 589 
+/-3d 
D 645 
+/-3d 
D 701 
+/-3d 
Treatment: 
Administer study druga 
X 
 
 
 
 
 
Patient dosing diaryb 
X 
 
X 
Study drug dispensation/accountc 
X 
 
X 
Con meds/procedures 
X 
 
X 
 
X 
 
Efficacy: d 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS 
(weekly)g 
X 
 
 
 
 
X 
IGA, EASI 
X 
 
 
 
 
X 
POEM, DLQI, EQ-5D e 
 
 
 
 
 
X 
Safety: d 
Weight 
X 
 
X 
 
 
X 
Vital signs 
X 
 
X 
X 
X 
X 
Ophthalmology exami (select sites 
and patients) 
X 
 
X 
 
X 
 
Adverse eventsf 
X 
 
X 
Laboratory Testing: d 
Hematology, Chemistry 
 
 
 
 
 
X 
Pregnancy test, WOCBP onlyh 
 
 
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Study Procedures 
Treatment Period 
Visit (V) 
V 19 
V 20 
V 21 
V 22 
V 23 
V 24 
Week (Wk) 
Wk 60 
Wk 68 
Wk 76 
Wk 84 
Wk 92 
Wk 100 
Day (D) 
Visit Window (d) 
D 421 
+/-3d 
D 477 
+/-3d 
D 533 
+/-3d 
D 589 
+/-3d 
D 645 
+/-3d 
D 701 
+/-3d 
Drug Concentration and Antibody Testing:d 
Drug Concentration sample 
 
 
 
 
 
X 
ADA sample 
 
 
 
 
 
X 
a.  Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). For patients who 
have not completed the study prior to the implementation of amendment 9, study drug dosing will change from dupilumab 300 mg weekly to every 2 weeks. 
b.  If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c.  Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
d.  To be collected before the injection of study drug.  The order of the assessment should be questionnaires first, followed by laboratory evaluations. 
e.  The questionnaires will be administered only to the subset of patients who fluently speak the language for which a validated translation of the questionnaire is 
available. 
f.  In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
g. Patients will be trained on using the IVRS/IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
h. Patients will be provided with a pregnancy test kit to take home for monthly urine sample testing in between clinic visits, or may choose to have the testing 
done at the study site. 
i. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit 
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Table 4: 
Schedule of Events – Visits 25 (Week 108) through Visit 30 (Week 148)  
Study Procedures 
Treatment Period 
Visit (V) 
V 25 
V 26 i 
V 27 
V 28 i 
V 29 
V 30 
Week (Wk) 
Wk 108 
Wk 116 
Wk 124 
Wk 132 
Wk 140 
Wk 148 
Day (D) 
Visit Window (d) 
D 757 
+/-3d 
D 813 
+/-3d 
D 869 
+/-3d 
D 925 
+/-3d 
D 981 
+/-3d 
D 1037 
+/-3d 
Treatment: 
 
 
 
 
 
 
Administer study druga 
X 
 
 
 
 
X 
Patient dosing diaryb 
X 
 
 
 
 
X 
Study drug dispensation/accountc 
X 
 
 
 
 
X 
Con meds/procedures 
X 
 
X 
 
X 
 
Efficacy:d 
 
 
 
 
 
 
Patient Assessment of Pruritus Intensity via IVRS/IWRS (weekly)f 
X 
 
 
 
 
X 
IGA, EASI 
 
 
X 
 
 
 
Safety: d 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
Vital signs 
X 
 
X 
 
X 
X 
Ophthalmology examh (select sites and patients) 
X 
 
X 
 
X 
 
Adverse eventse 
X  
 
 
 
 
X 
Laboratory Testing: d 
 
 
 
 
 
 
Hematology, Chemistry 
 
 
 
 
 
X 
Pregnancy test, WOCBP onlyg 
X 
 
 
 
 
X 
HIV screening 
 
 
 
 
 
 
HBsAg, HBcAb, hepatitis C antibody  
 
 
 
 
 
 
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Study Procedures 
Treatment Period 
Visit (V) 
V 25 
V 26 i 
V 27 
V 28 i 
V 29 
V 30 
Week (Wk) 
Wk 108 
Wk 116 
Wk 124 
Wk 132 
Wk 140 
Wk 148 
Day (D) 
Visit Window (d) 
D 757 
+/-3d 
D 813 
+/-3d 
D 869 
+/-3d 
D 925 
+/-3d 
D 981 
+/-3d 
D 1037 
+/-3d 
Drug Concentration and Antibody Testing: d 
 
 
 
 
 
 
Drug Concentration sample 
 
 
X 
 
 
 
ADA sample 
 
 
X 
 
 
X 
a.  Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). For patients who 
have not completed the study prior to the implementation of amendment 9, study drug dosing will change from dupilumab 300 mg weekly to every 2 weeks. 
b. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c. Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
d. To be collected before the injection of study drug. 
e. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
f. Patients will be trained on using the IVRS/IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
g. Patients will be provided with a pregnancy test kit to take home for monthly urine sample testing in between clinic visits, or may choose to have the testing 
done at the study site. 
h. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted 
at the baseline visit. 
i. Visits 26 and 28 were removed per amendment 9.  
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Table 5: 
Schedule of Events – Visits 31 (Week 156) through Visit 36 (Week 196) 
Study Procedures 
Treatment Period 
 
Visit (V) 
V 31 
V 32 i 
V 33 
V 34 i 
V 35 
V 36 i 
Week (Wk) 
Wk 156 
Wk 164 
Wk 172 
Wk 180 
Wk 188 
Wk 196 
Day (D) 
Visit Window (d) 
D 1093 
+/-3d 
D 1149 
+/-3d 
D 1205 
+/-3d 
D 1261 
+/-3d 
D 1317 
+/-3d 
D 1373 
+/-3d 
Treatment: 
Administer study druga 
X 
 
 
 
 
X 
Patient dosing diaryb 
X 
 
 
 
 
X 
Study drug dispensation/account.c 
X 
 
 
 
 
X 
Con meds/procedures 
X 
 
X 
 
X 
 
Efficacy: d 
Patient Assessment of Pruritus Intensity via 
IVRS/IWRS (weekly)f 
X 
 
 
 
 
X 
IGA, EASI 
X 
 
 
 
 
 
Safety: d 
Weight 
X 
 
X 
 
X 
 
Vital signs 
X 
 
X 
 
X 
 
Ophthalmology examh (select sites and patients) 
X 
 
X 
 
X 
 
Adverse eventse  
X 
  
 
 
 
X 
Laboratory Testing: d 
Hematology, Chemistry 
 
 
 
 
 
 
Pregnancy test, WOCBP onlyg 
 
 
 
 
 
 
HIV Screening 
 
 
 
 
 
 
HBsAg, HBcAb, hepatitis C antibody  
 
 
 
 
 
 
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Study Procedures 
Treatment Period 
 
Visit (V) 
V 31 
V 32 i 
V 33 
V 34 i 
V 35 
V 36 i 
Week (Wk) 
Wk 156 
Wk 164 
Wk 172 
Wk 180 
Wk 188 
Wk 196 
Day (D) 
Visit Window (d) 
D 1093 
+/-3d 
D 1149 
+/-3d 
D 1205 
+/-3d 
D 1261 
+/-3d 
D 1317 
+/-3d 
D 1373 
+/-3d 
Drug Concentration and Antibody Testing: d 
Drug Concentration sample 
 
 
 
 
 
 
ADA sample 
 
 
X 
 
 
 
a. Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). For patients who 
have not completed the study prior to the implementation of amendment 9, study drug dosing will change from dupilumab 300 mg weekly to every 2 weeks. 
b. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c. Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
d. To be collected before the injection of study drug. 
e. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
f. Patients will be trained on using the IVRS /IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
g. Patients will be provided with a pregnancy test kit to take home for monthly urine sample testing in between clinic visits, or may choose to have the testing 
done at the study site. 
h. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted 
at the baseline visit 
i. Visits 32, 34, and 36 were removed per amendment 9. 
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Table 6: 
Schedule of Events – Visits 37 (Week 204) through Visit 43 (Week 252)  
 
Study Procedures 
Treatment Period 
Visit (V) 
V 37 
V 38 i 
V 39 
V 40 i 
V 41j 
V 42 i 
V 43j 
Week (Wk) 
Wk 204 
Wk 212 
Wk 220 
Wk 228 
Wk 236 
Wk 244 
Wk 252 
Day (D) 
Visit Window (d) 
D 1429 
+/-3d 
D 1485 
+/-3d 
D 1541 
+/-3d 
D 1597 
+/-3d 
D 1653 
+/-3d 
D 1709 
+/-3d 
D 1765 
+/-3d 
Treatment: 
Administer study drug a 
X 
 
 
 
 
 
X 
Patient dosing diary b 
X 
 
 
 
 
 
X 
Study drug dispensation/account c 
X 
 
 
 
 
 
X 
Con meds/procedures 
X 
 
X 
 
X 
 
X 
Efficacy:d 
Patient Assessment of Pruritus Intensity via 
IVRS/IWRS (weekly)f 
X 
 
 
 
 
 
X 
IGA, EASI 
X 
 
 
 
 
 
 
Safety:d 
Weight 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
 
X 
 
X 
 
X 
Ophthalmology examh (select sites and 
patients) 
X 
 
X 
 
X 
 
X 
Adverse eventse  
X 
 
 
 
 
 
X 
Laboratory Testing:d 
Hematology, Chemistry 
X 
 
 
 
 
 
 
Pregnancy test, WOCBP onlyg 
X 
 
 
 
 
 
 
HIV Screening 
 
 
 
 
 
 
 
HBsAg, HBcAb, hepatitis C antibody  
 
 
 
 
 
 
 
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Study Procedures 
Treatment Period 
Visit (V) 
V 37 
V 38 i 
V 39 
V 40 i 
V 41j 
V 42 i 
V 43j 
Week (Wk) 
Wk 204 
Wk 212 
Wk 220 
Wk 228 
Wk 236 
Wk 244 
Wk 252 
Day (D) 
Visit Window (d) 
D 1429 
+/-3d 
D 1485 
+/-3d 
D 1541 
+/-3d 
D 1597 
+/-3d 
D 1653 
+/-3d 
D 1709 
+/-3d 
D 1765 
+/-3d 
Drug Concentration and Antibody Testing:d 
Drug Concentration sample 
 
 
 
 
 
 
 
ADA sample 
 
 
X 
 
 
 
 
a. Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). For patients who 
have not completed the study prior to the implementation of amendment 9, study drug dosing will change from dupilumab 300 mg weekly to every 2 weeks. 
b. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c. Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
d. To be collected before the injection of study drug. 
e. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
f. Patients will be trained on using the IVRS/IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
g. Patients will be provided with a pregnancy test kit to take home for monthly urine sample testing in between clinic visits, or may choose to have the testing 
done at the study site. 
h. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted 
at the baseline visit 
i. Visits 38, 40, and 42 were removed per amendment 9. 
j Patients who have not completed visit 44 (EOT) prior to implementation of amendment 10 will be asked to participate in a sub-study using the new dupilumab 
drug product.  Eligible patients will enter the sub study at either visit 41, 43, or 44 of the main study.  Any redundant procedures between the main study (eg, 
visit 41, 43, or 44) and the sub-study (eg, visit 1a) will only be performed once.  This optional sub-study requires a separate consent. 
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Table 7: 
Schedule of Events – End of Treatment, End of Study, Early Termination, Unscheduled Visit, and Re-entry 
Visit 
Study Procedures 
End of Treatment 
End of Study m 
Early Termination 
Unscheduled Visit j 
(if applicable) 
Re-entry Visit r 
(for patients who re-
enter the study) 
Visit (V) 
V 44s 
 
 
 
 
Week (Wk) 
260 
Last dose 
+12Wk 
 
 
 
Day (D) 
Visit Window (d) 
D 1821  
+/-3d 
Last dose 
+84D 
+/-30d 
 
 
 
Treatment: 
 
 
 
 
 
Inclusion/Exclusion (Re-entry) 
 
 
 
 
X 
Informed Consent (Re-entry) 
 
 
 
 
X 
Demographics (Re-entry) 
 
 
 
 
X 
Administer study druga 
X  
 
 
 
 
Patient dosing diaryb 
X 
 
X 
 
 
Study drug dispensation/accountc 
Xn 
 
X 
X 
 
Con meds/procedures 
X 
X 
X 
X 
X 
Efficacy: d 
 
 
 
 
 
Patient Assessment of Pruritus Intensity via 
IVRS/IWRS (weekly)f 
 
 
Xf 
Xh 
 
IGA, EASI 
X 
X 
X 
X 
 
Safety: d 
 
 
 
 
 
Weight 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
 
Ophthalmology examk (select sites and patients) 
 
X 
 
Xl 
 
Adverse eventse 
X 
X 
X 
X 
X 
Laboratory Testing: d 
 
 
 
 
 
Hematology, Chemistry 
X 
 
 
X 
Xo 
Pregnancy test, WOCBP onlyg 
Urine Monthly 
 
 
 
X 
Serump 
HIV screening 
 
 
 
X 
Xq 
HBsAg, HBcAb, hepatitis C antibody  
 
 
 
X 
Xq 
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Study Procedures 
End of Treatment 
End of Study m 
Early Termination 
Unscheduled Visit j 
(if applicable) 
Re-entry Visit r 
(for patients who re-
enter the study) 
Visit (V) 
V 44s 
 
 
 
 
Week (Wk) 
260 
Last dose 
+12Wk 
 
 
 
Day (D) 
Visit Window (d) 
D 1821  
+/-3d 
Last dose 
+84D 
+/-30d 
 
 
 
Drug Concentration and Antibody Testing: d 
 
 
 
 
 
Drug Concentration sample 
X 
X 
X 
X 
 
ADA sample 
X 
Xi 
Xi 
X 
 
a. Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). For patients who have not completed 
the study prior to the implementation of amendment 9, study drug dosing will change from dupilumab 300 mg weekly to every 2 weeks. 
b. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c. Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will be instructed to 
return all study drug at each clinic visit. 
d. To be collected before the injection of study drug. 
e. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
f. Patients will be trained on using the IVRS /IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over the previous week, 
and to record compliance with self-injection of study drug. 
g. Patients will be provided with a pregnancy test kit to take home for monthly urine sample testing in between clinic visits, or may choose to have the testing done at the study 
site. 
h If the call was performed on the patient’s weekly schedule, then it will not need to be repeated. 
i. Patients who test positive for ADA at their last study visit (early termination visit or end of study visit) may be asked to return to the clinic to have additional ADA samples 
collected for analysis (see Section 6.3.4.2 for details and time points). 
j. During an unscheduled visit, any of the study procedures noted may be performed, but not all are required. 
k. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at the baseline 
visit. 
l. Patients who experience AEs consistent with conjunctivitis or other superficial inflammation of the eye (blepharitis, keratitis, etc) should undergo additional (unscheduled) 
ophthalmology exams to allow accurate diagnosis and adequate treatment. 
m. If the end of study assessments cannot be completed on the scheduled date (ie, 12 weeks after the last dose of dupilumab), a late visit is acceptable and is preferable to foregoing 
these assessments altogether; this visit should be conducted as close as possible to the scheduled date. 
n. Only study drug accountability takes place at this visit.   
o. Sample will be collected only if the last sample was not collected within 12 months. 
p Serum pregnancy test must be negative before dosing. 
q Testing is required at re-entry for patients who have not been tested within 12 months prior to re-entry. 
r. Patients who have completed the end of study visit as per amendment 7 and who are eligible to resume treatment may re-enter the trial at the next scheduled visit they would have 
attended if they had not completed the study; the next visit should be scheduled within 7 days of the re-entry visit.  Patients are not eligible to re-enter the trial if more than 12 
weeks have elapsed since their end of study visit. 
s Patients who have not completed visit 44 (EOT) prior to implementation of amendment 10 will be asked to participate in a sub-study using the new dupilumab drug product.  
Eligible patients will enter the sub study at either visit 41, 43, or 44 of the main study.  Any redundant procedures between the main study (eg, visit 41, 43, or 44) and the sub-
study (eg, visit 1a) will only be performed once.  This optional sub-study requires a separate consent.  
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Table 8: 
Sub-Study Schedule of Events  
Study Procedures 
Sub-Study Treatment Period 
End of 
Studyd 
Early 
Termination 
Unscheduled 
Visite 
Sub-Study Visit (Va) 
V1aa 
V2a 
V3ab 
V4ac 
- 
- 
- 
Sub-Study Week (Wka) 
Wk 0a 
Wk 4a 
Wk 12a 
Wk 24a 
Last dose + 
12 weeks 
- 
- 
Sub-Study Day (Da) 
Visit Window (d) 
D1a 
±3da 
D29a 
±3d 
D85a 
±3df 
D169a 
±3d 
Last dose + 
84 days 
±3d 
- 
- 
Screening/Baseline (Sub-Study) 
 
 
 
 
 
 
 
Informed consent (Sub-Study) 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria (Sub-Study) 
X 
 
 
 
 
 
 
Treatment: 
Administer study drugg 
Xa,h 
X 
X 
X 
 
 
 
Patient dosing diaryi 
X 
X 
X 
X 
 
 
 
Study drug dispensation/accountj 
X 
X 
Xk 
Xl 
 
X 
 
Con meds/procedures 
X 
X 
X 
X 
X 
X 
X 
Efficacy:m 
Patient assessment of pruritus intensity via 
IVRS/IWRS (weekly)n 
X 
X 
X 
X 
X 
X 
Xo 
IGA, EASI 
X 
X 
X 
X 
X 
X 
X 
Safety:m 
Weight 
X 
 
 
 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Ophthalmology exam (select sites and 
patients)p 
X 
 
X 
 
X 
 
Xq 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing:m 
Hematology, chemistry 
X 
 
X 
 
X 
 
X 
Pregnancy test, WOCBP onlyr 
X 
X 
X 
X 
X 
X 
X 
Drug Concentration and Antibody Testing:m 
Drug concentration sample 
X 
 
X 
X 
X 
X 
X 
ADA sample 
X 
 
X 
X 
X 
X 
X 
a. The first new dupilumab drug product administration at visit 1a should occur 14 days (±3 days) after the previous administration of the current dupilumab drug 
product in the main study.  Although the protocol allows a visit window of ±3 days for visit 1a, the sponsor recommends a visit window ±1 day after the 
previous dose of the current dupilumab drug product.  Any redundant procedures between the main study (eg, visit 41, 43, or 44) and the sub-study (eg, 
visit 1a) will only be performed once. 
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b For patients who begin treatment with the new dupilumab drug product after visit 41 of the main study, the last dose of the new dupilumab drug product will be 
administered at sub-study visit 3a. 
c Visit only applies to patients who switch to the new dupilumab drug product at visit 41 of the main study.  
d End of study visit occurs 12 weeks after the last dose of dupilumab.  The same EOS assessments are performed for patients receiving the new dupilumab drug 
product as for the current dupilumab drug product. 
e During an unscheduled visit, any of the study procedures noted may be performed, but not all are required. 
f Sub-study visit 3a is to be conducted on sub-study day 85 (±3 days).  Although the protocol allows for a visit window ±3 days, it is strongly recommended that 
visit 3a occurs 14 days (±1 day) after the self-injection of the new dupilumab drug product on sub-study day 71. 
g Study drug will be administered every 2 weeks, either in the clinic or outside the clinic (self-administration or administration by a care provider).  
h Patients will be monitored at the study site for a minimum of 30 minutes.  
i If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
j Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
k Drug accountability for patients who enter the sub-study at visits 43 or 44 of the main study.  Drug accountability and dispensing for patients who entered the 
sub-study at visit 41 of the main study. 
l  Drug accountability for patients who enter the sub-study at visit 41 of the main study.  This visit is not applicable for patients who enter the sub-study at 
visit 43 or 44 of the main study. 
m To be collected before the injection of study drug. 
n Patients will be retrained on using the IVRS/IWRS at the sub-study baseline visit (if needed) and will call into the system weekly to report the overall intensity 
of their pruritus over the previous week, and to record compliance with self-injection of study drug. 
o If the call was performed on the patient’s weekly schedule, then it will not need to be repeated. 
p Only applies to patients who are in the ophthalmology sub-study in the main study (amendment 9).  An acceptable window for performing ophthalmology 
exams is within ±7 days of the visit date.   
q Patients who experience AEs consistent with conjunctivitis or other superficial inflammation of the eye (blepharitis, keratitis, etc) should undergo additional 
(unscheduled) ophthalmology exams to allow accurate diagnosis and adequate treatment. 
r Women of childbearing potential (WOCBP) will be provided with a pregnancy test kit to take home for monthly urine sample testing in between clinic visits, 
or may choose to have the testing done at the study site. 
 
 
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6.2. 
Study Visit Descriptions 
6.2.1. 
Visit 1/Screening/Day –28 to Day -1 
After the patient has provided signed informed consent, he/she will be assigned a unique patient 
number, and the following information will be collected.  Note:  The screening visit in this study 
may coincide with the last visit in the previous study.  Patients who fail screening or who fail to 
complete the baseline visit within 28 days of screening may be rescreened upon approval by the 
medical monitor. Assessments that are common to both studies will be performed only once: 
• Inclusion/exclusion criteria 
• Medical history 
• Demographics (eg, date of birth, race, ethnicity) 
• Concomitant medications/procedures 
• AEs 
The following procedures will be conducted by the investigator or designee: 
• Weight and height 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• IGA 
• EASI 
• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− Serum hCG – for women of childbearing potential 
− HIV screening (not required if patients had a negative HIV test result in the parent 
study within 1 year prior to baseline) 
− HBsAg (not required if patients had a negative test result within 1 year prior to 
baseline) 
− HBcAb (not required if patients had a negative test result within 1 year prior to 
baseline) 
− Hepatitis C antibody (not required if patients had a negative test result within 1 year 
prior to baseline) 
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6.2.2. 
Treatment Period 
6.2.2.1. 
Visit 2/Baseline/Day 1 
The following information will be collected: 
• Inclusion/exclusion criteria 
• Medical history 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Weight and height 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Physical examination 
• Ophthalmology exam (select sites and patients) 
• IGA 
• EASI 
• Injection training/observation (unless trained in the previous study) 
• Study drug dispensation/accountability 
• Administered only to the subset of patients who speak fluently the language in which 
the questionnaire can be translated: 
− POEM 
− DLQI 
− EQ-5D 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Counsel patient on proper dosing diary completion/reporting of each dose of study drug 
that is administered outside of the clinic 
• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− Urine pregnancy test– for women of childbearing potential 
− Drug concentration sample 
− ADA sample 
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• IVRS/IWRS training 
• Administer study drug –600 mg loading dose (300 mg initial dose, followed by a 
300 mg loading dose, unless last dose administered in the previous AD study is less 
than 4 weeks before their first dose in the current study, in which case administer 
300 mg study drug)/train patient (or caregiver)/observe patient injection technique 
− Monitor the patient for a minimum of 30 minutes after the SC injection:  in 
addition to the predose assessments, vital signs and AE assessments will be done 
at 30 (+/- 10) minutes post-injection 
6.2.2.2. 
Visit 3/Day 8/Week 1 (+/-2 Days) 
This visit was removed per amendment 6. 
6.2.2.3. 
Visit 4/Day 15/Week 2 (+/-2 Days) 
This visit was removed per amendment 6. 
6.2.2.4. 
Visit 5/Day 22/Week 3 (+/-2 Days) 
This visit was removed per amendment 6. 
6.2.2.5. 
Visit 6/Day 29/Week 4 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Ophthalmology exam (select sites and patients) 
• IGA 
• EASI 
• Laboratory samples: 
− Urine pregnancy test– for women of childbearing potential 
• Injection training/observation (unless trained in the previous study) 
• Administer study drug 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Counsel patient on proper dosing diary completion/reporting of each dose of study drug 
that is administered outside of the clinic 
• Study drug dispensation/accountability 
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6.2.2.6. 
Visit 7/Day 57/Week 8 (+/-3 Days) 
This visit was removed per amendment 6. 
6.2.2.7. 
Visit 8/Day 85/Week 12 (+/-3 Days) 
The following information will be collected: 
• AEs 
The following procedures and assessments will be conducted: 
• Ophthalmology exam (select sites and patients) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose of 
study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.8. 
Visit 9/Day 113/Week 16 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Ophthalmology exam (select sites and patients) 
• IGA 
• EASI 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− Urine pregnancy test – for women of childbearing potential 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose of 
study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
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6.2.2.9. 
Visit 10/Day 141/Week 20 (+/-3 Days) 
This visit was removed per amendment 6. 
6.2.2.10. Visit 11/Day 169/Week 24 (+/-3 Days) 
The following information will be collected: 
• AEs 
The following procedures and assessments will be conducted: 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose of 
study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.11. Visit 12/Day 197/Week 28 (+/-3 Days) 
This visit was removed per amendment 6. 
6.2.2.12. Visit 13/Day 225/Week 32 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Ophthalmology exam (select sites and patients) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose of 
study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
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6.2.2.13. Visit 14/Day 253/Week 36 (+/-3 Days) 
This visit was removed per amendment 6. 
6.2.2.14. Visit 15/Day 281/Week 40 (+/-3 Days) 
The following information will be collected: 
• AEs 
The following procedures and assessments will be conducted: 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose of 
study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.15. Visit 16/Day 309/Week 44 (+/-3 Days) 
This visit was removed per amendment 6. 
6.2.2.16. Visit 17/Day 337/Week 48 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• IGA 
• EASI 
• Ophthalmology exam (select sites and patients) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Administered only to the subset of patients who speak fluently the language in which 
the questionnaire can be translated: 
− POEM 
− DLQI 
− EQ-5D 
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• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− ADA sample 
− Drug concentration sample 
− Urine pregnancy test – for women of childbearing potential 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.17. Visit 18/Day 365/Week 52 (+/-3 Days) 
The following information will be collected: 
• AEs 
The following procedures and assessments will be conducted: 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.18. Visit 19/Day 421/Week 60 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• IGA 
• EASI 
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• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• Ophthalmology exam (select sites and patients) 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.19. Visit 20/Day 477/Week 68 (+/-3 Days) 
The following information will be collected: 
• AEs 
The following procedures and assessments will be conducted: 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.20. Visit 21/Day 533/Week 76 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Ophthalmology exam (select sites and patients) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
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• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability  
• Administer study drug 
6.2.2.21. Visit 22/Day 589/Week 84 (+/-3 Days) 
The following information will be collected: 
• AEs 
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.22. Visit 23/Day 645/Week 92 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Ophthalmology exam (select sites and patients) 
• Study drug dispensation/accountability 
• Administer study drug 
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6.2.2.23. Visit 24/Day 701/Week 100 (+/-3 Days) 
The following information will be collected: 
• AEs 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• IGA 
• EASI 
• Administered only to the subset of patients who speak fluently the language in which 
the questionnaire can be translated: 
− POEM 
− DLQI 
− EQ-5D 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− Urine pregnancy test – for women of childbearing potential 
− Drug concentration sample 
− ADA sample 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.24. Visit 25/Day 757/Week 108 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Ophthalmology exam (select sites and patients) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
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• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.2.25. Visit 26/Day 813/Week 116 (+/-3 Days) 
This visit was removed per amendment 9. 
6.2.2.26. Visit 27/Day 869/Week 124 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• IGA 
• EASI 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Ophthalmology exam (select sites and patients) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
− Drug concentration sample 
− ADA sample 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability  
• Administer study drug 
6.2.2.27. Visit 28/Day 925/Week 132 (+/-3 Days) 
This visit was removed per amendment 9. 
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6.2.2.28. Visit 29/Day 981/Week 140 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Ophthalmology exam (select sites and patients) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose 
of study drug that is administered outside of the clinic 
• Study drug dispensation/accountability 
• Administer study drug 
6.2.3. 
Visit 30/Day 1037/Week 148 (+/-3 Days) 
The following information will be collected: 
• AEs 
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− Urine pregnancy test – for women of childbearing potential 
− ADA sample 
• Confirm that the patient completed/reported the dosing diary for each dose of study 
drug that was administered outside of the clinic 
• Study drug accountability – return all PFS and study materials 
• Administer study drug 
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6.2.4. 
Visit 31/Day 1093/Week 156 through Visit 43/Day 1765/Week 252 (+/-3 Days) 
The study treatment duration will be up to 5 years.  Visits 31 through 43 will occur approximately 
every 8 weeks until the end of treatment.   
The following information will be collected: 
• Concomitant medications/procedures:  visit 31, 33, 35, 37, 39, 41, and 43. 
• AEs  
• Informed consent for the optional sub-study using the new dupilumab drug product: 
visit 41 or 43.  See Section 6.2.6 for further information about procedures and 
assessments to be performed during the sub-study. 
The following procedures and assessments will be conducted: 
• IGA/EASI:  visit 31, 37 
• Weight: visit 31, 33, 35, 37, 39, 41, and 43  
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate): 
visit 31, 33, 35, 37, 39, 41, and 43 
• Ophthalmology exam (select sites and patients):  visit 31, 33, 35, 37, 39, 41, and 43) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Hematology w/differential:  visit 37  
− Serum chemistry:  visit 37 
− Urine pregnancy test – for women of childbearing potential.  Starting at visit 31 
monthly until visit 43, urine pregnancy test must be negative before dosing. 
− ADA sample:  visit 33 and 39 
• Confirm that the patient completed/reported the dosing diary for each dose of study 
drug that was administered outside of the clinic 
• Study drug dispensation/ accountability 
• Administer study drug (weekly throughout the study) 
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6.2.5. 
End of Treatment Visit/Day 1821/Visit 44/Week 260 (+/-3 Days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
• Informed consent for the optional sub-study using the new dupilumab drug product: 
visit 44.  See Section 6.2.6 for further information about procedures and assessments 
to be performed during the sub-study. 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• IGA 
• EASI 
• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− Urine pregnancy test – for women of childbearing potential 
− Drug concentration sample 
− ADA sample 
• Confirm that the patient completed/reported the dosing diary for each dose of study 
drug that was administered outside of the clinic 
• Study drug accountability – return all PFS and study materials 
• Administer study drug 
6.2.6. 
Sub-Study Treatment Period 
Patients who have provided written informed consent to participate in the sub-study using the new 
dupilumab drug product (per amendment 10) will have the following assessments and procedures 
performed.  Patients who enter the sub-study from either visit 43 or visit 44 of the main study will 
have the duration of their study treatment increased by 4 or 12 weeks, respectively.   
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6.2.6.1. 
Sub-Study Visit 1a/Day 1a/Week 0a (±3 days) 
Note:  This visit should occur 14 days (±3 days) after the previous dose of current dupilumab drug 
product.  Although, the protocol allows for a window of ±3 days, the sponsor recommends a 
window ±1 day for sub-study visit 1a after the previous dose of the current dupilumab drug product 
is administered.  
Any redundant procedures between the main study (eg, visit 41, 43, or 44) and the sub-study (eg, 
visit 1a) will only be performed once. 
The following information will be collected: 
• Sign informed consent for sub-study 
• Inclusion/exclusion criteria for switching to the new dupilumab drug product 
treatment (see Section 4.2.4) 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate)  
• Ophthalmology exam (select sites and patients) 
• IGA 
• EASI 
• Study drug dispensation/accountability 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose of 
study drug that is administered outside of the clinic 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− Urine pregnancy test– for women of childbearing potential 
− Drug concentration sample 
− ADA sample 
• Administer study drug (new dupilumab drug product) 
− Monitor the patient for a minimum of 30 minutes after the SC injection:  in 
addition to the predose assessments, vital signs and AE assessments will be done 
at 30 (±10) minutes post-injection 
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6.2.6.2. 
Sub-Study Visit 2a/Day 29a/Week 4a (±3 days) 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• IGA 
• EASI 
• Laboratory samples: 
− Urine pregnancy test– for women of childbearing potential 
• Administer study drug (new dupilumab study drug product) 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Counsel patient on proper dosing diary completion/reporting of each dose of study drug 
that is administered outside of the clinic 
• Study drug dispensation/accountability 
6.2.6.3. 
Sub-Study Visit 3a/Day 85a/Week 12a (±3 days) 
This visit should occur on sub-study day 85a (±3 days).  Although the protocol allows a visit 
window of ±3 days, it is strongly recommended that visit 3a occurs 14 days (±1 day) after the 
self-injection of the new dupilumab drug product on sub-study day 71a. 
The following information will be collected: 
• AEs 
• Concomitant medications/procedures;  
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Ophthalmology exam (select sites and patients) 
• IGA 
• EASI 
• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− Urine pregnancy test – for women of childbearing potential 
− Drug concentration sample 
− ADA sample 
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• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose of 
study drug that is administered outside of the clinic 
• Study drug accountability 
• Administer study drug (new dupilumab drug product) 
• Study drug dispensation (Note:  patients who switched at visit 41 only) 
6.2.6.4. 
Sub-Study Visit 4a/Day 169a/Week 24a (±3 days) 
Note:  This visit is only applicable to patients who switched to the new dupilumab drug product at 
visit 41 of the main study. 
The following information will be collected: 
• AEs 
• Concomitant medications/procedures;  
The following procedures and assessments will be conducted: 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Ophthalmology exam (select sites and patients) 
• IGA 
• EASI 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
− Drug concentration sample 
− ADA sample 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• If needed, counsel patient on proper dosing diary completion/reporting of each dose of 
study drug that is administered outside of the clinic 
• Study drug accountability 
• Administer study drug (new dupilumab drug product) 
6.2.6.5. 
End of Study Visit (Last Dose+12 Weeks), Early Termination Visit, and 
Unscheduled Visits 
Assessments and procedures to be performed at the end of study visit (last new dupilumab drug 
product dose+12 weeks) are described in Section 6.2.7, those for early termination visit in 
Section 6.2.8, and those for an unscheduled visit in Section 6.2.9.  Except as noted, these 
assessments and procedures are the same as those done for patients who are receiving the current 
dupilumab drug product in the main study. 
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6.2.7. 
End of Study Visit (84 Days After Last Dose or 12 Weeks After Last Dose) 
If the end of study assessments cannot be completed on the scheduled date (ie, 12 weeks after the 
last dose of dupilumab), a late visit is acceptable and is preferable to foregoing these assessments 
altogether; this visit should be conducted as close as possible to the scheduled date.  Except as 
noted, the same end of study assessments are performed for patients receiving the current 
dupilumab drug product or new dupilumab drug product. 
The following information will be collected: 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Ophthalmology exam (select sites and patients) 
• IGA 
• EASI 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
− Drug concentration sample 
− ADA sample 
− Hematology w/differential (patients in sub-study only) 
− Serum chemistry (patients in sub-study only) 
6.2.8. 
Early Termination Visit 
Patients who withdraw from the study will be asked to complete 2 more visits:  once for early 
termination assessments, as described below, and again at 12 weeks after the last dose of 
dupilumab, for end of study assessments (Section 6.2.7).  These visits are applicable to patients 
receiving the current dupilumab drug product or the new dupilumab drug product. 
The following information will be collected: 
• Confirm that the patient completed/reported the dosing diary for each dose of study 
drug that was administered outside of the clinic 
• Concomitant medications/procedures 
• AEs 
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The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• IGA 
• EASI 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) 
• Laboratory samples: 
− Urine pregnancy test – for women of childbearing potential 
− Drug concentration sample 
− ADA sample 
• Study drug accountability – return all PFS and study materials 
6.2.9. 
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 study procedures noted may 
be performed, but not all are required. 
The following information will be collected: 
• Study drug accountability 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Weight 
• Vital signs (heart rate, blood pressure, body temperature, and respiration rate) 
• Ophthalmology exam (select sites and patients) 
• IGA 
• EASI 
• Patient assessment of pruritus intensity via IVRS/IWRS (weekly) (not to be repeated 
if performed on the patient’s weekly schedule) 
• Laboratory samples: 
− Hematology w/differential 
− Serum chemistry 
− Urine pregnancy test – for women of childbearing potential (to be performed only 
if coincides with the patient’s weekly schedule, or with the monthly pregnancy test) 
− HIV screening 
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− HBsAg, HBcAb, hepatitis C antibody 
− Drug concentration sample 
− ADA sample 
6.2.10. 
Re-entry Visit (Main Study Only) 
Patients who have completed their end of study visit of the main study as per amendment 7 will 
have their re-entry visit into the main study within 12 weeks of their end of study visit.  Patients 
are not eligible to re-enter the trial if more than 12 weeks have elapsed since their end of study 
visit.  This re-entry visit does not apply to the new dupilumab drug product sub-study. 
Note:  Medical history will not be collected for patients re-entering the study. 
The following information will be collected: 
• Inclusion/exclusion criteria 
• Informed consent 
• Demographics (eg, date of birth, race, ethnicity) 
• Concomitant medications/procedures 
• AEs 
The following procedures and assessments will be conducted: 
• Laboratory samples: 
− Hematology w/differential (sample will be collected only if the last sample was not 
collected within 12 months) 
− Serum chemistry (sample will be collected only if the last sample was not collected 
within 12 months) 
− HIV screening (required at re-entry for patients who have not been tested within 
12 months prior to re-entry) 
− HBsAg, HBsAb, HBcAb, hepatitis C antibody (required at re-entry for patients who 
have not been tested within 12 months prior to re-entry) 
− Serum pregnancy test – for women of childbearing potential (serum pregnancy test 
must be negative before dosing) 
6.3. 
Study Procedures 
6.3.1. 
Procedures Performed Only at the Screening/Baseline Visit 
Assessments performed only at the screening and/or baseline visit include medical history, 
medication history, physical examination, and demographics. 
6.3.1.1. 
Patient Training on the Interactive Voice Response System 
Patients will be trained on using the IVRS/IWRS at the baseline visit.  Patients will access the 
IVRS weekly to record Pruritus numerical rating scale (NRS), per Section 6.3.3.6.  
Details are provided in the study reference manual. 
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6.3.1.2. 
Physical Examination 
A thorough and complete physical examination, including weight, height, will be performed at 
time points according to Section 6.2. Care should be taken to examine and assess any abnormalities 
that may be present, as indicated by the patient’s medical history. 
6.3.2. 
Safety Procedures 
6.3.2.1. 
Vital Signs 
Sitting vital signs, including heart rate, blood pressure, body temperature, and respiration rate, will 
be collected predose at time points according to Section 6.2.  Vital signs will be taken at 30 (+/-10) 
minutes post-injection at visit 2 during the in-clinic 30-minute post-injection observation. 
6.3.2.2. 
Ophthalmological Examination 
This exam will be performed for certain patients of interest, as decided by the sponsor medical 
monitor in consultation with the investigator, at select study centers that have access and can refer 
patients to an eye specialist, either a General ophthalmologist or a Cornea and External Eye 
Disease (‘front-of-the-eye’) subspecialty expert.  Any baseline findings will be documented as part 
of the patient’s medical history and/or physical exam, as appropriate.  Any inflammatory 
ophthalmological condition that occurs post-baseline will be captured as an AE.  Additional tests 
and assessments may be performed to help understand the AEs.  The method and procedure for 
the exam are provided in the study reference manual. 
6.3.2.3. 
Injection Site Reaction  
Clinical staff may photograph the site and complete the ISR electronic case report form (eCRF), 
in the event a patient experiences a visible ISR.  Instructions for taking the photograph are provided 
in the study reference manual. 
6.3.2.4. 
Laboratory Testing 
Hematology, chemistry and serum pregnancy samples will be analyzed by a central laboratory. 
Blood samples for serum chemistry 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.  
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 6.2.  Tests 
will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin1 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen (BUN) 
Low-density lipoprotein (LDL) 
Carbon dioxide 
AST 
High-density lipoprotein (HDL) 
Calcium 
ALT 
Triglycerides 
Glucose 
Alkaline phosphatase 
Uric acid 
Albumin 
Lactate dehydrogenase (LDH) 
CPK1 
 
 
 
1 Direct and indirect bilirubin will be measured when the total bilirubin is above the ULN; CPK isoenzymes will 
be measured when CPK >5X the ULN 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Other Laboratory Tests 
Pregnancy testing will be performed for all women of childbearing potential.  Serum or urine 
pregnancy testing will be performed at time points according to Section 6.2. 
Testing for HIV antibody will be performed at screening; however, HIV testing is not required at 
screening for patients with a negative HIV result in the parent study within 1 year prior to baseline.  
Testing for HBsAg, HBcAb, and hepatitis C antibody will be performed at screening but an 
individual test is not required if patients had a negative result for the respective test within 1 year 
prior to baseline.   
Additional tests may be required to verify eligibility, or to clarify or help manage AEs.  Any 
laboratory tests that are not specifically noted in the protocol require written approval from the 
medical monitor. 
Abnormal Laboratory Values and Laboratory Adverse Events 
• All laboratory values must be reviewed by the investigator or authorized designee. 
• Significantly abnormal tests must be repeated to confirm the nature and degree of the 
abnormality.  When necessary, appropriate ancillary investigations should be initiated.  
If the abnormality fails to resolve or cannot be explained by events or conditions 
unrelated to the study medication or its administration, the medical monitor must be 
consulted. 
• The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 7.2.5. 
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6.3.3. 
Efficacy Procedures 
6.3.3.1. 
Investigator’s Global Assessment 
The IGA is an assessment scale used in clinical studies to determine severity of AD and clinical 
response to treatment based on a 5-point scale ranging from 0 (clear) to 4 (very severe).  The IGA 
score will be assessed at time points according to Section 6.2. 
The IGA is provided in the study reference manual. 
6.3.3.2. 
Eczema Area and Severity Index 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin 2001).  Four AD disease characteristics will 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, arms, and legs, 
and converted to a score of 0 to 6.  The EASI will be collected at time points according to 
Section 6.2. 
The EASI assessment tool is provided in the study reference manual. 
6.3.3.3. 
Patient Oriented Eczema Measure 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults (Charman 2004).  The format is a response to 7 items 
(dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) with a scoring system of 0 
to 28; a high score is indicative of a poor QOL.  The questionnaires will be administered only to 
the subset of patients who fluently speak the language for which a validated translation of the 
questionnaire is available, at time points according to Section 6.2. 
The POEM is provided in the study reference manual. 
6.3.3.4. 
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 (Badia 1999).  The format is a simple 
response to 10 items, 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.  The questionnaires will be administered only to 
the subset of patients who fluently speak the language for which a validated translation of the 
questionnaire is available, at time points according to Section 6.2. 
The DLQI is provided in the study reference manual. 
6.3.3.5. 
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 as 
a measure of health related QOL, defines health in terms of 5 dimensions:  mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression.  Each dimension has 3 ordinal levels of 
severity:  “no problem” (1), “some problems” (2), “severe problems” (3).  Overall health state is 
defined as a 5-digit number.  Health states defined by the 5-dimensional classification can be 
converted into corresponding index scores that quantify health status, where 0 represents “death” 
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and 1 represents “perfect health.”  The questionnaires will be administered only to the subset of 
patients who fluently speak the language for which a validated translation of the questionnaire is 
available, at time points according to Section 6.2. 
The EQ-5D is provided in the study reference manual. 
6.3.3.6. 
Pruritus Numerical Rating Scale 
The Pruritus NRS is a simple assessment tool that patients will use to report the average intensity 
of their pruritus (itch), during a 1 week recall period.  Patients will access the IVRS/IWRS weekly, 
preferably around the same time each week, and be asked the following question: 
• For average itch intensity: “On a scale of 0 – 10, with 0 being ‘no itch’ and 10 being 
the ‘worst itch imaginable’, how would you rate your itch overall, which is on 
average, during the past week?” 
Patients will be trained on using the IVRS/IWRS to record their Pruritus NRS score at the baseline 
visit, and visit 6, and will be queried by site staff for compliance at each scheduled (and any 
unscheduled) clinic visit.  Patients will complete the rating scale weekly through the last study 
visit, according to Section 6.2. 
6.3.4. 
Pharmacokinetic and Antibody Procedures 
6.3.4.1. 
Drug Concentration Measurements and Samples 
Samples for drug concentration will be collected at time points listed in Section 6.2.  Any unused 
serum samples collected for drug concentration measurements may be used to investigate 
unexpected AEs. 
6.3.4.2. 
Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Section 6.2. 
Patients who test positive for ADA at their last study visit (early termination or end of study) may, 
based on the benchmark ADA titer in effect at the time, be asked to return to the clinic to have 
additional ADA samples collected for analysis within 6 to 12 months after their last dose of study 
drug, and thereafter at intervals of approximately 3 to 6 months until their titers fall below the 
benchmark titer. 
6.3.5. 
Research Testing 
Per amendment 6, research samples, optional genomics sub-study, and biomarker testing 
assessments will no longer be collected. 
Any samples left over may be used to investigate unexpected AEs.  Residual samples will be stored 
for up to 15 years after the study closes for exploratory research purposes. 
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7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
7.1. 
Definitions 
7.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of the study drug. 
7.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated to 
study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a more 
severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital (any duration) or an 
emergency room visit for longer than 24 hours.  Prolongation of existing hospitalization is 
defined as a hospital stay that is longer than was originally anticipated for the event, or is 
prolonged due to the development of a new AE as determined by the investigator or treating 
physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of one’s 
ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or may 
require intervention to prevent 1 of the other serious outcomes listed above (eg, intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias 
or convulsions that do not result in hospitalization; or development of drug dependency or 
drug abuse). 
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7.2. 
Recording and Reporting Adverse Events 
7.2.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of the study.  Refer to the study reference manual for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 7.2.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 7.2.5. 
7.2.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug must be reported to the 
sponsor (or designee) and entered into the electronic data capture (EDC) system within 24 hours 
of identification.  Refer to the study reference manual for the procedure to be followed. 
Information not available at the time of the initial report must be documented in a follow-up report.  
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
The investigator must promptly report to the IRB/EC all unanticipated problems involving risks to 
patients.  This includes death from any cause and all SAEs related to the use of the study drug.  It 
is recommended that all SAEs be reported to the IRB/EC, regardless of assessed causality. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
• SAE with an onset within 30 days of the end of study/early termination visit - the 
SAE will be reported to the sponsor.  The investigator should make every effort to 
obtain follow-up information on the outcome until the event is considered chronic 
and/or stable. 
• SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
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7.2.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female patient during the study or within 12 weeks of 
the last dose of study drug. Any complication of pregnancy affecting a female study 
patient and/or fetus and/or newborn, must be reported as an SAE. 
Adverse Events of Special Interest: 
AEs of special interest (AESIs) will be entered into 
the EDC system within 24 hours of identification.  The site will also notify the 
Regeneron medical monitor of the AESIs within 24 hours of identification. 
Adverse events of special interest in this study include: 
• Anaphylactic reactions  
• Systemic hypersensitivity reactions 
• Helminthic infections 
• Any severe type of conjunctivitis or blepharitis 
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms) 
Additional AESIs for the sub-study using the new dupilumab drug product: 
• Any serious or severe ISR or any ISR lasting longer than 24 hours. 
Refer to the study reference manual for the procedures to be followed. 
7.2.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
Refer to the study reference manual for the procedures to be followed. 
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7.2.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
• the test result is associated with accompanying symptoms, and/or 
• the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the medical monitor in the event the investigator feels that an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 7.3.1. 
7.2.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
7.3. 
Evaluation of Severity and Causality 
7.3.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
• Mild:  Does not interfere in a significant manner with the patient’s normal functioning 
level.  It may be an annoyance.  Prescription drugs are not ordinarily needed for relief of 
symptoms, but may be given because of personality of the patient. 
• Moderate:  Produces some impairment of functioning but is not hazardous to health.  It is 
uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
• Severe:  Produces significant impairment of functioning or incapacitation and is a definite 
hazard to the patient’s health.  Treatment for symptom may be given and/or patient 
hospitalized. 
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7.3.2. 
Evaluation of Causality 
The relationship of AEs to study drug is a clinical decision that will be made, based on all 
available information, by the investigator, who will answer the following question: 
Is there a reasonable possibility that the AE was caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the study 
drug 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug (ie, a causal relationship cannot reasonably be ruled out) 
The investigator will provide a comment on the SAE reporting form to explain the basis of the 
causality assessment for SAEs. 
7.3.2.1 Causality Evaluation Factors 
Factors to consider when determining the relationship of an AE to study drug are included below. 
Not Related: 
• Existence of a clear alternative explanation or nonplausibility (eg, the patient is struck by 
an automobile when there is no indication that the drug caused disorientation, or cancer 
diagnosed a few days after first drug administration) 
• Due to external causes such as other treatment/s being administered 
• Due to the patient’s disease state or clinical condition 
• Does not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
• Does not reappear or worsen when dosing with study drug is resumed (ie, negative 
re-challenge) 
• Is not a known response to the study drug based upon preclinical data or prior clinical data 
Related: 
• Could not be explained by other treatment/s being administered 
• Could not be explained by the patient’s disease state or clinical condition 
• Follows a reasonable temporal sequence following the time of administration of the dose 
of study drug 
• Resolves or improves after discontinuation of study drug 
• Reappears or worsens when dosing with study drug is resumed (ie, positive re-challenge) 
• Known to be a response to the study drug based upon preclinical data or prior clinical data 
• Known to be strongly associated with drug exposure (eg, angioedema, Stevens-Johnson 
Syndrome) 
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7.4. 
Safety Monitoring 
The investigator will monitor the safety of study patients at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The medical monitor will have primary responsibility for 
the emerging safety profile of the compound.  The study monitor will be supported by other 
departments (eg, Pharmacovigilance and Risk Management; Biostatistics and Data Management).  
Safety monitoring will be performed on an on-going basis (eg, individual review of SAEs) and on 
a periodic cumulative aggregate basis. 
7.5. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the Investigator’s 
Brochure, and has a reasonable suspected causal relationship to the medicinal/investigational 
product). 
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8. 
STUDY VARIABLES 
8.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), disease 
characteristics including medical history, and medication history for each patient. 
8.2. 
Primary and Secondary Endpoints 
8.2.1. 
Primary Endpoint 
• The primary endpoint in the study is the incidence and rate (events per patient-year) 
of treatment-emergent adverse events (TEAEs) through the last study visit. 
8.2.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Key secondary endpoints 
− Incidence and rate (events per patient-year) of SAEs and AESIs 
− Proportion of patients with IGA = 0-1 at each visit 
− Proportion of patients with EASI-75 (≥75% reduction in EASI scores from 
baseline of the parent study) at each visit 
• Other secondary endpoints: 
− Proportion of patients with low disease activity state (eg, IGA ≤2) at each visit 
− Change and percent change from baseline in EASI score at each visit 
− Proportion of patients with EASI-50 (≥50% reduction in EASI scores from 
baseline of the parent study) at each visit 
− Proportion of patients with EASI-90 (≥90% reduction in EASI scores from 
baseline of the parent study) at each visit 
− Change and percent change from baseline in Pruritus NRS 
− Proportion of patients with improvement (reduction) of Pruritus NRS ≥3 from 
baseline 
− Proportion of patients with improvement (reduction) of Pruritus NRS ≥4 from 
baseline 
− Proportion of patients requiring rescue treatment: 
▪ Overall 
▪ Systemic treatment 
▪ Systemic corticosteroids 
▪ Systemic immunosuppressive drugs 
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▪ Phototherapy 
− Number of days on topical medication (per patient-year) 
− Proportion of patients using topical medications over various periods during the 
study 
− Changes from baseline to prespecified time points through the end of the study: 
▪ DLQI  
▪ POEM 
▪ EQ-5D 
8.2.3. 
Sub-Study Endpoints 
Primary Endpoints 
• Incidence of AESIs through the last study visit after switching to the new dupilumab 
drug product. 
Secondary Endpoints 
• Trough concentrations (Ctrough) of functional dupilumab in serum before and after 
switching to the new dupilumab drug product 
• Incidence of treatment-emergent ADA response in patients receiving the new 
dupilumab drug product 
Exploratory Endpoints 
− Proportion of patients with IGA = 0 or 1 before (at sub-study week 0a [sub-study 
baseline]) and after switching to new dupilumab drug product (at sub-study 
week 12a) 
− Change and percent change from baseline in EASI score at each visit 
− Change and percent change from baseline in Pruritus NRS 
8.3. 
Pharmacokinetic Variables 
The PK variables in the main study may include, but are not limited to, the following: 
• Ctrough 
• Ctrough,SS 
• Clast 
• Tlast 
For the sub-study, Ctrough will be assessed. 
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8.4. 
Anti-Drug Antibody Variables 
Anti-drug antibody variables include status (positive or negative) and titer as follows: 
• Total positive at any time 
• Preexisting immunoreactivity 
• Treatment-emergent 
• Persistently positive 
• Transiently positive 
• Titer values 
• Titer category 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000) 
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9. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the main study and for 
the sub-study.  The SAP may be revised during the study (including sub-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. 
Data collected through the implementation of new case report forms (CRFs) regarding the impact 
of the COVID-19 pandemic on the patients will be summarized (eg, discontinuation due to 
COVID-19).  Any additional analyses and methods required to investigate the impact of 
COVID-19 on the efficacy (eg, missing data due to COVID-19) and safety will be detailed in the 
SAP. 
Analysis variables are listed in Section 8. 
9.1. 
Statistical Hypothesis 
There is no statistical hypothesis in this open-label study. 
9.2. 
Justification of Sample Size 
No formal sample size or power calculations were performed for this study. 
9.3. 
Analysis Sets 
9.3.1. 
Safety Analysis Set 
The safety analysis set (SAF) includes all patients who received any study drug; it is based on the 
treatment received (as treated).  Efficacy, treatment compliance/administration, and all clinical 
safety variables will be analyzed using the SAF, as treated. 
9.3.2. 
Pharmacokinetic Analysis Set 
The PK population includes all treated patients who received any study drug and who had a 
qualified result for drug concentration at any time during the study. 
9.3.3. 
Analysis Set for Anti-Drug Antibody Data 
The ADA population includes all treated patients who received any study drug and had at least 
1 qualified result at any time during the study. 
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9.4. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
9.5. 
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. 
9.5.1. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively. 
9.5.2. 
Safety Analysis 
Safety analysis will be based on the SAF.  A summary of safety results will be presented. 
9.5.2.1. 
Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The treatment-emergent period is defined as day 1 (from start of administration of the 
first dose of study drug) to end of study. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a preexisting condition during the treatment-emergent period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
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Summaries of all TEAEs will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 7.3.1), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
Deaths and other SAEs will be listed and summarized. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized. 
9.5.2.2. 
Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a treatment-emergent potentially clinically significant 
value (PCSV) will be summarized for each clinical laboratory test. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
9.5.2.3. 
Treatment Exposure 
The duration of exposure during the study will be presented and calculated as: 
QW dosing: (Date of last study drug injection – date of first study drug injection) + 7 days, 
Q2W dosing: (Date of last study drug injection – date of first study drug injection) + 14 days. 
The number (%) of patients exposed to study drug will be presented by specific time periods.  The 
time periods of interest will be specified in the SAP. 
In addition, duration of exposure during the study will be summarized using number of patients, 
means, standard deviation, minimums, medians, and maximums. 
A summary of the number of doses will be provided. 
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9.5.2.4. 
Treatment Compliance 
The compliance with protocol-defined investigational product will be calculated as follows: 
Treatment Compliance =  
(Number of investigational product injections during exposure period)/(Number of planned 
investigational product injections during exposure period) x 100% 
The treatment compliance will be presented by specific ranges.  The ranges of interest will be 
specified in the SAP. 
9.5.3. 
Efficacy Analyses 
Descriptive statistics of the efficacy endpoints will be summarized for this open-label study.  These 
include the proportions for category endpoints and basic statistics of original, absolute, and 
percentage change from baseline for continuous endpoints. 
All observed data will be used for analysis. 
Subgroup analyses for key efficacy endpoints will be performed.  The subgroup of interest and 
endpoints to be analyzed will be specified in the SAP. 
9.5.4. 
Analysis of Drug Concentration Data 
The following analyses may be conducted: 
• Sparse sampling: 
− Descriptive statistics at each sampling time 
− Mixed model analysis of variance of steady-state trough concentrations to 
determine between- and within-subject variability, as well as least square means  
No formal statistical analysis will be performed. 
9.5.5. 
Analysis of Anti-Drug Antibody Data 
The ADA variables described in Section 8.4 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 the impact of ADA on safety and efficacy may be 
provided. 
9.5.6. 
Analysis of the Sub-Study 
Demographic and baseline characteristics will be summarized descriptively.  Safety analyses will 
be conducted in descriptive fashion as described in Section 9.5.2.1 and Section 9.5.2.2.  Efficacy 
analyses will be conducted in descriptive fashion as described in Section 9.5.3.  Treatment 
compliance and treatment exposure will be analyzed in a similar fashion as described in 
Section 9.5.2.3 and Section 9.5.2.4. 
Under Amendment 10, a primary analysis of the sub-study is planned once all patients who enter 
the sub-study complete 12 weeks of the new dupilumab drug product treatment period (sub-study 
week 12a visit or earlier for those patients who are withdrawn prematurely from the study). 
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9.5.6.1. 
Statistical Hypothesis for the Sub-Study  
There is no statistical hypothesis for the sub-study. 
9.5.6.2. 
Justification of the Sub-Study Sample Size  
No formal sample size or power calculations were performed for the sub-study.  
9.5.6.3. 
Analysis Sets for the Sub-Study 
Safety Analysis Set:  
The sub-study SAF includes all patients who receive any new dupilumab drug product in the sub-
study.  Efficacy, treatment compliance/administration, and all clinical safety variables will be 
analyzed using the SAF, as treated. 
Pharmacokinetic Analysis Sets:  
The sub-study PK population includes all treated patients who enter the sub-study (implemented 
under amendment 10), who receive any new dupilumab drug product, and who have a qualified 
result for drug concentration at any time during the sub-study period. 
Anti-Drug Antibody Analysis Set 
The sub-study ADA population includes all treated patients who receive any new dupilumab drug 
product and have at least 1 qualified result at any time during the sub-study period after the first 
dose of new dupilumab drug product.  All ADA analysis will be conducted using this population.  
9.5.6.4. 
Statistical Methods for Sub-Study 
Safety Analysis: 
Summaries of AESIs will include: 
• Treatment-emergent AESIs presented by AESI category, high-level term, and PT 
• The number (n) and proportion (%) of patients with at least 1 treatment-emergent 
AESI by AESI category, high-level term, and PT 
• Exposure-adjusted treatment-emergent AESIs presented by AESI category, high-level 
term, and PT 
Summaries of all TEAEs will include: 
• The number (n) and proportion (%) of patients with at least 1 TEAE by SOC and PT 
• The number (n) and proportion (%) of patients with at least 1 SAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 7.3.1), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• TEAEs leading to permanent treatment discontinuation presented by SOC and PT 
Deaths and other SAEs will be listed and summarized. 
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Treatment-emergent adverse events occurring before and after switching to the new dupilumab 
drug product will be summarized and listed separately using the SAF of the sub-study.   
PK Analysis: 
Trough concentrations of dupilumab will be summarized using descriptive statistics at each 
sampling time point including n, mean, median, standard deviation, geometric mean (as 
appropriate), coefficient of variation (if appropriate), and minimum and maximum values. 
ADA Analysis: 
Listings of ADA positivity, treatment-emergent ADA, and titers presented by patient and time 
point will be provided.  Incidence of treatment-emergent ADA will be assessed as absolute 
occurrence (N) and percent of patients (%) grouped by ADA titer level.  The ADA variables will 
be summarized and listed by before (sub-study week 0a) and after switching to the new dupilumab 
drug product using the SAF of the sub-study.  Additional details of ADA data analysis for the 
sub-study will be provided in the SAP. 
Efficacy Analysis:   
The efficacy endpoints will be summarized using descriptive statistics.  These include the 
proportions for categorical endpoints and basic statistics of original, absolute, and percentage 
change from baseline for continuous endpoints. 
All observed data will be used for analysis. 
All efficacy endpoints will be summarized by before and after switching to the new dupilumab 
drug product using the SAF of the sub-study. 
9.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline: 
• The baseline assessment will be the latest, valid predose assessment available. 
General rules for handling missing data: 
• If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed, 
otherwise, the missing day or month by the first day or the first month will be imputed. 
• No imputations for missing laboratory data, electrocardiogram data, vital sign data, or 
physical examination data will be made. 
Visit windows: 
• Assessments taken outside of protocol allowable windows will be displayed according 
to the CRF assessment recorded by the investigator. 
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Unscheduled assessments: 
• Extra assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries.  If more than 1 laboratory value is available for a given 
visit, the first observation will be used in summaries and all observations will be 
presented in listings. 
9.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
10.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, medication, medical history/surgical history) will be done using internationally 
recognized and accepted dictionaries. 
The CRF data for this study will be collected with an EDC tool. 
10.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system –study drug supply, patient dosing and pruritus assessment 
• EDC system – data capture 
• Statistical Analysis Software (SAS) – statistical review and analysis 
• PVRM Safety System 
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11. 
STUDY MONITORING 
11.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study.  In accordance 
with ICH guidelines, the monitor will compare the CRF entries with the appropriate source 
documents.  Additional review may include, but is not limited to, patient ICFs, documentation of 
patient recruitment and follow-up, AEs, SAEs, and concomitant therapy; as well as records of 
study drug dispensing, compliance, and accountability.  A copy of the drug dispensing log must 
be provided to the sponsor upon request. 
11.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
11.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs by 
trained site personnel.  A CRF must be completed for each and every patient enrolled in the study.  
After review of the clinical data for each patient, the investigator must provide an electronic 
signature.  A copy of each CRF page is to be retained by the investigator as part of the study record 
and must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the system.  For corrections made via data queries, a reason for any alteration must 
be provided. 
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12. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH Guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study medication will be shipped to the study 
site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient.   
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient's study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient. 
13.3. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by their initials and a patient identification 
number, only, on CRFs or other documents submitted to the sponsor.  Documents that will not be 
submitted to the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient's and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
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13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH Guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB/EC should be informed as soon as possible 
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk 
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design or operation of the protocol or ICF without 
an IRB/EC-approved amendment. 
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines 
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
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16. 
STUDY DOCUMENTATION 
16.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRFs must be signed 
by the investigator.  This certification form accompanies each set of CRFs.  The signed form will 
be provided to the sponsor with the final set of CRFs for each patient. 
16.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer if a longer period is required by relevant 
regulatory authorities.  The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  Records 
must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
17. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
18. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
19. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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20. 
REFERENCES 
Abdel-Razzak Z, Loyer P, et al. Cytokines down-regulate expression of major cytochrome p-450 
enzymes in adult human hepatocytes in primary culture. Mol. Pharmacol 1993; 44(4):707-715. 
Akhavan A, Rudikoff D. (2008). “Atopic dermatitis: systemic immunosuppressive therapy.” 
Semin Cutan Med Surg 27:151-155. 
Badia X, Mascaro JM, et al. (1999). “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 141:698-702. 
Beiber T. (2008). “Mechanisms of disease: atopic dermatitis.” N Engl J Med 358:1483-94. 
Charman CR, Venn AJ, et al. (2004). “The patient-oriented eczema measure.” Arch Dermatol 
140:1513-1519. 
Christensen H and Hermann M. Immunological response as a source to variability in drug 
metabolism and transport. Frontiers in pharmacology 2012; Vol 3:Art 8. 
Eichenfield LF, Tom WL, Chamlin SL, 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):338-351. 
Hanifin JM, Thurston M, et al. (2001). “The eczema area and severity index (EASI): assessment 
of reliability in atopic dermatitis.” Exp Dermatol 10: 11-18. 
Liptrott NJ, Penny M, et al. The impact of cytokines on the expression of drug transporters, 
cytochrome P 450 enzymes and chemokine receptors in human PBMC.  Brit J Pharmacol 2009; 
156:497–508. 
Schmitt J, Schmitt N, et al. (2007). “Cyclosporin in the treatment of patients with atopic eczema-a 
systematic review and meta-analysis.” JEADV 21: 606-619. 
Schmitt J, Schakel K, et al. (2009). “Prednisolone vs. ciclosporin for severe adult eczema.  An 
investigator-initiated double-blind placebo-controlled multicentre trial.” Brit J Dermatol journal 
compilation:1-8. 
Schram ME, Spuls PI, et al. (2012). “EASI, (objective) SCORAD and POEM for atopic eczema: 
responsiveness and minimal clinically important difference.” Allergy 67:99-106. 
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21. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: AN OPEN-LABEL STUDY OF DUPILUMAB IN PATIENTS 
WITH ATOPIC DERMATITIS WHO PARTICIPATED IN PREVIOUS DUPILUMAB 
CLINICAL TRIALS, and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study and the 
data generated. 
Study Title: 
An Open-Label Study of Dupilumab in Patients with Atopic Dermatitis 
who Participated in Previous Dupilumab Clinical Trials 
Protocol Number: 
R668-AD-1225  
Protocol Version: 
R668-AD-1225 Amendment 10 
 
See appended electronic signature page 
 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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Signature Page for VV-RIM-00152209 v1.0
Signature Page for VV-RIM-00152209 v1.0 Approved
ESig Approval
y-2021 21:26:40 GMT+0000
ESig Approval
21 21:31:48 GMT+0000
ESig Approval
-2021 21:35:38 GMT+0000
ESig Approval
000
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SAP_001.pdf: 
Regeneron Pharmaceuticals, Inc. 
R668-AD-1225 
Statistical Analysis Plan 
February 01, 2019 
CONFIDENTIAL 
Page 1 of 107 
Title: 
An Open-Label Study of Dupilumab in Patients 
With Atopic Dermatitis Who Participated In 
Previous Dupilumab Clinical Trials  
Protocol: 
R668-AD-1225.07 and  
R668-AD-1225.08 (PL, FI, FR) 
Investigational product: 
Dupilumab (REGN668) 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Statistician: 
. 
Clinical Trial Manager: 
 
Clinical Study Director: 
 
Version/Date: 
Version 2.0 Final / 01Feb2019 
VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00
NCT01949311


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 2 of 107 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
Study Biostatistician  
See appended electronic signature page 
 (Author) 
 
Study Medical Director 
“See appended electronic signature page 
 (Approver) 
 
Head of BDM or designee 
“See appended electronic signature page 
 (Approver) 
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R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 3 of 107 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background and Rationale ............................................................................................9 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objective .......................................................................................................11 
1.2.2. 
Secondary Objectives..................................................................................................11 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................11 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan ......................................12 
2. 
INVESTIGATIONAL PLAN .....................................................................................14 
2.1. 
Study Design and Randomization ...............................................................................14 
2.2. 
Sample Size and Power Considerations .....................................................................14 
2.3. 
Study Plan (Schedule of Study Assessment) ..............................................................14 
3. 
ANALYSIS POPULATIONS .....................................................................................21 
3.1. 
The Safety Analysis Set (SAF) ...................................................................................21 
3.2. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................21 
3.3. 
The Anti-Drug Antibody (ADA) Analysis Set (AAS) and Neutralizing 
Antibody (NAb) Analysis Set (NAS) .........................................................................21 
4. 
ANALYSIS VARIABLES .........................................................................................22 
4.1. 
Demographic and Baseline Characteristics in Current Study .....................................22 
4.2. 
Characteristics of Patient Status in Parent Studies .....................................................23 
4.3. 
Medical History and Atopic Disease Medical History ...............................................24 
4.4. 
Pre-treatment / Concomitant Medications and Procedures .........................................25 
4.5. 
Efficacy Variables .......................................................................................................26 
4.6. 
Safety Variables ..........................................................................................................30 
4.6.1. 
Adverse Events and Serious Adverse Events Variables .............................................30 
4.6.2. 
Laboratory Safety Variables .......................................................................................33 
4.6.3. 
Vital Sign Variables ....................................................................................................33 
4.6.4. 
12-Lead Electrocardiography (ECG) Variables ..........................................................34 
4.6.5. 
Physical Examination Variables .................................................................................34 
4.6.6. 
Ophthalmological Examination ..................................................................................34 
4.7. 
Pharmacokinetic (PK) Variables ................................................................................35 
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4.8. 
Antibody (ADA) Variable ..........................................................................................35 
4.9. 
Biomarkers Variables .................................................................................................35 
5. 
STATISTICAL METHODS .......................................................................................36 
5.1. 
Demographics and Baseline Characteristics ...............................................................36 
5.1.1. 
Demographics and Baseline Characteristics of Current Study ...................................36 
5.1.2. 
Characteristics in Parent Study ...................................................................................36 
5.2. 
General Medical History and AD History ..................................................................36 
5.3. 
Pre-treatment/Concomitant Medications/Procedures .................................................37 
5.4. 
Subject Disposition .....................................................................................................37 
5.5. 
Dupilumab Dose administration .................................................................................38 
5.6. 
Treatment Exposure and Observation Period .............................................................39 
5.7. 
Analyses of Efficacy Variables ...................................................................................40 
5.8. 
Analysis of Safety Data...............................................................................................42 
5.8.1. 
Adverse Events ...........................................................................................................42 
5.8.2. 
Clinical Laboratory Measurements .............................................................................43 
5.8.3. 
Analysis of Vital Signs ...............................................................................................44 
5.8.4. 
Physical Exams ...........................................................................................................44 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................44 
5.8.6. 
Analysis of Ophthalmological Examination ...............................................................44 
5.9. 
Analysis of Pharmacokinetic Data ..............................................................................45 
5.10. 
Analysis of ADA Data ................................................................................................46 
5.10.1. 
Analysis of ADA Data ................................................................................................46 
5.10.2. 
Analysis of Neutralizing Antibodies (NAb) ...............................................................46 
5.11. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................47 
5.11.1. 
Immunogenicity and Exposure ...................................................................................47 
5.11.2. 
Immunogenicity and Treatment Gaps .........................................................................47 
5.11.3. 
Immunogenicity and Safety and Efficacy ...................................................................47 
5.12. 
Analyses of Biomarkers ..............................................................................................48 
5.12.1. 
Analyses of Biomarkers ..............................................................................................48 
5.12.2. 
“Normalization” Biomarker Data Related Evaluations ..............................................49 
6. 
DATA CONVENTIONS ............................................................................................51 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................51 
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6.2. 
General Data Handling Conventions ..........................................................................51 
6.3. 
Data Handling Convention Missing Data ...................................................................51 
6.4. 
Analysis Visit Window ...............................................................................................54 
7. 
INTERIM ANALYSIS ...............................................................................................59 
8. 
SOFTWARE ...............................................................................................................59 
9. 
REFERENCES ...........................................................................................................60 
10. 
APPENDIX .................................................................................................................61 
10.1. 
Summary of Statistical Analyses ................................................................................61 
10.2. 
Schedule of Events .....................................................................................................62 
10.3. 
Criteria for Treatment-Emergent Potentially Clinical Significant Value ...................89 
10.4. 
SAS code for EQ-5D index utility scoring .................................................................94 
10.5. 
Exposure-Adjusted Analyses ......................................................................................95 
10.6. 
Search Criteria for TEAE of Special Interest/TEAE Syndrome .................................96 
10.7. 
Process to Derive Data Cut-off for the First Step Analysis ......................................100 
10.8. 
Process to Derive Data Cut-off for the Second Step Analysis ..................................102 
10.9. 
Algorithm to Add Not Reported Home Study Drug Injection Records Based 
on Drug Accountability Data for First Step analysis ................................................104 
10.10. 
Algorithm to Derive Treatment Exposure and Duration of Observational 
period ........................................................................................................................106 
 
LIST OF TABLES 
Table 1: 
Summary of Modification from the Approved Statistical Analysis Plan ...................12 
Table 2: 
Study dose level and study duration under each protocol version ..............................15 
Table 3: 
External/Internal Reference Estimates of TARC ........................................................50 
Table 4: 
Schedule of Events – Visits 1 through 8 (Week 12) ...................................................62 
Table 5: 
Schedule of Events – Visits 9 (Week 16) through 18 (Week 52) ...............................65 
Table 6: 
Schedule of Events – Visits 19 (Week 60) through 24 (Week 100) ...........................67 
Table 7: 
Schedule of Events – Visits 25 (Week 108) through End of Study 
(Week 160) .................................................................................................................69 
Table 8: 
Schedule of Events – Visits 1 through 8 (Week 12) ...................................................72 
Table 9: 
Schedule of Events – Visits 9 (Week 16) through 18 (Week 52) ...............................75 
Table 10: Schedule of Events – Visits 19 (Week 60) through 24 (Week 100) ...........................77 
Table 11: Schedule of Events – Visits 25 (Week 108) through Visit 30 (Week 148) ................79 
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Table 12: Schedule of Events – Visits 31 (Week 156) through Visit 36 (Week 196) ................81 
Table 13: Schedule of Events – Visits 37 (Week 204) through Visit 43 (Week 252) ................83 
Table 14: Schedule of Events – End of Treatment, End of Study, Early Termination, 
Unscheduled Visit, and Re-entry Visit .......................................................................85 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Flow Diagram Showing the Treatment Gap due to Protocol 
Amendment 7 and 8 ....................................................................................................16 
Figure 2: 
Study Flow Diagram for Protocol Amendment 7 (Global) ........................................17 
Figure 3: 
Study Flow Diagram for Protocol Amendment 7 (UK) ..............................................18 
Figure 4: 
Study Flow Diagram for Protocol Amendment 7 (France, Germany, Poland, 
Japan) ..........................................................................................................................18 
Figure 5: 
Study Flow Diagram for Protocol Amendment 8 (Poland, Finland) ..........................19 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AD 
Atopic dermatitis 
ADA 
Anti-Drug Antibodies 
AE 
Adverse event 
ALT (SGOT) 
Alanine aminotransferase 
AST (SGPT) 
Aspartate aminotransferase 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CRF 
Case report form 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema area and severity index 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
GB 
Great Britain 
HLT 
High Level Term 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IGA 
Investigator global assessment 
IL 
Interleukin 
IgE 
Immunoglobulin E 
LDH 
Lactate dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numerical rating scale 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
POEM 
Patient Oriented Eczema Measure 
PT 
Preferred term 
q2w 
Once every 2 weeks 
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q4w 
Once every 4 weeks 
QOL 
Quality of life 
qw 
Once every week 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SCORAD 
SCORing atopic dermatitis 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
WHODD 
World health organization drug dictionary 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying statistical approaches for the analysis of 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 R668-AD-1225 study. Since this is an open-label, non placebo-controlled 
extension study, there is no hypothesis testing to be performed. Descriptive statistics will be used 
to summarize efficacy data from this 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 review of the study and data. Furthermore, the SAP will be updated for any possible 
subsequent regulatory filings to clarify the data cutoff used for each regulatory filing. 
1.1. 
Background and Rationale 
Atopic dermatitis (AD) is a chronic/relapsing inflammatory skin disease characterized by intense 
pruritus and by scaly and dry eczematous lesions. It is often associated with other atopic 
disorders, such as allergic rhinitis and asthma. Severe disease can be extremely disabling due to 
major psychological problems, significant sleep loss, and impaired quality of life that leads to 
high socioeconomic costs. In industrialized countries the prevalence of AD is estimated to be 15 
to 30% for children and 2 to 10% for adults and occurs most often in infants and children with 
approximately 70 to 85% of cases starting before 5 years of age. Sixty percent of patients with 
childhood AD are free of symptoms by early adolescence but for 40% the disease continues 
beyond adolescence. The overall costs for AD are estimated to be similar to those for the 
treatment of asthma, and in the US the estimated direct costs range from $400 million to 
$4 billion. 
The pathophysiology of AD is influenced by a complex interplay between Immunoglobulin E 
(IgE)-mediated sensitization, the immune system, and environmental factors. The primary skin 
defect may be an immunologic disturbance that causes IgE-mediated sensitization, with 
epithelial-barrier dysfunction that is the consequence of both genetic mutations and local 
inflammation. 
Skin-infiltrating lymphocytes are thought to play a pivotal role in the initiation and amplification 
of atopic inflammation. The key cells involved in the patho-physiologic 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 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 (Th1) cells 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 
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pathophysiology of AD. These skin cells express high levels of the Th2-polarizing cytokine, 
thymic stromal lymphopoietin (TSLP), in AD lesions which may amplify and sustain the allergic 
response. 
The goal in treating AD is to reduce skin inflammation and relieve symptoms. Therapy has been 
focused on trying to control the T helper cell response. The pharmacological treatment of AD is 
primarily conducted with topical medications. Topical corticosteroids are the most frequently 
prescribed class of drugs; however, long term application of topical corticosteroids is not 
recommended because of the risk of irreversible skin atrophy, dyspigmentation, acneiform 
eruptions, and risks associated with systemic absorption. Topical calcineurin inhibitors are both 
effective and safe as short-term treatments, but systemic absorption raises the concern of skin 
malignancies and increased risk of lymphomas. Repeated application of any topical therapy over 
a long period of time leads to reduced patient compliance. Antihistamines, which are primarily 
sedating, are widely prescribed for acute symptomatic treatment of pruritus. 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. 
Biological agents including anti-tumor necrosis factor (TNF) α, anti IgE (omalizumab), anti-IL-5 
(mepolizumab), and anti-CD11a (efalizumab) have generally been ineffective in clinical trials. 
Up-regulation of IL-4 and IL-13 has been implicated as an important inflammatory component of 
AD disease progression. Dupilumab (the international non-proprietary name for REGN668, 
accepted by the World Health Organization and published in February 2013), 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 blockade of the function of both IL-4 and IL-13 signal 
transduction. Dupilumab is under development as a potential novel treatment for AD, an 
alternative to oral corticosteroids, calcineurin inhibitors, and other systemic immunosuppressive 
drugs such as methotrexate, cyclosporine, and azathioprine, which have numerous and 
considerable side effects. In addition, the broad immunosuppression caused by these drugs 
carries an increased risk of developing serious bacterial, fungal, viral, and mycobacterial 
infections, compared with the targeted Th2 inhibition. 
The primary purpose of the study is to collect long-term safety data on patients treated with 
dupilumab to better understand the safety profile and help fulfill the anticipated safety database 
requirements for long-term exposure. The study investigates dupilumab 300 mg qw, the higher of 
2 dose regimens administered in confirmatory Phase 3 clinical trials. Eligible patients are 
recruited from prior dupilumab controlled trials. Eligible patients must have received any study 
treatment and completed the specified assessments in the prior dupilumab controlled study or 
have been screened for a phase 3 study (R668-AD-1334 or R668-AD-1416), but could not be 
randomized because of randomization closure. This study may provide useful information 
regarding immunogenicity incidence upon re-exposure to dupilumab and any impact of 
anti-dupilumab antibodies on functional dupilumab serum (trough) concentration and associated 
clinical parameters. 
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1.2. 
Study Objectives  
1.2.1. 
Primary Objective  
The primary objective of study R668-AD-1225 is to assess the long-term safety of dupilumab 
administered to adult patients with AD.  
1.2.2. 
Secondary Objectives  
The secondary objectives of the study are to assess the immunogenicity of dupilumab in adult 
patients with AD, in the context of re-treatment, and to monitor efficacy parameters associated 
with long-term treatment. 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
The final protocol version is the global protocol amendment 7 dated 02Jun2017 followed by 
country specific protocol amendments for Great Britain (GB) dated 02Jun2017, Germany, 
Hungary and Japan dated 05Jun2017; and protocol amendment 8 for Poland dated 04Jan2018, 
Finland and France dated 08Jan2018. Below is a list of modifications from the statistical section 
in the protocol. 
 Removed the efficacy endpoint “Change and percent change from baseline in disease 
activity scores (EASI, IGA) and domains within scores at prespecified time points 
through the end of the study”. IGA score will be analyzed as a categorical variable 
instead of as continuous variable based on change and percent change from baseline 
value. The two endpoints for EASI are now written as “Percentage change from 
baseline in EASI score at each visit” and ‘Change from baseline in EASI score at each 
visit”. 
 Modified the efficacy endpoints to clarify the baseline value used to define the change 
from baseline and percent change from baseline values. 
 Removed the endpoints “Number of days on topical medication (per patient-year)”, 
and “Proportion of patients using topical medications over various periods during the 
study”, since the data collection through the concomitant medication CRFs does not 
support an accurate evaluation of these endpoints. 
 Removed the phrase “or lasting ≥ 4 weeks” condition from the AESI criteria for any 
type of conjunctivitis or blepharitis or keratitis [i.e. Any type of conjunctivitis or 
blepharitis or keratitis (severe or serious or lasting ≥ 4 weeks)] according to recent 
revision of list of AESIs across the dupilumab program in AD. 
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1.2.4. 
Modifications from the Approved Statistical Analysis Plan 
The statistical analysis plan (SAP) version 1.0 was approved on 28Apr2016 according to 
protocol amendment 4 (global) and protocol amendment 5 (local – GB) for the first step analysis. 
This SAP version 2.0 is based on protocol amendment 6 dated 05July2016, protocol 
amendment 7 
dated 
02Jun2017-05Jun2017, 
and 
protocol 
amendment 
8 
dated 
04Jan2018-08Jan2018. It is the second version of SAP for study R668-AD-1225. 
Table 1: 
Summary of Modification from the Approved Statistical Analysis Plan 
Description of statistical changes 
Rational  
 
Remove the four previous analysis subsets (Naïve, 
Re-treated, Interrupted Treatment, and Continuously 
Treated) in section 3.1. All outputs will show “total” 
column summarizing all patients’ data together. 
The layouts of all outputs are 
changed to avoid potential 
confounding factors introduced by 
between-study variation 
 
Remove the time to event endpoints in section 4.5 
 
Remove the topical medications endpoints in section 4.5 
 
Remove time to AESI, AE leading to treatment 
withdrawal analysis in section 5.8.1 
 
Remove several baseline subgroups for efficacy analysis 
in section 5.7 
o Treatment received in the parent studies  
o Parent studies 
o EASI-75 relative to baseline of parent study (≥75% 
improvement from baseline of parent study) 
responder or non-responder at the end of treatment 
visit in the parent studies.  
o IGA 0-1 responder or non-responder at the end of 
treatment visit in the parent studies.  
o Baseline IGA score of current study  
o Baseline EASI score of current study  
o Baseline moderate-to-severe EASI of current study  
o Baseline severe EASI of current study  
o Baseline NRS score of current study  
o Region for global submission 
o Region for Japan submission  
To avoid potential confounding 
introduced by between-study 
variation 
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Description of statistical changes 
Rational  
 
Add details of study design for protocol amendment 6, 7 
and 8.  
 
Clarify gaps in treatment for patients from Germany, 
Poland, France and Japan under protocol amendment 7, 
8 
 
Clarify that POEM, DLQI, EQ-5D, PGAD, PGAT, 
ECG, physical exam, research sample for biomarker 
analysis were removed starting from protocol 
amendment 6 in section 4.5 and 4.6 
 
Update the treatment exposure, compliance and duration 
of observational period calculation in section 5.5 and 
5.6 by accounting for the “off-treatment” or “off-study” 
gap introduced by protocol amendment 7 and 8 
 
Clarify the TEAE definition in section 5.8.1. AE onset 
during the “off-study” treatment gap between protocol 
amendments 6 and 7 are not considered TEAEs.  
 
Update AESI criteria and programming search algorithm 
in section 4.6.1 and section 10.6 
 
Add analysis for Ophthalmological Examination in 
section 4.6.6 and 5.8.6 
 
Update the analysis visit window mapping in section 6.4 
 
Update details of ADA analysis in section 5.10, 5.11 
 
Add a subgroup (prior treatment of dupilumab in parent 
study) for efficacy analysis in section 5.7  
To be consistent with Protocol 
amendment 6, 7, 8. 
 
Add planning of second step analysis in section 7 
 
Add Process to Derive Data Cut-off for the Second Step 
Analysis in section 10.8 
Added details of second step 
analysis   
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2. 
INVESTIGATIONAL PLAN 
2.1. 
Study Design and Randomization 
This is a multicenter, open-label extension study to assess the long-term safety and efficacy of 
repeat doses of dupilumab in adults with moderate-to-severe AD who have previously 
participated in controlled studies of dupilumab or were screened for a phase 3 study 
(R668-AD-1334 or R668-AD-1416) but could not be randomized because of randomization 
closure. There is no randomization required for entry into this OLE study.  
The parent studies include the following 14 studies. 
 R668-AD-0914 
 R668-AD-1021 
 R668-AD-1026 
 R668-AD-1117 
 R668-AD-1121 
 R668-AD-1224 
 R668-AD-1307 
 R668-AD-1314 
 R668-AD-1334 
 R668-AD-1412 
 R668-AD-1415 
 R668-AD-1416 
 R668-AD-1424 
 R668-AD-1433 
2.2. 
Sample Size and Power Considerations 
Based on the numbers of patients enrolled or screened in the antecedent dupilumab studies, it is 
anticipated that approximately 2500 patients will be enrolled in this global study. By then end of 
May2017, the study enrollment is completed. There are 2678 patients enrolled.  
No formal sample size or power calculations were performed for this study. 
2.3. 
Study Plan (Schedule of Study Assessment) 
The study consists of a screening period, a treatment period and a follow-up period.  The dose 
level, the duration of treatment period and follow-up period were modified for the study through 
several protocol amendments. These modifications are outlined in Table 1.   
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Table 2: 
Study dose level and study duration under each protocol version 
Protocol  
Version 
Country 
Dose Level 
(mg) 
Duration of  
Treatment Period 
Duration of 
Follow-up period 
Original and 
amendment 1 
Global 
200 
100 weeks 
16 weeks 
Amendment 2 and 3 
Global 
300  
100 weeks 
16 weeks 
Amendment 4 
Global 
300 
148 weeks or until 
commercially available 
16 weeks 
Amendment 5 and 6 
Great Britain 
300  
100 weeks 
16 weeks 
Amendment 6 
Global, Hungary, 
Japan 
300  
148 weeks or until 
commercially available 
16 weeks 
Amendment 7 
Global, Hungary 
300  
148 weeks or until 
commercially available 
12 weeks 
Amendment 7* 
France, Germany, 
Poland, Japan 
300  
Extend treatment 
period through 
approximately 
31 December 2017 
12 weeks 
Amendment 7 
Great Britain 
300  
100 weeks 
12 weeks 
Amendment 8** 
Poland, Finland 
300  
Extend treatment 
period to up to 5 years 
(week 260) 
12 weeks 
Amendment 8** 
France 
300  
Extend treatment 
period to 
approximately 
September 2018 
12 weeks 
*  Note:  Under protocol amendment 7 for France, Germany, Poland and Japan, patients who had already 
completed the End of Treatment visit under protocol amendment 6 were permitted to resume 
treatment with study drug. Patients who had completed the End of Study visit were permitted to re-
enter the study. The treatment period ended for all patients in these countries on or about 
31 December 2017. 
** Note:  Patients in Poland, Finland and France who had completed their End of Treatment/End of 
Study visit as per amendment 7 were permitted to resume treatment/re-enter the study provided that no 
more than 12 weeks had elapsed since their End of Study visit. The duration of the overall treatment 
period for patients in Poland and Finland was extended to 5 years, and to September 2018 for patients 
in France. 
The study flow diagrams under protocol amendment 7 and 8 are provided in Figure 2, Figure 3, 
Figure 34 and Figure 35 below: 
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Under protocol amendment 6, the planned study duration was up to three years or until 
dupilumab became commercially available in the geographic region of the patient. Protocol 
amendment 7 was adopted in order to permit those patients in France, Germany, Poland and 
Japan who had already completed three years of treatment to either continue or re-start treatment 
through 31 December 2017. Patients who were in the 16-week safety follow-up period were 
permitted to resume treatment. Patients who had an End of Study visit were permitted to re-enter 
the study after being re-consented. Patients who had completed 3 years of treatment resumed 
treatment in a newly created series of visits called the “treatment extension” period.  All patients 
were scheduled to have an End of Treatment visit on or around 31 December 2017. 
Protocol amendment 8 extended the treatment period for up to 5 years for patients in Poland and 
Finland and to September 2018 in France. Again, patients who had previously had an End of 
Treatment visit under Amendment 7 and were in the 12-week safety follow-up period were 
permitted to resume treatment. Patients who had an End of Study visit were permitted to re-enter 
the study after being re-consented. This is illustrated in Figure 1. 
As a consequence of these two amendments, certain patients from these countries experienced 
gaps in treatment. One gap occurred between the Amendment 6 end of treatment (EoT) date and 
resumption of treatment under Amendment 7 for approximately 113 patients with a median 
duration of gap around 17 weeks and maximum duration of around 33 weeks. In addition, there 
are approximately 272 patients from Poland, Finland and France who experienced a second 
treatment gap from the EoT date under Amendment 7 and resumption of treatment under 
Amendment 8 with a median duration of gap around 10 weeks and maximum duration of around 
21 weeks. 
Figure 1: 
Overall Study Flow Diagram Showing the Treatment Gap due to Protocol 
Amendment 7 and 8 
 
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Figure 2: 
Study Flow Diagram for Protocol Amendment 7 (Global) 
Screening 
Treatment Periodb, c 
End of 
Study 
 
  Baseline 
End of 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V1 
V2 
V3e 
V4e 
V5e 
V6 
V7e 
V8 
V9-V29d 
V30 
V31 
D -28 to 
-1a 
D1 
W1 
W2 
W3 
W4 
W8 
W12 
W16-W52 
 
Year 2 
W60-W100 
(q8 weeks) 
Year 3 
W108-W140 
(q8 weeks) 
 
W148 
~End of 
Year 3 
W160 
(or 
12 weeks 
after last 
dose) 
a Patients who fail screening or who fail to complete the baseline visit within 28 days of screening may be rescreened 
upon approval by the medical monitor.   
b A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will be administered 
on day 1 unless the patient has received a dose of dupilumab in the 4 weeks prior to baseline.  If the patient has 
received a dose of dupilumab in the past 4 weeks, then they will receive a single 300 mg dose at baseline.  The first 
dose should be at least 1 week after the last dose in the previous study, and then 300 mg dupilumab qw starting on 
day 8. 
c Patients will be monitored at the study site for a minimum of 30 minutes at the baseline visit. 
d Visits 10, 12, 14, and 16 have been removed per amendment 6.  This yields a schedule in which visits are 8 weeks 
apart from week 16 through week 48.  The week 48 visit is followed by a visit at 52 weeks, then visits occur every 
8 weeks thereafter up to and including the End of Treatment visit (week 148). 
e Visits 3, 4, 5, and 7 were removed per amendment 6.  
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Figure 3: 
Study Flow Diagram for Protocol Amendment 7 (UK) 
Screening 
Treatment Periodb, c 
End of 
Study 
 
     Baseline 
End of 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V1 
V2c 
V3e 
V4e 
V5e 
V6 
V7e 
V8 
V9-V23d 
V24 
V25 
D -28 
to -1a 
D1 
W1 
W2 
W3 
W4 
W8 
W12 
W16-W52 
Year 2 
W60-W92 
(q8 weeks) 
 
W100 
~End of 
Year 2 
W112 (or 
12 weeks 
after last 
dose) 
a Patients who fail screening or who fail to complete the baseline visit within 28 days of screening may be rescreened 
upon approval by the medical monitor.   
b A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will be administered 
on day 1 unless the patient has received a dose of dupilumab in the 4 weeks prior to baseline.  If the patient has 
received a dose of dupilumab in the past 4 weeks, then they will receive a single 300 mg dose at baseline.  The first 
dose should be at least 1 week after the last dose in the previous study, and then 300 mg dupilumab qw starting on 
day 8. 
c Patients will be monitored at the study site for a minimum of 30 minutes at the baseline visit. 
d Visits 10, 12, 14, and 16 have been removed per amendment 6.  This yields a schedule in which visits are 8 weeks 
apart from week 16 through week 48.  The week 48 visit is followed by a visit at 52 weeks.  Visits from 60 weeks 
through the EOT visit occur every 8 weeks. 
e Visits 3, 4, 5, and 7 were removed per amendment 6.  
Figure 4: 
Study Flow Diagram for Protocol Amendment 7 (France, Germany, Poland, 
Japan) 
  Screening 
Treatment Periodb, c 
 
  
 Baseline   
  
  
  
  
  
  
  
  
  
V1 
V2 
V3e 
V4e 
V5e  
V6 
V7e 
V8 
V9-V30d 
V31f-V33 
EOTg 
EOS 
D-28 
to D-
1a 
D1 
W1 
W2 
W3 
W4 
W8 
W12 
W16-
W148      
(every 8 
weeks) 
  
12 weeks 
after last dose 
a Patients who fail screening or who fail to complete the baseline visit within 28 days of screening may be rescreened 
upon approval by the medical monitor.   
b A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will be administered 
on day 1 unless the patient has received a dose of dupilumab in the 4 weeks prior to baseline.  If the patient has 
received a dose of dupilumab in the past 4 weeks, then they will receive a single 300 mg dose at baseline.  The first 
dose should be at least 1 week after the last dose in the previous study, and then 300 mg dupilumab qw starting on 
day 8. 
c Patients will be monitored at the study site for a minimum of 30 minutes at the baseline visit. 
d Visits 10, 12, 14, and 16 have been removed per amendment 6.  This yields a schedule in which visits are 8 weeks 
apart from week 16 through week 48.  The week 48 visit is followed by a visit at 52 weeks, then visits occur every 
8 weeks thereafter up to and including the End of Treatment visit (week 148). 
e Visits 3, 4, 5, and 7 were removed per amendment 6.  
f Patients who have completed their End of Study (EOS) visit and are resuming treatment per Amendment 7 may re-
enter the trial at visit 31 after the trial re-entry visit.  Patients who have completed their End of Treatment (EOT) 
visit may resume treatment at visit 31. 
g All patients will be scheduled for an EOT visit on or about 31 December 2017.   
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Figure 5: 
Study Flow Diagram for Protocol Amendment 8 (Poland, Finland) 
  Screening 
Treatment Periodb, c 
 
  
 Baseline   
  
  
  
  
  
  
  
  
  
V1 
V2 
V3e 
V4e 
V5e  V6 
V7e 
V8 
V9-V30d 
V31f g-V43 
V44/EOTg 
EOS 
D-28 
to D-
1a 
D1 
W1 
W2 
W3 
W4 
W8 
W12 
W16-
W148     
(every 8 
weeks) 
(every 8 weeks) 
12 weeks 
after last 
dose 
 a Patients who fail screening or who fail to complete the baseline visit within 28 days of screening may be rescreened 
upon approval by the medical monitor.   
b A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will be administered 
on day 1 unless the patient has received a dose of dupilumab in the 4 weeks prior to baseline.  If the patient has 
received a dose of dupilumab in the past 4 weeks, then they will receive a single 300 mg dose at baseline.  The first 
dose should be at least 1 week after the last dose in the previous study, and then 300 mg dupilumab qw starting on 
day 8. 
c Patients will be monitored at the study site for a minimum of 30 minutes at the baseline visit. 
d Visits 10, 12, 14, and 16 have been removed per amendment 6.  This yields a schedule in which visits are 8 weeks 
apart from week 16 through week 48.  The week 48 visit is followed by a visit at 52 weeks; then visits occur every 
8 weeks thereafter up to and including the End of Treatment visit). 
e Visits 3, 4, 5, and 7 were removed per amendment 6.  
f Patients who have completed their end of treatment (EOT) visit as per amendment 7 may resume treatment with 
study drug at the next scheduled visit they would have attended if they had not had an EOT visit.   
g Patients who have completed their End of Study (EOS) visit as per amendment 7 will be re-evaluated for eligibility 
at a trial Re-Entry visit.  Patients eligible to re-enter the trial may resume treatment at the next scheduled visit they 
would have attended if they had not completed the study.  Patients are not eligible to re-enter the trial if more than 
12 weeks have elapsed since their End of Study visit. 
The Schedule of Events table for global protocol amendment 7 and protocol amendment 8 for 
Poland/Finland is presented in Appendix 10.2. 
After providing informed consent, patients will be assessed for study eligibility at the screening 
visit. The screening visit in this study may coincide with the last visit in the previous study, in 
which case assessments that are common to both studies will be performed only once. 
In the original protocol and protocol amendment 1, it stated that “Patients enrolled in this study 
will receive weekly doses of 200 mg subcutaneous (SC) dupilumab. A loading dose of 400 mg 
dupilumab (200 mg initial dose, followed by a 200 mg loading dose) will be administered on day 
1 (unless last dose administered in the previous AD study is less than 4 weeks before their first 
dose in the current study, in which case they will receive 200 mg dupilumab), which will allow 
systemic concentrations to reach steady state faster, and potentially reduce the time to clinical 
effect.” 
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Starting from protocol amendment 2, eligible patients received a 600 mg SC dupilumab loading 
dose (300 mg initial dose, followed by a 300 mg loading dose) on day 1 (unless the last dose 
administered in the previous dupilumab AD study was less than 4 weeks before their first dose in 
the current study, in which case they received 300 mg dupilumab; the first dose of 300 mg should 
be at least 1 week after the last dose in the previous dupilumab study), and then 300 mg SC 
dupilumab qw starting on day 8.  Patients returned for visits as specified in the schedule of events 
according to the most current protocol amendment for their geographic region.  
Patients and/or caregivers who were willing and able to administer dupilumab doses outside the 
clinic were trained on injecting study drug unless they had already been trained during their 
participation in the previous study.  These patients self-injected study drug (or had the drug 
administered by a caregiver) during weeks in which no clinic visit was scheduled.  Safety, 
laboratory, and clinical assessments were performed at specified clinic visits. 
Patients who received treatment with a prohibited or restricted medication were to be 
discontinued from study drug for the duration of the prohibited treatment (plus 5 half-lives, as 
applicable).  Study treatment could be resumed in consultation with the medical monitor. 
Patients who tested positive for ADA at their last study visit (early termination or end of study) 
may be asked to return to the clinic to have additional ADA samples collected for analysis. 
Samples for clinical chemistry and hematology, drug concentrations and anti-drug antibodies 
(ADAs) were collected at various time points throughout the study according to the protocol. 
One sample for DNA analysis was collected from patients who consented to participate in the 
optional genomic sub-study. 
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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 will be used for all 
statistical analyses: 
3.1. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) consists of all patients who received any study drug. Efficacy, 
treatment compliance/administration, and all clinical safety variables will be analyzed using the 
SAF. 
3.2. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK analysis set consists of all treated patients who had at least one non-missing drug 
concentrations result following the first dose of study drug.  
3.3. 
The Anti-Drug Antibody (ADA) Analysis Set (AAS) and 
Neutralizing Antibody (NAb) Analysis Set (NAS) 
The ADA population consists of all treated patients who received any study drug and who had at 
least one non-missing ADA result after the first dose of the study drug. 
The neutralizing antibody (NAb) Analysis Set (NAS) consists of all patients who received any 
study drug and who had at least one non-missing Nab result or who had all samples negative in 
the ADA assay after first dose of the study drug. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics in Current Study 
The following demographic and baseline characteristics variables in current study will be 
summarized: 
 Demographic variables:  
 Age (year) 
 Age group (≥18-<40 year, ≥40-<65 year, ≥65 year) and elder group 
(≥65 - <75 year, ≥75 - <85 year; ≥85 year)  
 Sex (Male, Female) 
 Ethnicity (Hispanic or Latino, Not-Hispanic or Latino) 
 Race (White, Black or African American, Asian, Other) 
 Baseline Weight (kg) 
 Baseline weight group (<70 kg, ≥70-<100 kg, ≥100 kg) 
 Baseline Height (cm) 
 BMI (kg/m2) 
 BMI group (kg/m2) (<15, ≥15-<25, ≥25-<30, ≥30) 
 Baseline characteristics in current study:  
 Previous AD study number  
 Duration of AD at Day 1 of current study (< 26 years, >=26 years) 
 Previous treatment received in the parent study (placebo, dupilumab)  
 Previous dupilumab dose received in the parent study  
 Pruritus numerical rating scale (NRS) 
 Investigator’s Global Assessment (IGA) score 
 Eczema Area and Severity Index (EASI) score 
 Patient global assessment of disease status  
 Patient Oriented Eczema Measure (POEM) 
 Dermatology Life Quality Index (DLQI) 
 EQ-5D 
 Country 
 Geographic region 
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4.2. 
Characteristics of Patient Status in Parent Studies 
The following variables summarizing baseline disease characteristics in the parent study are 
defined: 
1. Baseline disease characteristics in parent study 
 Investigator’s Global Assessment (IGA) score 
 Eczema Area and Severity Index (EASI) score  
 Pruritus NRS 
 Patient global assessment of disease status 
 Patient Oriented Eczema Measure (POEM) 
 Dermatology Life Quality Index (DLQI) 
 EQ-5D 
The baseline value of a patient in the parent study, which is defined as the last 
non-missing value on or before the first dose date in the parent study, will be derived and 
summarized for all efficacy assessments. If a patient participated in more than one study 
before enrolling into AD-1225 study, the baseline value of the earliest parent study will 
be used and summarized. For example, for a patient who entered from AD-1415 (SOLO-
CONTINUE) study, the baseline value of the patient in the parent study is the baseline 
value in the SOLO studies (either AD-1334 or AD-1416) in which the patient participated 
before rollover into the AD-1415 study. 
2. The following variables for patient status at the end of treatment visit in the parent study 
(defined as the scheduled end of treatment visit in the parent study protocol 
[e.g., Week 16 for a parent study with a 16-week treatment period]) will be derived and 
summarized:  
Number and percentage of patients: 
 Achieving IGA 0 or 1  
 Achieving EASI-75 (>=75% reduction in EASI scores from baseline of the parent 
study) 
 Achieving EASI-50 (>=50% reduction in EASI scores from baseline of the parent 
study) 
 Achieving EASI-90 (>=90% reduction in EASI scores from baseline of the parent 
study) 
 Achieving improvement (reduction) of pruritus NRS >=4 from baseline of the 
parent study 
 Achieving improvement (reduction) of pruritus NRS >=3 from baseline of the 
parent study 
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Patients with a missing value at end of treatment visit in the parent study after censoring 
for rescue treatment use or study withdrawal will be counted as non-responders at the end 
of treatment visit in the parent study.  For patients who had been screened for a phase 3 
study (R668-AD-1334 or R668-AD-1416) but could not be randomized because of 
randomization closure, the patient’s status at end of treatment visit in the parent study 
will be blank. For patients from the 4-week treatment period of phase I or II studies 
(i.e. R668-AD-0914, R668-AD-1026 and R668-AD-1121), the patient’s status at end of 
treatment visit in the parent study will be blank, since most patients have shown 
non-response to treatment after a treatment duration of only 4 weeks. 
3. The treatment gap between the date of the last dose of dupilumab in the parent study and 
the first dose date in the current study will be derived and summarized by the following 
categories: <8 weeks, >13 weeks. 
4. The following variables for patients’ exposure to dupilumab in the parent study will be 
provided: 
 Cumulative dupilumab dose (mg) in the parent study. For patients who participated in 
more than one parent study (e.g. patients enrolled in R668-AD-1415 study who 
previously participated in R668-AD-1334 or R66-AD-1416 study) the cumulative 
dupilumab dose in parent study is the sum of all dupilumab doses received in all 
parent studies. 
 Duration of treatment of dupilumab (in weeks) in the parent study, defined as date of 
last dupilumab injection – date of first study drug injection) + 7]/7. The duration will 
be categorized by ≤ 4 weeks (ie. 28 days), 5-≤12 weeks, 13-≤16 weeks 17-≤24 weeks, 
25-≤52 weeks and >52 weeks. 
4.3. 
Medical History and Atopic Disease Medical History 
Medical history will be coded to a Preferred Term (PT), high level term (HLT) and associated 
primary System Organ Class (SOC) according to the latest available version of MedDRA at the 
coding CRO. 
The atopic disease (AD) medical history includes diagnosis of AD and AD treatment history, 
asthma, allergic conjunctivitis, allergic rhinitis, chronic rhinosinusitis, nasal polyps, eosinophilic 
esophagitis, food allergy hives and other allergies due to medications, animals, plants, mold, dust 
mites, etc.  The AD medical history was collected through atopic / allergic disease history case 
report form (CRF) in the parent study and will be summarized in current study.  
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4.4. 
Pre-treatment / Concomitant Medications and Procedures 
Medications/Procedures will be recorded from the day of informed consent until the EOS visit. 
Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 4 
(chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary (WHODD) at the coding CRO. Patients will be counted once in all ATC categories 
linked to the medication. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the first study drug in current study. 
Concomitant medications/procedures: medications taken or procedures performed following the 
first dose of study drug of current study through the EOS visit.  
Treatment with the following concomitant medications is prohibited during the study: 
 Treatment with nonsteroidal systemic immunosuppressive medications (including, but 
not 
limited 
to, 
cyclosporine, 
mycophenolate-mofetil, 
IFN-γ, 
azathioprine, 
methotrexate, or other immunomodulating biologics).  
 Systemic corticosteroids were removed as a prohibited medication as of 
Amendment 7. 
 Treatment with an investigational drug (other than dupilumab) 
 Live (attenuated) vaccines  
FluMist Influenza 
Intranasal influenza 
Measles (Rubeola) 
Measles-mumps-rubella (MMR) 
combination 
Measles-mumps-rubella-varicella 
(MMRV) combination 
Mumps 
Oral polio (Sabin) 
Chickenpox (Varicella) 
Rubella 
Smallpox (Vaccinia) 
Yellow fever 
Bacillus-Calmette–Guérin 
(BCG) 
Rotavirus 
Varicella Zoster (shingles) 
 
Chickenpox (Varicella) 
If medically necessary, patients may receive prohibited medication(s) at the discretion of the 
investigator (e.g., as rescue treatment for intolerable AD symptoms or to manage serious 
intercurrent conditions). However, patients who receive prohibited medication(s) will be 
discontinued from study drug for the duration of treatment with these prohibited medications, 
plus 5 half-lives. These patients will be asked to continue with the assessments of the early 
termination and end of study visits. 
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4.5. 
Efficacy Variables 
Analysis of efficacy variables will be performed in the overall SAF population, as described in 
Section 3.1.   
Starting from protocol amendment 6, the following assessments were removed from the schedule 
of events. All available data collected prior to implementation of protocol amendment 6 will still 
be summarized.  
 POEM 
 Dermatology Life Quality Index (DLQI) 
 EQ-5D 
 Patient Global Assessment of Disease Status 
 Patient Global Assessment of Treatment Effect 
All efficacy related endpoints for this study are secondary endpoints. Secondary endpoints 
include: 
 Key secondary endpoints 
 Proportion of patients with IGA score of either 0 or 1 at each visit 
 Proportion of patients with EASI-75 relative to baseline of parent study (≥75% 
reduction in EASI scores from baseline of parent study) at each visit 
 Other secondary endpoints 
 Proportion of patients with low disease activity state (ie., IGA ≤2) at each visit 
 Proportion of patients achieving an IGA reduction of >=2 from Day 1 of current 
study at each visit for patients with Day 1 IGA score of current study >= 2 
 Percentage change from Day 1 of current study in EASI score at each visit 
 Percentage change from baseline of parent study in EASI score at each visit 
 Change from Day 1 of current study in EASI score at each visit 
 Change from baseline of parent study in EASI score at each visit 
 Proportion of patients with EASI-50 relative to baseline of parent study (≥50% 
reduction in EASI scores from baseline of parent study) at each visit 
 Proportion of patients with EASI-90 relative to baseline of parent study (≥90% 
reduction in EASI scores from baseline of parent study) at each visit  
 Percent change from Day 1 of current study in pruritus NRS at each week 
 Percent change from baseline of parent study in pruritus NRS at each week 
 Change from Day 1 of current study in pruritus NRS at each week 
 Change from baseline of parent study in pruritus NRS at each week 
 Proportion of patients with improvement (reduction) of pruritus NRS ≥4 from 
Day 1 of current study or achieving NRS score of 0 at each visit  
 Proportion of patients with improvement (reduction) of pruritus NRS ≥4 from 
baseline of parent study or achieving NRS score of 0 at each visit  
 Proportion of patients with improvement (reduction) of pruritus NRS ≥3 from 
Day 1 of current study or achieving NRS score of 0 at each visit 
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 Proportion of patients with improvement (reduction) of pruritus NRS ≥3 from 
baseline of parent study or achieving NRS score of 0 at each visit 
 Proportion of patients requiring rescue treatment: 
 Overall 
 Systemic treatment 
 Systemic corticosteroids 
 Systemic immunosuppressive drugs 
 Phototherapy 
 Changes from Day 1 of current study in DLQI 
 Changes from baseline of parent study in DLQI 
 Changes from Day 1 of current study in POEM 
 Changes from baseline of parent study in POEM 
 Percent changes from Day 1 of current study in POEM 
 Percent changes from baseline of parent study in POEM 
 Changes from Day 1 of current study in EQ-5D 
 Changes from baseline of parent study in EQ-5D 
 Patient global assessment of disease severity at each visit through the end of the 
study 
 Patient global assessment of treatment effect at each visit through the end of the 
study 
Eczema Area and Severity Index (EASI) 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin 2001).  The EASI score calculation is based upon the Physician’s 
Assessment of Individual Signs [erythema (E), induration/papulation (I), excoriation (X), and 
lichenification (L)], where each sign is scored as 0 = Absent, 1 = Mild, 2 = Moderate, or 
3 = Severe, and also upon the Area Score [based on the % (BSA) affected] where 0 = 0% BSA, 
1 = 1-9% BSA, 2 = 10-29% BSA, 3 = 30-49% BSA, 4 = 50-69% BSA, 5 = 70-89% BSA, 
6 = 90-100% BSA.  
For each of major section of the body (head, upper extremities, trunk and lower extremities), 
EASI score = (E+I+X+L) x Area Score.  The total EASI score is the weighted total of the 
section EASI using the weights 10% = head, 20% = upper extremities, 30% = trunk, 40% = 
lower extremities. The minimum possible EASI score is 0 and the maximum possible EASI score 
is 72 where a higher score indicates increased extent and severity of atopic dermatitis.  The EASI 
score of each sign (E, I, X and L) can be calculated in a similar way, for example, the EASI score 
of erythema = weighted sum of E x Area Score at each section. 
The EASI will be collected at the scheduled and unscheduled clinic visits as indicated in 
Section 10.2. 
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Investigator’s Global Assessment (IGA) 
The IGA is a static 5-point measure of AD disease severity used in clinical studies to determine 
severity of AD and clinical response to treatment.  The ratings (0 = clear, 1 = almost clear, 
2 = mild, 3 = moderate, 4 = severe) are an overall assessment of AD skin lesions based on 
erythema and papulation/infiltration. IGA score will be assessed at the scheduled and 
unscheduled clinic visits as indicated in Section 10.2. 
Pruritus Numeric Rating Scale (NRS) 
The Pruritus NRS is a simple assessment tool that patients will use to report the average intensity 
of their pruritus (itch), during a 1 week recall period.  Patients will access the IVRS/IWRS 
weekly, preferably around the same time each week, and be asked the following question: 
 For average itch intensity: “On a scale of 0 – 10, with 0 being ‘no itch’ and 10 being 
the ‘worst itch imaginable’, how would you rate your itch overall, which is on 
average, during the past week?” 
Patients will be trained on using the IVRS/IWRS to record their Pruritus NRS score at the 
baseline visit, and visit 6, and will be queried by site staff for compliance at each scheduled (and 
any unscheduled) clinic visit. 
The baseline NRS is defined as the last NRSs reported prior to the first dose of study drug. 
Patient Oriented Eczema Measure (POEM) 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to 
assess disease symptoms in children and adults with atopic eczema (Charman 2004). The format 
is patient response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and 
weeping) based on symptom frequency during the past week (ie, 0 = ‘no days’, 1 = ‘1 to 2 days’, 
2 = ‘3 to 4 days’, 3 = ‘5 to 6’ days, and 4 = ‘every day’). The total score is the sum of the 7 items 
which is ranged from 0 to 28; a high score is indicative of a poor QOL.  The following POEM 
banding scores have been established (Charman 2004): 0 to 2 = Clear or almost clear; 3 to 
7 = Mild eczema; 8 to 16 = Moderate eczema; 17 to 24 = Severe eczema; 25 to 28 = Very severe 
eczema.  If two or more response options are selected for a question, then the response option 
with the highest score is recorded. If one question of the seven is left unanswered, then that 
question is scored as 0 and the scores are summed and expressed as usual out of a maximum of 
28.  If two or more questions are left unanswered, then the questionnaire is not scored and is set 
to missing. 
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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 skin diseases such as AD on dermatology-related Quality of Life 
(QoL). Domains measured include daily activities, leisure, personal relationships, symptoms and 
feelings, treatment, and work and school.  The format is a simple response to 10 items, which 
assess QoL over the last week. Each DLQI item has four response categories ranging from “Not 
at all” (0) to “Very much” (3). “Not relevant” is also a valid response, and it is also scored as 0. 
Question 7 includes a response of “Yes”, which is scored as 3. If question 7 is answered 'yes' this 
is scored 3 even if in the same question one of the other boxes is ticked. If question 7 is answered 
'no' or 'not relevant' but then either 'a lot' or 'a little' is ticked this is then scored 2 or 1.  The DLQI 
total score is a sum of the 10 questions.  Total score ranges from 0 to 30, and higher scores 
indicate greater HRQOL impairment.  If only one of the 10 questions is left unanswered this is 
scored 0 and the scores are summed and expressed as usual out of a maximum of 30.  If two or 
more questions are left unanswered the questionnaire is not scored. If two or more response 
options are ticked for one question, the response option with the highest score should be 
recorded.  
EQ-5D 
The EuroQOL 5-Dimension Health Questionnaire (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 (Greiner 2005).  The EQ-5D as a measure of health related 
QOL, defines health in terms of 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 3 ordinal levels of severity: “no 
problem” (1), “some problems” (2), “severe problems” (3). Overall health state is defined as a 
5-digit number. 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.”  
The 5 dimensional 3-level systems are converted into a single index utility score. 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 UK population. The 
minimum value for the single index utility score is –0.594, The Visual Analogue Scale (VAS) 
records the respondent’s self-rated health on a vertical visual analogue scale. The VAS 
‘thermometer’ has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst 
imaginable health state) at the bottom. This information can be used as a quantitative measure of 
health outcomes as judged by the individual respondents. EQ-5D self-reported VAS data 
generates information on the self-perceived overall health-related quality of life. Appendix 10.4 
provides the SAS code to derive the index utility score using UK based population.  
Patient Global Assessment of Disease Status 
Patients will rate their overall wellbeing based on a 5-point Likert scale. Patients will be asked: 
“Considering all the ways in which your eczema affects you, indicate how well you are doing”. 
Response choices are: “Poor” (1); “Fair” (2); “Good” (3); “Very Good” (4); “Excellent” (5).  
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Patient Global Assessment of Treatment Effect 
Patients will rate their satisfaction with the study treatment based on a 5-point Likert scale. 
Patients will be asked: “How would you rate the way your eczema responded to the study 
medication?” Response choices are: “Poor” (1); “Fair” (2); “Good” (3); “Very Good” (4); 
“Excellent” (5).  
The questionnaires (POEM, DLQI, and EQ-5D) will be administered only to the subsets of 
patients who speak fluently the languages in which the questionnaire is presented (based on 
availability of validated translations in participating countries). 
4.6. 
Safety Variables  
4.6.1. 
Adverse Events and Serious Adverse Events Variables 
The primary endpoint in the study is the incidence and rate (events per patient-year) of 
treatment-emergent adverse events (TEAEs) through the last study visit. 
The key secondary endpoints related to AE is  
 Incidence and rate (events per patient-year) of SAEs and AEs of special interest 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded to a 
“Preferred Term” and associated primary “System Organ Class (SOC)” according to the Medical 
Dictionary for Regulatory Activities (MedDRA, latest version). 
An Adverse Event is any untoward medical occurrence in a patient administered a study drug 
which may or may not have a causal relationship with the study drug.  Therefore, an AE is any 
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease 
which is temporally associated with the use of a study drug, whether or not considered related to 
the study drug. 
AEs also include: any worsening (i.e., any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug; 
abnormal laboratory findings considered by the investigator to be clinically significant; and any 
untoward medical occurrence. 
A Serious Adverse Event is any untoward medical occurrence that at any dose results in death; 
is life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; 
results in persistent or significant disability/ incapacity; is a congenital anomaly/ birth defect; or 
is an important medical event. 
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The criteria for determining whether an abnormal laboratory, vital sign or ECG finding should be 
reported as an AE are as follows: 
 Test result is associated with accompanying symptoms, and/or 
 Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 Test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy 
The pre-treatment period is defined as the period from the subject providing informed consent up 
to the first dose of study drug in current study.  
The treatment period is the period starting from the first dose date up to the last dose date + 7 
days. As there are two gaps in treatment due to protocol amendment 7 and 8, the gaps in 
treatment are not included as part of the treatment period. 
The follow-up period is the period starting 1 day after end of treatment period up to the end of 
study visit. As some patients were allowed to complete the follow-up period under protocol 
amendment 6 then re-enter the study, or were allowed to complete the follow-up period under 
protocol amendment 7 and then re-enter the study, the follow-up period consists of all the 
separate follow-up periods under protocol amendment 6, 7 and 8. 
The overall study period consists of treatment and follow-up period. 
The pre-treatment AE and treatment emergent AE (TEAE) are defined as following:  
 Pre-treatment signs and symptoms (Pre-treatment AEs) are AEs that developed or 
worsened in severity during pre-treatment period. 
 Treatment-emergent AEs (TEAEs) are AEs that developed or worsened in severity 
compared to the Day 1 of current study during the treatment and follow-up period. As 
the protocol indicated that only the worsening pre-existing AEs and new AEs reported 
during the treatment and follow-up period will be collected in the study, all AEs with 
onset during the treatment and follow-up period are considered as TEAEs. So TEAE 
includes all AE onset during the treatment period and during follow-up period. 
Under protocol amendment 7, patients in France, Germany, Poland and Japan who had 
completed their end of study visit under protocol amendment 6 were permitted to re-enter the 
study. Similarly, under protocol amendment 8, patients in Poland, Finland and France who had 
already completed their end of study visit under protocol amendment 7 were permitted to re-enter 
the study.  
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Treatment discontinuation required under protocol amendment 6 followed by resumption of 
treatment permitted under protocol amendment 7 resulted in a gap in treatment for certain 
patients in these four countries. There was a similar treatment gap for certain patients in Poland, 
Finland and France who had an EoT/EoS visit under amendment 7 and subsequently resumed 
treatment under amendment 8.  
Hence any AE with an onset between the end of study visit under protocol amendment 6 and the 
date of first injection under amendment 7; or between end of study visit under protocol 
amendment 7 and date of first injection under amendment 8 is not considered TEAEs.   
The list of adverse events of special interest (AESI) was revised several times. Below is the AESI 
list under protocol amendments 4 and 5: 
 Anaphylactic reactions 
 Acute allergic reaction 
 Severe injection site reactions that last longer than 24 hours 
 Mycosis fungoides 
 Cutaneous T-cell dyscrasia 
 Any severe infection 
 Any infection requiring treatment with parenteral antibiotics 
 Any infection requiring treatment with oral antibiotics/anti-viral/anti-fungal for longer 
than 2 weeks 
 Any clinical endoparasitosis 
 Any opportunistic infection 
Under protocol amendment 6, suicide-related events and certain eye-related events were added as 
AESIs. Under protocol amendment 7, the list of AESI are as follows:  
 Anaphylactic reactions  
 Systemic or extensive hypersensitivity reactions 
 Malignancy (except basal cell carcinoma) 
 Helminthic infections 
 Any suicide-related events 
 Any type of conjunctivitis or blepharitis, or keratitis (severe or serious) 
The SAP summarizes AESIs according to the most current list under protocol amendments 7 and 
8. The definition of AESI is same under protocol amendment 7 and 8.  
Appendix 10.6 provides a list of AESIs search criteria. 
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4.6.2. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory.  
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin1 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen (BUN) 
 Low-density lipoprotein (LDL) 
Carbon dioxide 
AST 
 High-density lipoprotein (HDL) 
Calcium 
ALT 
Triglycerides 
Glucose 
Alkaline phosphatase 
Uric acid 
Albumin 
Lactate dehydrogenase (LDH) 
CPK 
 
 
 
1 Direct and indirect bilirubin will be measured when the total bilirubin is above the ULN; CPK isoenzymes will be 
measured when CPK >5X the ULN 
Hematology  
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Microscopic analysis will only be done by the central lab in the event of abnormal dipstick 
results. 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast  
Pregnancy serum or urine testing will be performed for all women of childbearing potential. 
4.6.3. 
Vital Sign Variables 
The following vital signs parameters will be collected: 
 Respiratory rate (bpm) 
 Heart rate (bpm) 
 Systolic and diastolic blood pressures (mmHg) 
 Body temperature (oC) with the measure method (oral/tympanic/axillary/rectal) 
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Heart rate and blood pressure will be obtained with the patient in sitting position after the patient 
has rested comfortably for at least 5 minutes. Vital signs will also be taken at 30 (+/- 10) minutes 
post-injection at visits 2, 3, and 4, during the in-clinic 30-minute post-injection observation. 
4.6.4. 
12-Lead Electrocardiography (ECG) Variables 
Standard 12-Lead ECG parameters include: Ventricular HR, PR interval, QRS interval, corrected 
QT interval (QTcF=QT/[RR0.33] and QTcB=QT/[RR0.5]) ECG status: normal, abnormal not 
clinical significant or abnormal clinical significant. Electrocardiograms should be performed 
before blood is drawn during visits requiring blood draws. 
ECG measurement was removed from the schedule of events starting from protocol 
amendment 6.  
4.6.5. 
Physical Examination Variables 
A thorough and complete physical examination will be performed. The physical examination 
variable values are dichotomized to normal and abnormal. 
Physical examination was removed from the schedule of events except for the baseline 
assessment starting from protocol amendment 6.  
4.6.6. 
Ophthalmological Examination 
Starting from protocol amendment 6, the ophthalmological examination was added to the 
schedule of events. This exam will be performed for certain patients of interest, as determined by 
the sponsor medical monitor in consultation with the investigator, at select study centers that 
have access and can refer patients to an eye specialist, either a General ophthalmologist or a 
Cornea and External Eye Disease (‘front-of-the-eye’) subspecialty expert. Any baseline findings 
will be documented as part of the patient’s medical history and/or physical exam, as appropriate. 
Any inflammatory ophthalmological condition that occurs post-baseline will be captured as an 
AE. Additional tests and assessments may be performed to help understand the AEs. The method 
and procedure for the exam are provided in the study reference manual. 
The ophthalmological exam data includes: 
 Past ocular history 
 Past and current treatment of ophthalmology 
 Ophthalmic adverse event assessment 
 Ophthalmological examination and procedures 
 Intraocular pressure 
 Slit lamp biomicroscopy 
 Indirect ophthalmoscopy 
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4.7. 
Pharmacokinetic (PK) Variables  
Samples for drug concentration will be collected at time points according to Appendix 10.2. PK 
variables consist of functional dupilumab concentration and time (both actual and nominal). 
4.8. 
Antibody (ADA) Variable 
ADA variables include the ADA status, titer, neutralizing antibody (NAb) status, and time-
point/visit. ADA samples will be collected at the clinic visits according to Appendix 10.2. 
4.9. 
Biomarkers Variables  
Research samples, optional genomics substudy, and exploratory biomarker testing assessments 
was removed from the schedule of events starting from protocol amendment 6. Prior to protocol 
amendment 6, the following biomarkers were collected in this study:  
 TARC  
 total serum IgE  
 hs-CRP, ANA, anti dsDNA, anti-TPO  
Thymus and activation-regulated chemokine and total serum IgE are markers of Th2 activity and 
are downstream of IL-4/IL-13 signaling.  These analytes will be assessed as measures of 
Th2 activity and drug effect (PD).  These results may also be used for modeling dupilumab 
activity with drug levels in the comparison of dosing regimens.  Thymus and activation-regulated 
chemokine levels have also been closely associated with AD disease activity and severity, and 
will be evaluated as an exploratory marker of efficacy.  These markers may also be assessed for 
their potential value in predicting treatment response. 
Th2 and Th1 immune functions are believed to play a role in regulating each other.  To determine 
whether or not there is a change in non-Th2 mediated inflammation, hs-CRP, as well as 
autoantibodies anti-dsDNA, anti-TPO, and ANA will be measured. 
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5. 
STATISTICAL METHODS 
All data including both safety and efficacy will be summarized overall for all patients in SAF. 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, Q1 (25% percentile), Q3 (75% percentile), 
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 
5.1.1. 
Demographics and Baseline Characteristics of Current Study 
The following demographics and baseline characteristics of current study as specified in 
Section 4.1 will be summarized overall for all patients in SAF.  
 Demographics,  
 Baseline characteristics in current study 
5.1.2. 
Characteristics in Parent Study 
The following demographics and baseline characteristics from the parent study as specified in 
Section 4.2 will be summarized overall for all patients in SAF.  
 Baseline characteristics in parent study,  
 End of treatment status of a patient in the parent study, 
 Duration of off treatment period (days) before baseline 
 Duration of patient exposure to dupilumab in the parent study  
5.2. 
General Medical History and AD History 
Medical history in current study will be summarized by primary SOC and PT. The table will be 
sorted by decreasing frequency of SOC followed by PT. Medical history will be listed. 
AD medical history will be summarized by number and percentage of patients with each type of 
AD medical history. 
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5.3. 
Pre-treatment/Concomitant Medications/Procedures 
Number and proportion of patients taking prior/concomitant medication will be summarized, 
sorted by decreasing frequency of ATC Level 2 and ATC level 4. Patients will be counted only 
once for each medical class (ATC level 2 and 4) linked to the medication. 
Listing of pre-treatment medication and concomitant medications will include generic name and 
ATC levels 2 and 4, indication, study day onset (for medications started before treatment, the 
study day onset (defined as date of medication start - date of the first dose; for medications 
started on or after treatment, the study day onset = date of medication start - date of the first 
dose+1), the study end date (defined similarly as for study onset day), ongoing status, dose, 
frequency, route. 
5.4. 
Subject Disposition 
The following summaries by table will be provided for all patients in SAF: 
 The total number of screened patients 
 The total number of enrolled patients 
 The total number of patients enrolled and reconsented under each protocol 
amendment 
 The total number of patients in each analysis set 
 The total number of patients who completed the study including a summary of 
patients who completed the study under each protocol amendment, completed up to 
week 52, completed up to week 100, complete up to week 148, completed up to 
week 156, completed up to week 208, completed up to week 260, and completed up 
to week 272 
 The total number of patients who discontinued the study and the reasons for 
discontinuation 
 The total number of patients who completed study treatment including a summary of 
patients who completed treatment under each protocol amendment 
 The total number of patients who discontinued the study treatment and the reasons for 
discontinuation 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation cumulatively by visits (i.e. end of week 1, end of week 2, end of week 
4, end of week 8, end of week 12, end of week 16, end of week 24, end of week 36, 
end of week 48, end of weeks 52, end of week 76, end of week 100, end of week 124, 
end of week 148, end of week 164, end of week 208, end of week 260, end of study). 
The visits in weeks are categorized based on study days from the first dose date in 
current study. For example, end of week 1 corresponds to study day 8. 
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As patients from different countries can have different study duration and treatment duration 
according to the country specified protocol amendment, subgroup analysis of the disposition data 
by country of interest will be provided.   
The following listings will be provided: 
 Listing of subject disposition including: date of enrollment, date of the last visit, 
received dose, completed study or discontinued by reason, a flag indicating if a patient 
completed study under protocol amendment 6 then retry into study under protocol 
amendment 7 
 A listing of patients enrolled but not treated 
 A listing of patients prematurely discontinued from the study or treatment, along with 
reasons for discontinuation, summary tables of reasons will be provided 
 A listing and a summary table of major protocol deviations will be provided 
5.5. 
Dupilumab Dose administration 
The compliance with protocol-defined investigational product will be calculated as follows: 
Treatment Compliance= (Number of injections during exposure period) / (Number of planned 
injections during exposure period) x 100% 
Loading doses for the same patient will be counted as 1.  
Treatment compliance will be calculated and summarized for the following periods of interest.  
 Overall study treatment period 
 The treatment period prior to “treatment gap” (defined below) 
As shown in Figure 1 of Section 2.3, due to the implementation of protocol 
amendments 7 and 8, patients in certain countries experienced a gap in treatment 
between completion of the treatment period under a prior protocol amendment and the 
beginning of a new protocol amendment. Specifically, there are two types of treatment 
gaps:   
o Patients from Germany, France, Poland and Japan who completed the 3-year 
treatment period under protocol amendment 6, and resumed dupilumab treatment 
after reconsenting to amendment 7.  
o Patients from Poland, Finland and France who completed the treatment period 
under protocol amendment 7 and resumed treatment after reconsenting to protocol 
amendment 8.   
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 The “continuous-treatment” period (defined below) 
For the QW regimen being evaluated in this study, the decline in concentrations of 
dupilumab following an interruption in treatment of ≤ 8 weeks is not expected to be 
sufficient to have a substantial impact on the pharmacodynamic effect of dupilumab. For 
patients with a treatment gap ≤ 8 weeks, a “continuous-treatment” period is defined as 
the combined prior to “treatment gap” period and “post-gap” period. For patients who 
did not reconsent to protocol amendment 7 or 8, the “continuous-treatment” period is the 
study treatment period.  
 The treatment extension period under protocol amendment 7 for patients from Germany, 
Poland, France and Japan who completed 3-year treatment 
 The treatment extension period under protocol amendment 8 for patients from Poland, 
Finland and France who reconsent to protocol amendment 8  
Treatment compliance during both “treatment extension” periods will be summarized. Number of 
patient with each type of gap in treatment and duration of gap will be summarized.  
Summary of study drug administration will include the number of study drug doses administered, 
and treatment compliance. The treatment compliance will be presented by the following specific 
ranges: <80%, and ≥80%. 
Listing of dose administration: including date/time, study day, number of injections, locations of 
injections and dosing information will be presented. 
5.6. 
Treatment Exposure and Observation Period 
The duration of treatment exposure period during the study in week is calculated as: 
[(Date of last study drug injection – date of first study drug injection) + 7]/7 
regardless of unplanned intermittent discontinuations. For the exposure calculation, the two 
treatment gaps due to patients resuming treatment under protocol amendment 7 or 8 will be 
excluded. The duration of exposure will be summarized using number of patients, means, SD, 
minimums, medians, and maximums. A summary of the number of doses will also be provided. 
The duration of observation period during the study in weeks is calculated as: 
[(Date of the last visit – date of the first study medication dose) +1]/7. 
For the duration of observation period calculation, the study gap for patients who have completed 
the study under protocol amendment 6 then retry into the study under protocol amendment 7 will 
be excluded. 
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The duration of observation periods will be summarized using number of patients, means, SD, 
minimums, medians, and maximums. The number (%) of patients with observation periods will 
be presented by specific time periods. The time periods of interest are specified as: ≥ 1 week, 
≥ 4 weeks, ≥ 12 weeks, ≥ 16 weeks, ≥ 24 weeks, ≥ 52 weeks, ≥ 76 weeks, ≥ 100 weeks, 
≥ 104 weeks, ≥ 124 weeks, ≥ 148 weeks, ≥ 156 weeks, ≥ 164 weeks, ≥ 208 weeks, ≥ 260 weeks, 
≥ 272 weeks.  
As of protocol amendment 2, the weekly dose of dupilumab was changed from 200 mg to 
300 mg. The number of patients exposed to 200 mg dose, the number of 200 mg doses and 
duration of treatment exposure with 200 mg and 300 mg in weeks will be calculated and 
summarized separately. 
Appendix 10.10 provides the detailed algorithm for calculating duration of treatment exposure 
and observational period. 
5.7. 
Analyses of Efficacy Variables 
The efficacy variables will be summarized for all patients in SAF. The continuous efficacy 
variables will be summarized using number of patients, means, SD, minimums, medians, Q1, Q3 
and maximums. Categorical efficacy variables will be summarized using patient counts and 
proportion. No formal statistical hypothesis testing will be performed. The graph of mean value 
for continuous variable or proportion for categorical variable by visit will be provided. 
All observed values, regardless of whether rescue treatment is used or data is collected after 
withdrawal from study treatment will be used for analysis. No missing values will be imputed.  
For the categorical efficacy variables, the proportion of patients with each response at each visit 
will be calculated using the number of patients with a non-missing value at the visit as the 
denominator. 
As described in Section 5.6, there are up to two potential “treatment gaps” due to patient re-entry 
to the study for protocol amendments 7 and 8 for patients from Germany, France, Poland and 
Japan. The primary focus of the efficacy data will be on the data collected prior to these potential 
“treatment gaps”. 
 If the “treatment gap” is ≤8 weeks, then all efficacy data will be summarized together, 
i.e. data will be analyzed as if the patient had been dosed continuously 
 If the “treatment gap” is >8 weeks, efficacy data collected before and after the treatment 
gap will be summarized separately. 
Data collected under end of study visit (i.e. off-treatment measurement at the end of 12-week or 
16-week safety follow up period) will be summarized separately from the data while the patient 
was on treatment.  
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 For the analysis of Pruritus NRS, the weekly NRS collected during the safety follow-up period, 
during the treatment gap between amendments 6 and 7, and between amendments 7 and 8 will be 
separated from the NRS collected during treatment. The primary focus of NRS data will be on 
the data collected during treatment.  
Subgroup analyses for efficacy 
Different subgroups within the overall SAF population will be defined as below. The analyses 
will be performed for the secondary efficacy variables related to EASI, IGA and pruritus NRS by: 
 Duration of AD at Day 1 of current study (< 26 years, ≥26 years) 
 Baseline body weight of current study ((<70 kg, ≥70-<100 kg, ≥100 kg) 
 Baseline BMI of current study (<15, [15-25), [25-30), ≥30) 
 Age (≥18-<40, ≥40-<65, ≥65) 
 Gender (Male, Female) 
 Race (White, Black or African American, Asian, Others) 
 Ethnicity: Hispanic or Latino (yes/no) 
 Previous usage of ciclosporin (CsA) (Yes, No) 
 Previous usage of methotrexate (MTX) (Yes, No) 
 Previous usage of Azathioprine (Aza) (Yes, No) 
 Previous use of systemic immunosuppressants for AD (Yes, No) 
 History of asthma (Yes, No) 
 History of nasal polys (Yes, No) 
 History of allergic rhinitis (Yes, No) 
 History of food allergies (Yes, No) 
 Previous treatment of dupilumab in parent study (Yes, No) 
 For patients who received dupilumab in parent study, data from the following 
two subgroups will also be summarized.  
o Re-treatment (treatment gap > 8 weeks): – Patients who came from the 
dupilumab arms of parent studies, and if the gap period between the last 
dupilumab study drug injection in parent study and the first study drug 
injection in current study is > 8 weeks (greater than 64 days). 
o Continuous treatment (gap < 8 weeks) – patients who came from the 
dupilumab arms of parent studies, and if the gap period between the last 
dupilumab study drug injection in parent study and the first study drug 
injection in current study is < 8 weeks (less than or equal to 64 days).   
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5.8. 
Analysis of Safety Data 
The summary of safety and tolerance will be performed for all patients in SAF. 
The safety analysis will be based on the reported AEs, clinical laboratory evaluations, physical 
examination, vital signs, and 12-lead ECG. 
Thresholds for treatment-emergent Potentially Clinically Significant Values (PCSV) in 
laboratory variables, vital signs and ECG are defined in Appendix 10.3. The baseline when 
determining treatment-emergent PCSV refers to the baseline value of current study. 
The time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
Subgroups are defined by key baseline factors recorded on the CRF and listed to be considered 
for safety analyses: 
 Age group (≥18-<40, ≥40-<65, ≥65)  
 Sex (Male, Female) 
 Ethnicity: Hispanic or Latino (no/yes) 
 Race (White, Black or African American, Asian, Other) 
 Duration of AD based on data from parent studies (< 26 years, ≥26 years) 
 Baseline weight group (<70 kg, ≥70-<100 kg, ≥100 kg) 
5.8.1. 
Adverse Events 
Listings of TEAEs, serious TEAEs, TEAEs resulting in death and study drug discontinuation will 
be generated. 
Number and proportions of patients reporting TEAEs will be summarized for the following 
TEAEs, sorted by the decreasing frequency of SOC, HLT and PT: 
 TEAEs 
 TEAEs by SOC/PT 
 TEAEs by SOC/HLT/PT 
 TEAEs by PT 
 Common TEAEs by SOC/HLT/PT (incidence with HLT ≥5%) 
 Common TEAEs by SOC/HLT/PT (incidence with PT ≥5%) 
 TEAEs by severity by SOC/PT 
 Severe TEAEs by SOC/PT 
 TEAEs related to study medication as assessed by the investigator by SOC/PT 
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 Severe TEAEs related to study medication as assessed by the investigator by 
SOC/PT  
 Serious TEAEs by SOC/PT 
 Serious TEAEs by SOC/PT 
 Serious TEAEs by SOC/HLT/PT 
 Serious TEAEs related to study medication as assessed by the investigator by 
SOC/PT  
 TEAEs leading to permanent discontinuation of study treatment by SOC/PT 
 Death by SOC/PT 
In addition, the number of events per 100 patient-year (NEPY) and number of patients with at 
least one event per 100 patient-years (EAIR) will be calculated and summarized for the 
following: 
 TEAEs by SOC and PT 
 Severe TEAEs by SOC/PT 
 TEAEs related to study medication as assessed by the investigator by SOC/PT 
 Severe TEAEs related to study medication as assessed by the investigator by SOC/PT 
 Serious TEAEs by SOC/PT 
 TEAEs leading to permanent discontinuation of study treatment by SOC/PT 
 AESI by AESI category and HLT/PT 
These calculations will be adjusted for the duration of the TEAE period. The detailed 
methodology of NEPY and EAIR is described in Appendix 10.5.  
5.8.2. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to standard international units. Summaries of laboratory variables will include: 
 Descriptive statistics of laboratory result and change from baseline by visit 
 The number (n) and percentage (%) of patients with abnormal lab value during study 
whose screening and baseline values are normal (overall and per each lab parameter) 
 The number (n) and percentage (%) of patients with treatment-emergent PCSVs 
during study, depending on data 
 Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
Listing of all laboratory parameters normal range, abnormal flag and treatment-emergent PCSV 
by subject and visit will be provided. 
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The graph of mean change and/or percentage change from baseline value for lab parameters by 
visit will be provided. 
5.8.3. 
Analysis of Vital Signs 
Summaries of vital sign variables will include: 
 Descriptive statistics of vital sign variable and change from baseline by visit 
 The number (n) and percentage (%) of patients with treatment-emergent PCSV, 
depending on data 
 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 PCSVs, depending on 
data. 
5.8.4. 
Physical Exams 
The number (n) and percentage (%) of patients with abnormal physical exams will be 
summarized at the scheduled visits. A summary of treatment-emergent abnormal findings will be 
provided. 
5.8.5. 
Analysis of 12-Lead ECG 
Summaries of 12-lead ECG parameters will include: 
 Each ECG parameter and change from baseline 
 The number (n) and percentage (%) of patients with PCSV, depending on data 
 ECG status (i.e. normal, abnormal) summarized by a shift table 
Listings will be provided with flags indicating PCSVs, depending on data. 
5.8.6. 
Analysis of Ophthalmological Examination 
For those patients enrolled in the optional ophthalmology sub study, the ophthalmology exam 
data will be included as a subset of the safety analysis set. Patients in the safety analysis set who 
enrolled in the ophthalmology sub-study will be categorized into subgroups based on whether or 
not they had an existing ophthalmological AE at the time of sub-study entry. 
 No ophthalmological AE 
 At least one ophthalmological AE 
o Ended prior to sub-study entry 
o Ongoing at sub-study entry  
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Summary of ophthalmological exam data will be performed for all patients in the safety analysis 
set who enrolled in the ophthalmology sub-study and by the above defined subgroups (i.e. 
ophthalmological AE or not at the sub-study entry) using descriptive statistics and will include: 
 Summary of patient disposition 
 Summary of demographic and baseline characteristics of current study 
 Summary of past ocular history 
 Summary of past and current treatment of ophthalmology 
 Summary of concomitant medications and procedures taken during the 
ophthalmology sub-study 
 Summary of Treatment Emergent Ophthalmology Adverse Events (TEAE) Onset 
during the Ophthalmology Sub-study (i.e. between the inform consent date of sub-
study up to the last visit of sub-study) by SOC/PT 
 Summary of Ophthalmic Adverse Event Assessment 
 Summary of Ophthalmological Examination and Procedures 
 Summary of observed intraocular pressure and its change from baseline at the 
beginning of sub-study 
 Slit lamp biomicroscopy, shift table for normal/abnormal status for each test 
 Indirect ophthalmoscopy shift table for normal/abnormal status for each test 
5.9. 
Analysis of Pharmacokinetic Data 
For this study, sampling will be sparse and the types of analyses will be: 
 Descriptive statistics at each sampling time 
No formal statistical analysis will be performed within the scope of this plan. For the descriptive 
statistical analysis, concentrations below the lower limit of quantitation (LLOQ) will be set to 
zero. 
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5.10. 
Analysis of ADA Data 
5.10.1. 
Analysis of ADA Data 
The ADA variables described in Section 4.8 will be summarized using descriptive statistics in 
the ADA analysis set. Frequency tables of the proportion of patients with pre-existing 
immunoreactivity, treatment-emergent, treatment-boosted, persistent ADA responses, and titer 
categories will be presented as absolute occurrence (n) and percent of patients (%).  
 Pre-existing immunoreactivity is defined as either an ADA positive response in the 
assay at baseline of parent study with all ADA results negative post first dose of the 
current study, OR a positive response at baseline of parent study with all ADA results 
less than 4-fold baseline titer levels of parent study, post first dose of the current 
study.  
 Treatment emergent response is defined as a positive response in the ADA assay post 
first dose of current study when baseline results of parent study are negative or 
missing. The treatment emergent responses will be further characterized as Persistent, 
Indeterminate or Transient 
 Persistent Response – defined as a treatment emergent ADA response with two or 
more consecutive ADA positive sampling time points separated by greater than 
(>) 12-week period (greater than 84 days), with no ADA negative samples in 
between. 
 Indeterminate Response – defined as a treatment-emergent response with only the 
last collected sample positive in the ADA assay 
 Transient Response - defined as a treatment emergent ADA positive assay 
response that is not considered persistent or indeterminate. 
 Treatment boosted response is 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 of parent 
study, when baselines results of parent study are positive. 
The baseline used to define ADA status (treatment emergent, pre-existing immunoreactivity, etc) 
refers to the baseline ADA value in the parent study. 
 Titer Values (Titer value category) 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000) 
5.10.2. 
Analysis of Neutralizing Antibodies (NAb) 
The absolute occurrence (n) and percent (%) of  treatment-emergent or treatment boosted ADA 
positive patients  that are positive in the NAb assay will be summarized for patients in the NAb 
analysis set.  
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5.11. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.11.1. 
Immunogenicity and Exposure 
Associations between ADA and systemic exposure to dupilumab may be explored. Plots of 
dupilumab concentration may be provided for analyzing the potential impact of treatment-
emergent, persistent and titer ADA responses (high, moderate or low) on PK. 
5.11.2. 
Immunogenicity and Treatment Gaps 
Associations between ADA (e.g. ADA status, ADA maximum titers, and neutralizing antibody 
status) and treatment gaps (i.e. ≤8 weeks or >8 weeks) due to patients resuming treatment under 
protocol amendment 7 or 8 will be explored. 
5.11.3. 
Immunogenicity and Safety and Efficacy 
Association of ADA with safety events may be explored with a primary focus on the following 
safety events during the TEAE period:  
 Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
 Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Association of treatment emergent and persistent ADA responses and impact on selected efficacy 
endpoints (ie proportion of patients with IGA 0 or 1, proportion of patients with EASI-75, 
percent change in EASI score) may be explored (e.g. scatter plot or spaghetti plot).  
These above mentioned safety and efficacy analyses will be conducted using the following ADA 
response categories: 
 ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response  
 ADA negative patients, that is patients with pre-existing immunoreactivity or negative 
in the ADA assay at all time points 
 Patients with persistent ADA response, 
 NAb positive patients, that is patients who had positive in the NAb assay at any time 
point analyzed.  
 Peak post-baseline titer level in treatment emergent or treatment boosted ADA 
positive patients:  
 High,  
 Moderate,  
 Low 
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5.12. 
Analyses of Biomarkers 
5.12.1. 
Analyses of Biomarkers 
Descriptive statistics for the observed values, change and percent change from Day 1 of current 
study, change and percent change from baseline of parent study by visit will be summarized for 
all patients in SAF.  It will be provided for the following biomarker variables: 
 TARC  
 total serum IgE  
 hs-CRP,  
 anti-TPO  
Corresponding figures will be provided.  
Correlation of baseline TARC (measured value) and baseline IgE (measured value) of current 
study with the following categorical clinical endpoints at each visit will be explored for patients 
without prior experience to dupilumab in the parent studies (i.e. dupilumab naïve patients). 
Subgroup analysis of these endpoints by baseline value tertiles (<=33rd percentile, <33 - <=67th 
percentile , >67th percentile) will be provided. 
 IGA 0-1  
 EASI-75 relative to baseline of current study 
 Proportion of patients with improvement (reduction) of pruritus NRS ≥4 from 
baseline of current study 
 Proportion of patients with improvement (reduction) of pruritus NRS ≥3 from 
baseline of current study 
Correlation of baseline TARC (measured value) and IgE (measured value) of current study with 
the following continuous clinical endpoints will be explored using the Spearman’s rho test for 
patients without prior experience to dupilumab in the parent studies (i.e. dupilumab naïve 
patients). Both Spearman correlation coefficients and p-value will be reported. 
 Percent change from Day 1 of current study in EASI score 
 Percent change from Day 1 of current study in weekly pruritus NRS 
Shift tables from baselines status to post-baseline status for ANA, anti-TPO and anti-dsDNA will 
be provided. 
All above analyses will be performed on the SAF for all observed data. No missing data will be 
imputed. 
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5.12.2. 
“Normalization” Biomarker Data Related Evaluations 
The additional analysis will be performed on the following biomarkers to evaluate the proportion 
of patients for whom biomarker concentrations “normalize” (shift from above normal to within 
the normal range) at each visit. 
 Total IgE  
 TARC  
These evaluations will be done using two subsets of the SAF specifically defined as below:  
 Include patients with the elevated total IgE, or TARC at baseline of current study. 
Patients in SAF with a normal (below the ULN) serum biomarker level at Day 1 of 
current study will be excluded from the analysis for that biomarker, and 
 Include patients with the elevated total IgE, or TARC at baseline of parent study. 
Patients in SAF with a normal (below the ULN) serum biomarker level at baseline of 
parent study will be excluded from the analysis for that biomarker, and 
These patients should also have at least one post-Day 1 of current study measurement and 
received treatment.  
Therefore, the analysis population for each of the biomarkers of interest will vary depending on 
the number of SAF patients meeting “elevation” criteria at baseline. All observed biomarker data 
without imputation for missing value will be used for this analysis. Summary tables with 
normal/elevated status for total IgE, and TARC at baseline and each post-baseline visit (until 
end-of-study) will be provided. 
Method for Determining a ULN for Total IgE  
Total IgE are established clinical assays; the upper limit of normal (ULN) from the central lab 
reference range will determine the threshold for normal vs. elevated status. The reference ranges 
for the total IgE (Phadia AB 2014) are specified in below table, from the product inserts provided 
by the manufacturer of the assays. 
Allergen (Analyte) 
Phadia Code 
Catalog # 
Reference Range 
Allergen Total IgE 
 
14-4509-01 
0-119 kU/L for both 
adult sexes 
Method for Determining a ULN for TARC 
A standard reference range for TARC in healthy adult populations has not been established.  To 
determine an appropriate ULN for these analyses, a literature review was conducted to identify 
summary estimates of TARC in healthy adult volunteers, in studies using identical methodology 
(ELISA, R&D Systems, Minneapolis) to measure serum TARC levels (pg/mL).  Two comparable 
studies were identified and estimates are provided in Table 3.  Along with these estimates, data 
from a FIH Study (R668-AS-0907) was included to supplement available information and ensure 
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consistency across internally and externally obtained measurements of serum TARC.  The 
R668-AS-0907 study comprised healthy volunteers and the TARC measurements provided in 
Table 3 were obtained at Day 1, prior to administration of study drug or placebo. 
From the two external and one internal estimates, a combined mean and SD were calculated 
(using the study healthy volunteers sample size as weights).  The mean combined serum TARC 
level + two standard deviations was used to determine the ULN.  After combining data across 
studies, the calculated ULN for serum TARC is 1081.5 pg/mL. Under the assumption that serum 
TARC levels are normally distributed in healthy adults, approximately 95 percent of normal 
serum TARC levels will fall within this range.  From the summary data identified by literature 
review, as well as our internal data, serum TARC levels in healthy adults appear to have a slight 
right skew.  However, for the purposes of this analysis, the normal distribution assumption 
should provide a more conservative estimate of the ULN (in comparison to using 95th percentile 
or maximum study measurements), thereby increasing the burden of establishing normalization 
of serum TARC levels in our patient population.  Additionally, from internal study 
R668-AS-0907, the 90 - 95 percentile for TARC at Day 1 was 1042 – 1142 pg/mL, consistent 
with the calculated ULN (percentile information from external sources was not available). 
Table 3: 
External/Internal Reference Estimates of TARC 
Sample 
Type 
Detection 
Method 
Healthy Controls 
Reference 
Sample 
Size 
Mean 
Standard 
Deviation 
Serum 
ELISA 
(R&D, 
Minneapolis 
USA) 
48 
616 
290.6 
Internal REGN Study:  R668-AS-
0907 
Serum 
ELISA 
(R&D, 
Minneapolis 
USA) 
44 
437.9 
292 
K. Jahnz-Rozyk, et al,"Serum thymus 
and activation-regulated chemokine, 
macrophage derived chemokine and 
eotaxin as markers of severity of 
atopic dermatitis." Allergy 2005: 60: 
685–688 
Serum 
ELISA 
(R&D, 
Minneapolis 
USA) 
20 
258 
123 
Caproni M, et al; "Serological 
detection of eotaxin, IL-4, IL-13, 
IFN-g,MIP-1a, TARC and IP-10 in 
chronic autoimmune urticaria and 
chronic idiopathic urticaria." J 
Dermatol. Science (2004) 36, 57-59 
COMBINED: 
112 
482.1 
299.7 
ULN: 1081.5 (482.1+2*299.7) 
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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 first administration of study drug in the current 
study. 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. 
The baseline value of parent study is defined as the baseline value a patient had prior to the first 
dose in the parent study. For patients who have been screened for a phase 3 study 
(R668-AD-1334 or R668-AD-1416), but could not be randomized because of randomization 
closure, the initial baseline value of the parent study will be the last nonmissing value during the 
screening period in the parent study. 
6.2. 
General Data Handling Conventions 
For the laboratory safety variables and biomarker data, if the data are below the lower limit of 
quantification (LLOQ) / limit of linearity, then 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. For example, if the assessment of relationship of a TEAE to the 
investigational product is missing, it will be classified as “related” in the frequency tables by 
relation to the investigational product. 
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Adverse event start date  
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month) then impute 
AE start day using the day of first dose. If this leads to a date after the AE end date, use AE end 
date instead. Otherwise impute the AE start day using the first day of the month. If this leads to a 
date before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
If AE start month is missing, and AE start year is not missing: If AE start year is less than the 
first dose year, use the informed consent day and month. If AE start year is equal to the first dose 
year, use the first dose day and month. If this leads to a date after the AE end date, use AE end 
date instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE starting date imputation, In order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use end of 
follow up date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 
31 December as the day and month. If this leads to a date after end of study follow up date, use 
the end of follow up date instead. 
If AE end year is missing: Impute AE end date using the end of follow up date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment medication or concomitant medication or 
both, the missing medication start date is estimated as early as possible, and the missing 
medication end date is estimated as late as possible. If the medication start date is missing, the 
onset day will not be calculated in medication listings. 
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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 inline with the protocol 
which specifies to collect up to 2 years prior medication. Since the start date of prior medication 
will not be used in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing:  Impute end date using the last 
day of the month. If this leads to a date on or after first dose intake date, use first dose intake 
date -1 instead.  Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month.  If this leads to a date on or after first dose intake date, use first dose intake 
date -1 instead.  Imputation flag is ‘M’ 
If end year is missing: Impute end date using the first dose intake date –1. Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use end of follow up date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the end of follow up 
date instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of follow up date. Imputation flag is ‘Y’. 
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Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study DM and study MD. 
PCSV 
Patients who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.4. 
Analysis Visit Window 
Data analyzed by-visit-analysis (including efficacy, laboratory data, visit sign, ECG) will be 
summarized by the study scheduled visits described in the study protocol and SAP, “Schedule of 
Event”. The analysis visit windows will be exhaustive so that all available values obtained from 
unscheduled visits, early termination (ET) visit and end of treatment (EOT)/end of study (EOS) 
have the potential to be summarized. No analysis visit window mapping will be applied for the 
PK and ADA data.  
Under protocol amendment 6, the planned study duration was up to three years or until 
dupilumab became commercially available in the geographic region of the patient. Protocol 
amendment 7 was adopted in order to permit those patients in France, Germany Poland and 
Japan who had already completed three years of treatment to either continue or re-start treatment 
through 31 December 2017. Patients who were in the safety follow-up period were permitted to 
resume treatment. Patients who had an End of Study visit were permitted to re-enter the study 
after being re-consented. Patients who had completed 3 years of treatment resumed treatment in a 
newly created series of visits called the “treatment extension” period.  All patients were 
scheduled to have an End of Treatment visit on or around 31 December 2017. 
Protocol amendment 8 extended the treatment period for up to 5 years for patients in Poland and 
Finland and to September 2018 in France. Again, patients who had previously had an End of 
Treatment visit under Amendment 7 and were in the safety follow-up period were permitted to 
resume treatment. Patients who had an End of Study visit were permitted to re-enter the study 
after being re-consented. 
As a consequence of these two amendments, certain patients from these countries experienced 
gaps in treatment. One gap occurred between the Amendment 6 EoT date and resumption of 
treatment under Amendment 7. In addition, patients from Poland experienced a second treatment 
gap from the EoT date under Amendment 7 and resumption of treatment under Amendment 8. 
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The data collected at the scheduled visits under protocol amendment 7 and protocol amendment 
8 for patients from these countries was collected outside of previously defined visit windows. 
Hence the analysis visit window will be done separately for data collected under protocol 
amendment 7/8 for patients from France, Germany, Poland, Japan and Finland and all remaining 
data. All remaining data consists of: 
 data collected up to protocol amendment 6 for patients from France, Germany, 
Poland, Japan and Finland  
 data from all other countries  
Analysis visit window mapping for all remaining data  
No analysis visit windows will be applied for the study scheduled visits except unscheduled 
visits, early termination visit, the end of treatment/ end of study visits, which are V30 (week 148), 
V25 (week 112) and V25 (week 108) for patients from UK, V31 (week 164) and V31 (week 160) 
for all countries except UK.  
The following analysis visit windows will be used to map the unscheduled visits, early 
termination, end of treatment/ end of study visits, based on the study day: 
Visit 
Target Day 
Analysis Visit Window Based 
on Study day* 
Screening 
<1 
<1 
Baseline 
1 
1 
Week 1 
8 
[2,11] 
Week 2 
15 
[12,18] 
Week 3 
22 
[19, 25] 
Week 4 
29 
[26, 43] 
Week 8 
57 
[44, 71] 
Week 12 
85 
[72, 99] 
Week 16 
113 
[100, 127] 
Week 20 
141 
[128, 155] 
Week 24 
169 
[156, 183] 
Week 28 
197 
[184, 211] 
Week 32 
225 
[212, 239] 
Week 36 
253 
[240, 267] 
Week 40 
281 
[268, 295] 
Week 44 
309 
[296, 323] 
Week 48 
337 
[324, 351] 
Week 52 
365 
[352, 393] 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 56 of 107 
Visit 
Target Day 
Analysis Visit Window Based 
on Study day* 
Week 60 
421 
[394, 449] 
Week 68 
477 
[450, 505] 
Week 76 
533 
[506, 561] 
Week 84 
589 
[562, 617] 
Week 92 
645 
[618, 673] 
Week 100 
701 
[674, 729] 
Week 108 
757 
[730, 785] 
Week 116 
813 
[786, 841] 
Week 124 
869 
[842, 897] 
Week 132 
925 
[898, 953] 
Week 140 
981 
[954, 1009] 
Week 148 
1037 
[1010, 1093] 
End of study 
1149 
>=1094 
785 for UK 
>=730 
*study day is calculated relative to the date of first study drug injection. 
Analysis visit window mapping for data collected under protocol amendment 7/8 for 
patients from France, Germany, Poland, Japan and Finland 
Analysis visit windows will be applied to map all study scheduled visits except extension end of 
study visit or end of study visit under protocol amendment 7 or 8, based on the study day. Data 
collected at extension end of study visit or end of study visit under protocol amendment 7 or 8 
will be summarized using the nominal visit (i.e. extension end of study visit or end of study visit).   
Visit 
Target Day 
Analysis Visit Window Based 
on Study day* 
Screening 
<1 
<1 
Baseline 
1 
1 
Week 1 
8 
[2,11] 
Week 2 
15 
[12,18] 
Week 3 
22 
[19, 25] 
Week 4 
29 
[26, 43] 
Week 8 
57 
[44, 71] 
Week 12 
85 
[72, 99] 
Week 16 
113 
[100, 127] 
Week 20 
141 
[128, 155] 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 57 of 107 
Visit 
Target Day 
Analysis Visit Window Based 
on Study day* 
Week 24 
169 
[156, 183] 
Week 28 
197 
[184, 211] 
Week 32 
225 
[212, 239] 
Week 36 
253 
[240, 267] 
Week 40 
281 
[268, 295] 
Week 44 
309 
[296, 323] 
Week 48 
337 
[324, 351] 
Week 52 
365 
[352, 393] 
Week 60 
421 
[394, 449] 
Week 68 
477 
[450, 505] 
Week 76 
533 
[506, 561] 
Week 84 
589 
[562, 617] 
Week 92 
645 
[618, 673] 
Week 100 
701 
[674, 729] 
Week 108 
757 
[730, 785] 
Week 116 
813 
[786, 841] 
Week 124 
869 
[842, 897] 
Week 132 
925 
[898, 953] 
Week 140 
981 
[954, 1009] 
Week 148 
1037 
[1010, 1065] 
Week 156 
1093 
[1066, 1149] 
Week 172 
1205 
[1150, 1261] 
Week 188 
1317 
[1262, 1373] 
Week 204 
1429 
[1374, 1485] 
Week 220 
1541 
[1486, 1597] 
Week 236 
1653 
[1598, 1709] 
Week 252 
1765 
[1710, 1793] 
End of study 
1821 
>=1794 
*study day is calculated relative to the date of first study drug injection. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 58 of 107 
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. 
Analysis visit window mapping for weekly pruritus NRS  
For the weekly pruritus NRS collected via IVRS, the following analysis visit windows will be 
used based on the study day: 
Visit 
Target Day 
Analysis Visit Window 
Based on Study day* 
Screening 
<1 
<1 
Baseline 
1 
1 
Week 1 
8 
[2,11] 
Week 2 
15 
[12,18] 
Week 3 
22 
[19, 25] 
Week 4 
29 
[26, 32] 
Week 5 
36 
[33, 39] 
Week 6 onwards (every week) 
43 (every 7 days) 
…. 
* study day is calculated relative to the date of first study drug injection. 
If there are multiple patient reported NRSs in the same week, then the average value of all scores 
in the week will be used for analysis. 
Analysis visit window mapping for Ophthalmological Examination   
No analysis visit windows will be applied for the ophthalmological exam scheduled visits in the 
sub-study. Data will be summarized using the nominal visit.  
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 59 of 107 
7. 
INTERIM ANALYSIS 
This is an open-label extension study. No formal interim analyses will be planned for this study. 
A first step analysis was performed to support the submission of market application for 
dupilumab in AD indication in third quarter of year 2016. All data prior to the cutoff date 
(11Apr2016) were included in this analysis. The process to derive the data cut-off for the first 
step analysis is outlined in Appendix 10.7. 
A second step analysis will be performed in first quarter of year 2019 in order to have long term 
data of dupilumab in AD indication. All data prior to the cutoff date (around 01Dec2018) for 
patients in Poland, Finland, Russia, New Zealand, Singapore and all data for patients from 
remaining countries will be included in this analysis. Patients from remaining countries will 
either complete or early withdrawn from the study at time of database lock. The process to derive 
the data cut-off for the second step analysis is outlined in Appendix 10.8. 
Future analyses will be performed to support the subsequent regulatory filings. The details and 
data cutoff date will be specified in future SAP addendum. 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 60 of 107 
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. 
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;140:1513-1519. 
Greiner W, Claes C, Buschbach JJV, Graf von der Schulenburg JM. Validating the EQ-5D with 
time trade-off for the German population. Eur J Health Econ 2005; 6(2):124-130.  
Hanifin JM, Thurston M, Omoto M et al. The eczema area and severity index (EASI): 
assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001;10: 
11-18. 
ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of clinical 
study reports (E3). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for clinical 
trials (E8). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
Phadia AB, 2014-Apr-24: ImmunoCAP® Total IgE Fluoroenzyme immunoassay, CLIA 
Complexity Category = Moderately Complex, Directions for Use 52-5292-US/01. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 61 of 107 
10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Endpoint 
Analysis 
Population 
Primary Statistical Method  
Supportive 
Statistical Method 
Subgroup 
Analysis 
Other Analyses 
Continuous variables 
SAF 
Descriptive Statistics 
No 
Yes for key 
secondary 
endpoint 
No 
Categorical variables 
SAF 
Descriptive Statistics 
No 
Yes for key 
secondary 
endpoint 
No 
Time to event variable 
SAF 
Kaplan-Meier curve 
No 
No 
No 
Safety Analyses: 
 
Analysis 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Populations 
Method 
Analysis 
Analysis 
Analyses 
Adverse Events 
SAF 
Descriptive Statistics 
No 
Yes for 
selected AEs 
No 
Laboratory Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 62 of 107 
10.2. 
Schedule of Events 
Study assessments and procedures for protocol amendment 7 global are presented by study period and visit in Table 4. 
Table 4: 
Schedule of Events – Visits 1 through 8 (Week 12) 
Study Procedures 
Screening* 
Baseline 
Treatment Period 
Visit (V) 
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
Week (Wk) 
 
 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Day (D) 
Visit Window (d) 
-28 to -1 a 
D 1 
D 8 
+/-2d 
D 15 
+/-2d 
D 22 
+/-2d 
D 29 
+/-3d 
D 57 
+/-3d 
D 85 
+/-3d 
Screening/Baseline: 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Medical History/Demographics 
X 
X 
 
 
 
 
 
 
Training on IVRS/IWRS 
 
X 
 
 
 
 
 
 
Treatment: 
Injection training/observation 
 
X 
 
 
 
X 
 
 
Administer study drugc 
 
Xb 
 
 
 
 
 
 
Patient dosing diary d 
 
X 
 
 
 
X 
 
X 
Study drug 
dispensation/account.e 
 
X 
 
 
 
X 
 
X 
Con meds/procedures 
X 
X 
 
 
 
X 
 
 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 63 of 107 
Study Procedures 
Screening* 
Baseline 
Treatment Period 
Visit (V) 
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
Week (Wk) 
 
 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Day (D) 
Visit Window (d) 
-28 to -1 a 
D 1 
D 8 
+/-2d 
D 15 
+/-2d 
D 22 
+/-2d 
D 29 
+/-3d 
D 57 
+/-3d 
D 85 
+/-3d 
Efficacy: f 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS 
(weekly)i 
 
X 
 
 
 
X 
 
 
IGA, EASI 
X 
X 
 
 
 
X 
 
 
POEM, DLQI, EQ-5D g 
 
X 
 
 
 
 
 
 
Safety: f 
Weight 
X 
X 
 
 
 
 
 
 
Height 
X 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
 
 
 
X 
 
 
Physical examination 
 
X 
 
 
 
 
 
 
Ophthalmology examk (select 
sites and patients) 
 
X 
 
 
 
X 
 
X 
Adverse eventsh 
X 
X 
 
 
 
X 
 
X 
Laboratory Testing: f 
Hematology, Chemistry 
X 
X 
 
 
 
 
 
 
Pregnancy test, WOCBP only 
Serum 
Urinel 
 
 
 
Urinel 
 
Urinel 
HIV screening j 
X 
 
 
 
 
 
 
 
HBsAg, HBcAb, hepatitis C 
antibody j 
X 
 
 
 
 
 
 
 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 64 of 107 
Study Procedures 
Screening* 
Baseline 
Treatment Period 
Visit (V) 
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
Week (Wk) 
 
 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Day (D) 
Visit Window (d) 
-28 to -1 a 
D 1 
D 8 
+/-2d 
D 15 
+/-2d 
D 22 
+/-2d 
D 29 
+/-3d 
D 57 
+/-3d 
D 85 
+/-3d 
Drug Concentration/PK and Anti-drug Antibody Testing: f 
Drug concentration/PK sample 
 
X 
 
 
 
 
 
 
ADA sample 
 
X 
 
 
 
 
 
 
*Note:  The screening visit in this study may coincide with the last visit in the previous study.  Assessments that are common to both studies will be performed 
only once. 
a. Patients who fail screening or who fail to complete the baseline visit within 28 days of screening may be rescreened upon approval by the medical monitor. 
b. A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will be administered on day 1 unless the patient has received a dose 
of dupilumab in the 4 weeks prior to baseline.  If the patient has received a dose of dupilumab in the past 4 weeks, then they will receive a single 300 mg dose 
at baseline.  The first dose should be at least 1 week after the last dose in the previous study, and then 300 mg dupilumab qw starting on day 8.  In addition to 
the predose assessments, vital signs and AEs will be assessed at 30 (+/- 10) minutes postdose. 
c. Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). 
d. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic  
e. Starting at visit 2, study drug will be dispensed to the patient for all doses that will be administered before the next clinic visit.  Patients will be instructed to 
return all study drug at each clinic visit. 
f. To be collected before the injection of study drug.  The order of the assessment should be questionnaires first, followed by laboratory evaluations.   
g. The questionnaires will be administered only to the subset of patients who fluently speak the language for which a validated translation of the questionnaire is 
available. 
h. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.   
i. Patients will be trained on using the IVRS/IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over the 
previous week, and to record compliance with self-injection of study drug. 
j. Any of these tests is required only for patients who have not had a documented negative result for the respective test within 1 year prior to baseline (the negative 
HIV result must be from a parent study).  
k. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit, which can take place at any time between the screening and baseline visits, inclusive. 
l. Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 65 of 107 
Table 5: 
Schedule of Events – Visits 9 (Week 16) through 18 (Week 52) 
Study Procedures 
Treatment Period 
Visit (V) 
V 9 
V 10 
V 11 
V 12 
V 13 
V 14 
V 15 
V 16 
V 17 
V 18 
Week (Wk) 
Wk 16 
Wk 20 
Wk 24 
Wk 28 
Wk 32 
Wk 36 
Wk 40 
Wk 44 
Wk 48 
Wk 52 
Day (D) 
Visit Window (d) 
D 113 
+/-3d 
D 141 
+/-3d 
D 169 
+/-3d 
D 197 
+/-3d 
D 225 
+/-3d 
D 253 
+/-3d 
D 281 
+/-3d 
D 309 
+/-3d 
D 337 
+/-3d 
D 365 
+/-3d 
Treatment: 
 
Administer study drug a 
X 
 
 
 
 
 
 
 
 
 
Patient dosing diaryb 
X 
 
X 
 
X 
 
X 
 
X 
X 
Study drug 
dispensation/account.c 
X 
 
X 
 
X 
 
X 
 
X 
X 
Con meds/procedures 
X 
 
 
 
X 
 
 
 
X 
 
Efficacy: d 
 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS 
(weekly)g 
X 
 
 
 
 
 
 
 
X 
 
IGA, EASI  
X 
 
 
 
 
 
 
 
X 
 
POEM, DLQI, EQ-5D e 
 
 
 
 
 
 
 
 
X 
 
Safety: d 
 
Weight 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
X 
 
 
 
X 
 
 
 
X 
 
Ophthalmology exami (select 
sites and patients) 
X 
 
 
 
X 
 
 
 
X 
 
Adverse eventsf 
X 
 
X 
 
X 
 
X 
 
 
X 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 66 of 107 
Study Procedures 
Treatment Period 
Visit (V) 
V 9 
V 10 
V 11 
V 12 
V 13 
V 14 
V 15 
V 16 
V 17 
V 18 
Week (Wk) 
Wk 16 
Wk 20 
Wk 24 
Wk 28 
Wk 32 
Wk 36 
Wk 40 
Wk 44 
Wk 48 
Wk 52 
Day (D) 
Visit Window (d) 
D 113 
+/-3d 
D 141 
+/-3d 
D 169 
+/-3d 
D 197 
+/-3d 
D 225 
+/-3d 
D 253 
+/-3d 
D 281 
+/-3d 
D 309 
+/-3d 
D 337 
+/-3d 
D 365 
+/-3d 
Laboratory Testing: d 
 
Hematology, Chemistry 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy test, WOCBP only 
Urineh, monthly throughout the study treatment  
Drug Concentration and Antibody Testing: d 
Drug Concentration sample 
 
 
 
 
 
 
 
 
X 
 
ADA sample 
 
 
 
 
 
 
 
 
X 
 
a. Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). 
b. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic.   
c. Study drug will be dispensed to the patient for all doses that will be administered before the next clinic visit.  Patients will be instructed to return all study drug 
at each clinic visit. 
d. To be collected before the injection of study drug.  The order of the assessment should be questionnaires first, followed by laboratory evaluations.   
e. The questionnaires will be administered only to the subset of patients who fluently speak the language for which a validated translation of the questionnaire is 
available. 
f. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet. 
g. Patients will be trained on using the IVRS/IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over the 
previous week, and to record compliance with self-injection of study drug. 
h. Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
i. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit. 
 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 67 of 107 
Table 6: 
Schedule of Events – Visits 19 (Week 60) through 24 (Week 100) 
Study Procedures 
Treatment Period 
Visit (V) 
V 19 
V 20 
V 21 
V 22 
V 23 
V 24 
Week (Wk) 
Wk 60 
Wk 68 
Wk 76 
Wk 84 
Wk 92 
Wk 100 
Day (D) 
Visit Window (d) 
D 421 
+/-3d 
D 477 
+/-3d 
D 533 
+/-3d 
D 589 
+/-3d 
D 645 
+/-3d 
D 701 
+/-3d 
Treatment: 
Administer study druga 
X 
 
 
 
 
 
Patient dosing diaryb 
X 
X 
X 
X 
X 
X 
Study drug 
dispensation/account.c 
X 
X 
X 
X 
X 
X 
Con meds/procedures 
X 
 
X 
 
X 
 
Efficacy: d 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS 
(weekly)g 
X 
 
 
 
 
X 
IGA, EASI 
X 
 
 
 
 
X 
POEM, DLQI, EQ-5D e 
 
 
 
 
 
X 
Safety: d 
Weight 
X 
 
X 
 
 
X 
Vital signs 
X 
 
X 
X 
X 
X 
Ophthalmology exami (select 
sites and patients) 
X 
 
X 
 
X 
 
Adverse eventsf 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 68 of 107 
Study Procedures 
Treatment Period 
Visit (V) 
V 19 
V 20 
V 21 
V 22 
V 23 
V 24 
Week (Wk) 
Wk 60 
Wk 68 
Wk 76 
Wk 84 
Wk 92 
Wk 100 
Day (D) 
Visit Window (d) 
D 421 
+/-3d 
D 477 
+/-3d 
D 533 
+/-3d 
D 589 
+/-3d 
D 645 
+/-3d 
D 701 
+/-3d 
Laboratory Testing: d 
Hematology, Chemistry 
 
 
 
 
 
X 
Pregnancy test, WOCBP only 
Urineh, monthly throughout the study treatment  
Drug Concentration and Antibody Testing: d 
Drug Concentration sample 
 
 
 
 
 
X 
ADA sample 
 
 
 
 
 
X 
a.  Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). 
b.  If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c.  Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug vials at each clinic visit. 
d.  To be collected before the injection of study drug.  The order of the assessment should be questionnaires first, followed by laboratory evaluations. 
e.  The questionnaires will be administered only to the subset of patients who fluently speak the language for which a validated translation of the questionnaire is 
available. 
f.  In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
g. Patients will be trained on using the IVRS /IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
h. Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
i. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 69 of 107 
Table 7: 
Schedule of Events – Visits 25 (Week 108) through End of Study (Week 160) 
Study Procedures 
Treatment Period 
End of Tx 
End of 
Studym 
Early 
Terminatio
n 
Unschedul
ed Visitj 
(if 
applicable) 
Visit (V) 
V 25 
V 26 
V 27 
V 28 
V 29 
V30 
V31 
Week (Wk) 
Wk 108 
Wk 116 
Wk 124 
Wk 132 
Wk 140 
Wk 148 
Wk160 
or last dose 
+12Wk 
 
 
Day (D) 
Visit Window (d) 
D 757 
+/-3d 
D 813 
+/-3d 
D 869 
+/-3d 
D 925 
+/-3d 
D 981 
+/-3d 
D 1037 
+/-3d 
D1121 or 
Last dose 
+84D 
 
 
Treatment: 
Administer study druga 
X 
 
 
 
 
 
 
 
 
Patient dosing diaryb 
X 
X 
X 
X 
X 
X 
 
X 
 
Study drug dispensation/account.c 
X 
X 
X 
X 
X 
X 
 
X 
 
Con meds/procedures 
X 
 
X 
 
X 
 
X 
X 
X 
Efficacy: d 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS (weekly)f 
X 
 
X 
 
 
 
X 
Xf 
Xh 
IGA, EASI 
 
 
X 
 
 
 
X 
X 
X 
Safety: d 
Weight 
X 
 
X 
 
 
X 
X 
X 
X 
Vital signs 
X 
 
X 
 
X 
X 
X 
X 
X 
Ophthalmology examk (select sites 
and patients) 
X 
 
X 
 
X 
 
X 
 
Xl 
Adverse eventse  
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 70 of 107 
Study Procedures 
Treatment Period 
End of Tx 
End of 
Studym 
Early 
Terminatio
n 
Unschedul
ed Visitj 
(if 
applicable) 
Visit (V) 
V 25 
V 26 
V 27 
V 28 
V 29 
V30 
V31 
Week (Wk) 
Wk 108 
Wk 116 
Wk 124 
Wk 132 
Wk 140 
Wk 148 
Wk160 
or last dose 
+12Wk 
 
 
Day (D) 
Visit Window (d) 
D 757 
+/-3d 
D 813 
+/-3d 
D 869 
+/-3d 
D 925 
+/-3d 
D 981 
+/-3d 
D 1037 
+/-3d 
D1121 or 
Last dose 
+84D 
 
 
Laboratory Testing: d 
Hematology, Chemistry 
 
 
 
 
 
X 
 
 
X 
Pregnancy test, WOCBP only 
Urineg, monthly throughout the study treatment  
Urine 
HIV screening 
 
 
 
 
 
 
 
 
X 
HBsAg, HBcAb, hepatitis C 
antibody  
 
 
 
 
 
 
 
 
X 
Drug Concentration and Antibody Testing: d 
Drug Concentration sample 
 
 
X 
 
 
 
X 
X 
X 
ADA sample 
 
 
X 
 
 
X 
Xi 
Xi 
X 
a  Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). 
b. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c. Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug vials at each clinic visit. 
d. To be collected before the injection of study drug. 
e. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
f. Patients will be trained on using the IVRS /IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
g. Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
h If the call was performed on the patient’s weekly schedule, then it will not need to be repeated. 
i. Patients who test positive for ADA at their last study visit (early termination visit or end of study visit) may be asked to return to the clinic to have additional 
ADA samples collected for analysis. 
j. During an unscheduled visit, any of the study procedures noted may be performed, but not all are required. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


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R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
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k. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit. 
l. Patients who experience AEs consistent with conjunctivitis or other superficial inflammation of the eye (blepharitis, keratitis, etc) should undergo additional 
(unscheduled) ophthalmology exams to allow accurate diagnosis and adequate treatment. 
m If the end of study assessments cannot be completed on the scheduled date (ie, 12 weeks after the last dose of dupilumab), a late visit is acceptable and is 
preferable to foregoing these assessments altogether; this visit should be conducted as close as possible to the scheduled date. 
 
 
 
Study assessments and procedures for protocol amendment 8 for Poland/Finland are presented by study period and visit in Table 12, 
Table 13, and Table 14. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
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Table 8: 
Schedule of Events – Visits 1 through 8 (Week 12) 
Study Procedures 
Screening* 
Baseline 
Treatment Period 
Visit (V) 
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
Week (Wk) 
 
 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Day (D) 
Visit Window (d) 
-28 to -1 a 
D 1 
D 8 
+/-2d 
D 15 
+/-2d 
D 22 
+/-2d 
D 29 
+/-3d 
D 57 
+/-3d 
D 85 
+/-3d 
Screening/Baseline: 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Medical History/Demographics 
X 
X 
 
 
 
 
 
 
Training on IVRS/IWRS 
 
X 
 
 
 
 
 
 
Treatment: 
Injection training/observation 
 
X 
 
 
 
X 
 
 
Administer study drugc 
 
Xb 
 
 
 
 
 
 
Patient dosing diary d 
 
X 
 
 
 
X 
 
X 
Study drug 
dispensation/account.e 
 
X 
 
 
 
X 
 
X 
Con meds/procedures 
X 
X 
 
 
 
X 
 
 
Efficacy: f 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS 
(weekly)i 
 
X 
 
 
 
X 
 
 
IGA, EASI 
X 
X 
 
 
 
X 
 
 
POEM, DLQI, EQ-5D g 
 
X 
 
 
 
 
 
 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
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Study Procedures 
Screening* 
Baseline 
Treatment Period 
Visit (V) 
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
Week (Wk) 
 
 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Day (D) 
Visit Window (d) 
-28 to -1 a 
D 1 
D 8 
+/-2d 
D 15 
+/-2d 
D 22 
+/-2d 
D 29 
+/-3d 
D 57 
+/-3d 
D 85 
+/-3d 
Safety: f 
Weight 
X 
X 
 
 
 
 
 
 
Height 
X 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
 
 
 
X 
 
 
Physical examination 
 
X 
 
 
 
 
 
 
Ophthalmology examk (select 
sites and patients) 
 
X 
 
 
 
X 
 
X 
Adverse eventsh 
X 
X 
 
 
 
X 
 
X 
Laboratory Testing: f 
Hematology, Chemistry 
X 
X 
 
 
 
 
 
 
Pregnancy test, WOCBP only 
Serum 
Urinel 
 
 
 
Urinel 
 
Urinel 
HIV screening j 
X 
 
 
 
 
 
 
 
HBsAg, HBcAb, hepatitis C 
antibody j 
X 
 
 
 
 
 
 
 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 74 of 107 
Study Procedures 
Screening* 
Baseline 
Treatment Period 
Visit (V) 
V 1 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
Week (Wk) 
 
 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Day (D) 
Visit Window (d) 
-28 to -1 a 
D 1 
D 8 
+/-2d 
D 15 
+/-2d 
D 22 
+/-2d 
D 29 
+/-3d 
D 57 
+/-3d 
D 85 
+/-3d 
Drug Concentration/PK and Anti-drug Antibody Testing: f 
Drug concentration/PK sample 
 
X 
 
 
 
 
 
 
ADA sample 
 
X 
 
 
 
 
 
 
*Note:  The screening visit in this study may coincide with the last visit in the previous study.  Assessments that are common to both studies will be performed 
only once. 
a. Patients who fail screening or who fail to complete the baseline visit within 28 days of screening may be rescreened upon approval by the medical monitor. 
b. A loading dose of 600 mg SC (two 300 mg doses administered on the same day) dupilumab will be administered on day 1 unless the patient has received a dose 
of dupilumab in the 4 weeks prior to baseline.  If the patient has received a dose of dupilumab in the past 4 weeks, then they will receive a single 300 mg dose 
at baseline.  The first dose should be at least 1 week after the last dose in the previous study, and then 300 mg dupilumab qw starting on day 8.  In addition to 
the predose assessments, vital signs and AEs will be assessed at 30 (+/- 10) minutes postdose. 
c. Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). 
d. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic  
e. Starting at visit 2, study drug will be dispensed to the patient for all doses that will be administered before the next clinic visit.  Patients will be instructed to 
return all study drug at each clinic visit. 
f. To be collected before the injection of study drug.  The order of the assessment should be questionnaires first, followed by laboratory evaluations.   
g. The questionnaires will be administered only to the subset of patients who fluently speak the language for which a validated translation of the questionnaire is 
available. 
h. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.   
i. Patients will be trained on using the IVRS/IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over the 
previous week, and to record compliance with self-injection of study drug. 
j. Any of these tests is required only for patients who have not had a documented negative result for the respective test within 1 year prior to baseline (the negative 
HIV result must be from a parent study).  
k. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit, which can take place at any time between the screening and baseline visits, inclusive. 
l. Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
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Table 9: 
Schedule of Events – Visits 9 (Week 16) through 18 (Week 52) 
Study Procedures 
Treatment Period 
Visit (V) 
V 9 
V 10 
V 11 
V 12 
V 13 
V 14 
V 15 
V 16 
V 17 
V 18 
Week (Wk) 
Wk 16 
Wk 20 
Wk 24 
Wk 28 
Wk 32 
Wk 36 
Wk 40 
Wk 44 
Wk 48 
Wk 52 
Day (D) 
Visit Window (d) 
D 113 
+/-3d 
D 141 
+/-3d 
D 169 
+/-3d 
D 197 
+/-3d 
D 225 
+/-3d 
D 253 
+/-3d 
D 281 
+/-3d 
D 309 
+/-3d 
D 337 
+/-3d 
D 365 
+/-3d 
Treatment: 
 
Administer study drug a 
X 
 
 
 
 
 
 
 
 
 
Patient dosing diaryb 
X 
 
X 
 
X 
 
X 
 
X 
X 
Study drug 
dispensation/account.c 
X 
 
X 
 
X 
 
X 
 
X 
X 
Con meds/procedures 
X 
 
 
 
X 
 
 
 
X 
 
Efficacy: d 
 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS 
(weekly)g 
X 
 
 
 
 
 
 
 
X 
 
IGA, EASI  
X 
 
 
 
 
 
 
 
X 
 
POEM, DLQI, EQ-5D e 
 
 
 
 
 
 
 
 
X 
 
Safety: d 
 
Weight 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
X 
 
 
 
X 
 
 
 
X 
 
Ophthalmology exami (select 
sites and patients) 
X 
 
 
 
X 
 
 
 
X 
 
Adverse eventsf 
X 
 
X 
 
X 
 
X 
 
X 
X 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 76 of 107 
Study Procedures 
Treatment Period 
Visit (V) 
V 9 
V 10 
V 11 
V 12 
V 13 
V 14 
V 15 
V 16 
V 17 
V 18 
Week (Wk) 
Wk 16 
Wk 20 
Wk 24 
Wk 28 
Wk 32 
Wk 36 
Wk 40 
Wk 44 
Wk 48 
Wk 52 
Day (D) 
Visit Window (d) 
D 113 
+/-3d 
D 141 
+/-3d 
D 169 
+/-3d 
D 197 
+/-3d 
D 225 
+/-3d 
D 253 
+/-3d 
D 281 
+/-3d 
D 309 
+/-3d 
D 337 
+/-3d 
D 365 
+/-3d 
Laboratory Testing: d 
 
Hematology, Chemistry 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy test, WOCBP only 
Urineh, monthly throughout the study treatment  
Drug Concentration and Antibody Testing: d 
Drug Concentration sample 
 
 
 
 
 
 
 
 
X 
 
ADA sample 
 
 
 
 
 
 
 
 
X 
 
a. Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). 
b. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic.   
c. Study drug will be dispensed to the patient for all doses that will be administered before the next clinic visit.  Patients will be instructed to return all study drug 
at each clinic visit. 
d. To be collected before the injection of study drug.  The order of the assessment should be questionnaires first, followed by laboratory evaluations.   
e. The questionnaires will be administered only to the subset of patients who fluently speak the language for which a validated translation of the questionnaire is 
available. 
f. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet. 
g. Patients will be trained on using the IVRS/IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over the 
previous week, and to record compliance with self-injection of study drug. 
h. Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
i. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit. 
 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
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Table 10: 
Schedule of Events – Visits 19 (Week 60) through 24 (Week 100) 
Study Procedures 
Treatment Period 
Visit (V) 
V 19 
V 20 
V 21 
V 22 
V 23 
V 24 
Week (Wk) 
Wk 60 
Wk 68 
Wk 76 
Wk 84 
Wk 92 
Wk 100 
Day (D) 
Visit Window (d) 
D 421 
+/-3d 
D 477 
+/-3d 
D 533 
+/-3d 
D 589 
+/-3d 
D 645 
+/-3d 
D 701 
+/-3d 
Treatment: 
Administer study druga 
X 
 
 
 
 
 
Patient dosing diaryb 
X 
weekly throughout the study treatment 
X 
Study drug 
dispensation/account.c 
X 
throughout the study treatment at each visit 
X 
Con meds/procedures 
X 
 
X 
 
X 
 
Efficacy: d 
Patient Assessment of Pruritus 
Intensity via IVRS/IWRS 
(weekly)g 
X 
 
 
 
 
X 
IGA, EASI 
X 
 
 
 
 
X 
POEM, DLQI, EQ-5D e 
 
 
 
 
 
X 
Safety: d 
Weight 
X 
 
X 
 
 
X 
Vital signs 
X 
 
X 
X 
X 
X 
Ophthalmology exami (select 
sites and patients) 
X 
 
X 
 
X 
 
Adverse eventsf 
X 
throughout the study 
X 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 78 of 107 
Study Procedures 
Treatment Period 
Visit (V) 
V 19 
V 20 
V 21 
V 22 
V 23 
V 24 
Week (Wk) 
Wk 60 
Wk 68 
Wk 76 
Wk 84 
Wk 92 
Wk 100 
Day (D) 
Visit Window (d) 
D 421 
+/-3d 
D 477 
+/-3d 
D 533 
+/-3d 
D 589 
+/-3d 
D 645 
+/-3d 
D 701 
+/-3d 
Laboratory Testing: d 
Hematology, Chemistry 
 
 
 
 
 
X 
Pregnancy test, WOCBP only 
Urineh, monthly throughout the study treatment  
Drug Concentration and Antibody Testing: d 
Drug Concentration sample 
 
 
 
 
 
X 
ADA sample 
 
 
 
 
 
X 
a.  Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). 
b.  If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c.  Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
d.  To be collected before the injection of study drug.  The order of the assessment should be questionnaires first, followed by laboratory evaluations. 
e.  The questionnaires will be administered only to the subset of patients who fluently speak the language for which a validated translation of the questionnaire is 
available. 
f.  In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
g. Patients will be trained on using the IVRS /IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
h. Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
i. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 79 of 107 
Table 11: 
Schedule of Events – Visits 25 (Week 108) through Visit 30 (Week 148)  
Study Procedures 
Treatment Period 
 
 
 
 
 
 
 
Visit (V) 
V 25 
V 26 
V 27 
V 28 
V 29 
V30 
Week (Wk) 
Wk 108 
Wk 116 
Wk 124 
Wk 132 
Wk 140 
Wk 148 
Day (D) 
Visit Window (d) 
D 757 
+/-3d 
D 813 
+/-3d 
D 869 
+/-3d 
D 925 
+/-3d 
D 981 
+/-3d 
D 1037 
+/-3d 
Treatment: 
 
 
 
 
 
 
Administer study druga 
X 
weekly throughout the study treatment 
X 
Patient dosing diaryb 
X 
weekly throughout the study treatment 
X 
Study drug dispensation/accountc 
X 
throughout the study treatment at each visit 
X 
Con meds/procedures 
X 
 
X 
 
X 
 
Efficacy: d 
 
 
 
 
 
 
Patient Assessment of Pruritus Intensity via 
IVRS/IWRS (weekly)f 
X 
 
weekly throughout the study 
X 
IGA, EASI 
 
 
X 
 
 
 
Safety: d 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
 
Vital signs 
X 
 
X 
 
X 
 
Ophthalmology examh (select sites and 
patients) 
X 
 
X 
 
X 
 
Adverse eventse 
X  
throughout the study 
X 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


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R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 80 of 107 
Study Procedures 
Treatment Period 
 
 
 
 
 
 
 
Visit (V) 
V 25 
V 26 
V 27 
V 28 
V 29 
V30 
Week (Wk) 
Wk 108 
Wk 116 
Wk 124 
Wk 132 
Wk 140 
Wk 148 
Day (D) 
Visit Window (d) 
D 757 
+/-3d 
D 813 
+/-3d 
D 869 
+/-3d 
D 925 
+/-3d 
D 981 
+/-3d 
D 1037 
+/-3d 
Laboratory Testing: d 
 
 
 
 
 
 
Hematology, Chemistry 
 
 
 
 
 
X 
Pregnancy test, WOCBP onlyg 
X 
Urine monthly throughout the study 
X 
HIV screening 
 
 
 
 
 
 
HBsAg, HBcAb, hepatitis C antibody  
 
 
 
 
 
 
Drug Concentration and Antibody Testing: 
d 
 
 
 
 
 
 
Drug Concentration sample 
 
 
X 
 
 
 
ADA sample 
 
 
X 
 
 
X 
a.  Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider).  
b. If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c. Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
d. To be collected before the injection of study drug. 
e. In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
f. Patients will be trained on using the IVRS /IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
g. Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
h. An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 81 of 107 
Table 12: 
Schedule of Events – Visits 31 (Week 156) through Visit 36 (Week 196)  
Study Procedures 
Treatment Period 
 
Visit (V) 
V 31 
V 32 
V 33 
V 34 
V 35 
V 36 
Week (Wk) 
Wk 156 
Wk 164 
Wk 172 
Wk 180 
Wk 188 
Wk 196 
Day (D) 
Visit Window (d) 
D 1093 
+/-3d 
D 1149 
+/-3d 
D 1205 
+/-3d 
D 1261 
+/-3d 
D 1317 
+/-3d 
D 1373 
+/-3d 
Treatment: 
Administer study druga 
X 
weekly throughout the study treatment 
X 
Patient dosing diaryb 
X 
weekly throughout the study treatment 
X 
Study drug dispensation/account.c 
X 
throughout the study treatment at each visit 
X 
Con meds/procedures 
X 
 
X 
 
X 
 
Efficacy: d 
Patient Assessment of Pruritus Intensity via 
IVRS/IWRS (weekly)f 
X 
weekly throughout the study 
X 
IGA, EASI 
X 
 
 
 
 
 
Safety: d 
Weight 
X 
 
X 
 
X 
 
Vital signs 
X 
 
X 
 
X 
 
Ophthalmology examh (select sites and 
patients) 
X 
 
X 
 
X 
 
Adverse eventse  
X 
throughout the study 
X 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 82 of 107 
Study Procedures 
Treatment Period 
 
Visit (V) 
V 31 
V 32 
V 33 
V 34 
V 35 
V 36 
Week (Wk) 
Wk 156 
Wk 164 
Wk 172 
Wk 180 
Wk 188 
Wk 196 
Day (D) 
Visit Window (d) 
D 1093 
+/-3d 
D 1149 
+/-3d 
D 1205 
+/-3d 
D 1261 
+/-3d 
D 1317 
+/-3d 
D 1373 
+/-3d 
Laboratory Testing: d 
Hematology, Chemistry 
 
 
 
 
 
 
Pregnancy test, WOCBP onlyg 
Urine 
Urine monthly throughout the study 
 
HIV Screening 
 
 
 
 
 
 
HBsAg, HBcAb, hepatitis C antibody  
 
 
 
 
 
 
Drug Concentration and Antibody Testing: d 
Drug Concentration sample 
 
 
 
 
 
 
ADA sample 
 
 
X 
 
 
 
a Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider).  
b If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
d To be collected before the injection of study drug. 
e In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
f Patients will be trained on using the IVRS /IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
g Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
h An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 83 of 107 
Table 13: 
Schedule of Events – Visits 37 (Week 204) through Visit 43 (Week 252)  
Study Procedures 
Treatment Period 
Visit (V) 
V 37 
V 38 
V 39 
V 40 
V 41 
V 42 
V 43 
Week (Wk) 
Wk 204 
Wk 212 
Wk 220 
Wk 228 
Wk 236 
Wk 244 
Wk 252 
Day (D) 
Visit Window (d) 
D 1429 
+/-3d 
D 1485 
+/-3d 
D 1541 
+/-3d 
D 1597 
+/-3d 
D 1653 
+/-3d 
D 1709 
+/-3d 
D 1765 
+/-3d 
Treatment: 
Administer study druga 
X 
weekly throughout the study treatment 
 
X 
Patient dosing diaryb 
X 
weekly throughout the study treatment 
 
X 
Study drug dispensation/account.c 
X 
throughout the study treatment at each visit 
 
X 
Con meds/procedures 
X 
 
X 
 
X 
 
X 
Efficacy: d 
Patient Assessment of Pruritus Intensity 
via IVRS/IWRS (weekly)f 
X 
weekly throughout the study 
 
X 
IGA, EASI 
X 
 
 
 
 
 
 
Safety: d 
Weight 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
 
X 
 
X 
 
X 
Ophthalmology examh (select sites and 
patients) 
X 
 
X 
 
X 
 
X 
Adverse eventse  
X 
throughout the study 
 
X 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 84 of 107 
Study Procedures 
Treatment Period 
Visit (V) 
V 37 
V 38 
V 39 
V 40 
V 41 
V 42 
V 43 
Week (Wk) 
Wk 204 
Wk 212 
Wk 220 
Wk 228 
Wk 236 
Wk 244 
Wk 252 
Day (D) 
Visit Window (d) 
D 1429 
+/-3d 
D 1485 
+/-3d 
D 1541 
+/-3d 
D 1597 
+/-3d 
D 1653 
+/-3d 
D 1709 
+/-3d 
D 1765 
+/-3d 
Laboratory Testing: d 
Hematology, Chemistry 
X 
 
 
 
 
 
 
Pregnancy test, WOCBP onlyg 
X 
 
Urine  Monthly throughout study 
HIV Screening 
 
 
 
 
 
 
 
HBsAg, HBcAb, hepatitis C antibody  
 
 
 
 
 
 
 
Drug Concentration and Antibody Testing: d 
Drug Concentration sample 
 
 
 
 
 
 
 
ADA sample 
 
 
X 
 
 
 
 
a  Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider).  
b If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
d To be collected before the injection of study drug. 
e In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
f Patients will be trained on using the IVRS /IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
g Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
h An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit 
 
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Table 14: 
Schedule of Events – End of Treatment, End of Study, Early Termination, Unscheduled Visit, and Re-entry 
Visit  
Study Procedures 
End of 
Treatment 
End of 
Studym 
Early 
Termination 
Unscheduled 
Visitj 
(if applicable) 
Re-entry Visitr 
(for patients who 
re-enter the 
study) 
Visit (V) 
V 44 
 
 
 
 
Week (Wk) 
260 
Last dose 
+12Wk 
 
 
 
Day (D) 
Visit Window (d) 
D 1821  
+/-3d 
Last dose 
+84D 
+/-30d 
 
 
 
Treatment: 
 
 
 
 
 
Inclusion/Exclusion (Re-entry) 
 
 
 
 
X 
Informed Consent (Re-entry) 
 
 
 
 
X 
Demographics (Re-entry) 
 
 
 
 
X 
Administer study druga 
X  
 
 
 
 
Patient dosing diaryb 
X 
 
X 
 
 
Study drug dispensation/accountc 
Xn 
 
X 
X 
 
Con meds/procedures 
X 
X 
X 
X 
X 
Efficacy: d 
 
 
 
 
 
Patient Assessment of Pruritus Intensity via 
IVRS/IWRS (weekly)f 
 
 
Xf 
Xh 
 
IGA, EASI 
X 
X 
X 
X 
 
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Study Procedures 
End of 
Treatment 
End of 
Studym 
Early 
Termination 
Unscheduled 
Visitj 
(if applicable) 
Re-entry Visitr 
(for patients who 
re-enter the 
study) 
Visit (V) 
V 44 
 
 
 
 
Week (Wk) 
260 
Last dose 
+12Wk 
 
 
 
Day (D) 
Visit Window (d) 
D 1821  
+/-3d 
Last dose 
+84D 
+/-30d 
 
 
 
Safety: d 
 
 
 
 
 
Weight 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
 
Ophthalmology examk (select sites and 
patients) 
 
X 
 
Xl 
 
Adverse eventse 
X 
X 
X 
X 
X 
Laboratory Testing: d 
 
 
 
 
 
Hematology, Chemistry 
X 
 
 
X 
Xo 
Pregnancy test, WOCBP onlyg 
Urine Monthly 
 
 
 
X 
SerumP 
HIV screening 
 
 
 
X 
Xq 
HBsAg, HBcAb, hepatitis C antibody  
 
 
 
X 
Xq 
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Study Procedures 
End of 
Treatment 
End of 
Studym 
Early 
Termination 
Unscheduled 
Visitj 
(if applicable) 
Re-entry Visitr 
(for patients who 
re-enter the 
study) 
Visit (V) 
V 44 
 
 
 
 
Week (Wk) 
260 
Last dose 
+12Wk 
 
 
 
Day (D) 
Visit Window (d) 
D 1821  
+/-3d 
Last dose 
+84D 
+/-30d 
 
 
 
Drug Concentration and Antibody Testing: d 
 
 
 
 
 
Drug Concentration sample 
X 
X 
X 
X 
 
ADA sample 
X 
Xi 
Xi 
X 
 
a Study drug will be administered weekly, either in the clinic or outside the clinic (self-administration or administration by a care provider). 
b If needed, counsel patient on proper dosing diary completion/reporting of each dose of study drug that is administered outside of the clinic. 
c Study drug will be dispensed to the patient for each dose that will be administered off-site between the current clinic visit and the next clinic visit.  Patients will 
be instructed to return all study drug at each clinic visit. 
d To be collected before the injection of study drug. 
e In the event the patient experiences a visible ISR at any clinic visit, the clinical site may photograph the ISR and complete the ISR worksheet.  
f Patients will be trained on using the IVRS /IWRS at the baseline visit, and will call into the system weekly to report the overall intensity of their pruritus over 
the previous week, and to record compliance with self-injection of study drug. 
g Patients will be provided with a pregnancy test kit to take home for monthly testing in between clinic visits, or may choose to have the testing done at the study 
site. 
h If the call was performed on the patient’s weekly schedule, then it will not need to be repeated. 
i Patients who test positive for ADA at their last study visit (early termination visit or end of study visit) may be asked to return to the clinic to have additional 
ADA samples collected for analysis. 
j During an unscheduled visit, any of the study procedures noted may be performed, but not all are required. 
k An acceptable window for performing ophthalmology exams is within +/- 7 days of the visit date.  This does not apply to the ophthalmology exam conducted at 
the baseline visit. 
l Patients who experience AEs consistent with conjunctivitis or other superficial inflammation of the eye (blepharitis, keratitis, etc) should undergo additional 
(unscheduled) ophthalmology exams to allow accurate diagnosis and adequate treatment. 
m .If the end of study assessments cannot be completed on the scheduled date (ie, 12 weeks after the last dose of dupilumab), a late visit is acceptable and is 
preferable to foregoing these assessments altogether; this visit should be conducted as close as possible to the scheduled date. 
n Only study drug accountability takes place at this visit.   
o Sample will be collected only if the last sample was not collected within 12 months. 
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p Serum pregnancy test must be negative before dosing. 
q Testing is required at re-entry for patients who have not been tested within 12 months prior to re-entry. 
r Patients who have completed the End of Study visit as per amendment 7 and who are eligible to resume treatment may re-enter the trial at the next scheduled 
visit they would have attended if they had not completed the study; the next visit should be scheduled within 7 days of the re-entry visit.  Patients are not 
eligible to re-enter the trial if more than 12 weeks have elapsed since their End of Study visit. 
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10.3. 
Criteria for Treatment-Emergent Potentially Clinical Significant 
Value 
Parameter 
Treatment Emergent PCSV 
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 PCSV 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 PCSV 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 PCSV 
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 PCSV 
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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Parameter 
Treatment Emergent PCSV 
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. 
ECG 
Ref.: CPMP 1997 guideline. 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms & < 120 ms at baseline 
 
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Parameter 
Treatment Emergent PCSV 
Comments 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms) 
Borderline: 
 431-450 ms and < 431ms at baseline for Male; 
451-470 ms and < 451 ms at baseline for Female 
Prolonged:  
>450 to <500 ms and <= 450 ms at baseline for 
Male;  
 >470 to <500 ms and <= 470 ms at baseline for 
Female 
 ≥500 ms and < 500 ms at baseline 
 
Increase from baseline 
Borderline: Increase from baseline 30-60 ms 
Prolonged: Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
 
 
 
*QTc prolonged and QTc>60 ms are the 
PCSA to be identified in individual 
subjects/patients listings. 
 
5 independent criteria 
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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-0.069; 
if eqq1cd=3     then eq5d=eq5d-0.314; 
********Self-care**********; 
if eqq2cd=2     then eq5d=eq5d-0.104; 
if eqq2cd=3     then eq5d=eq5d-0.214; 
******Usual activities*****; 
if eqq3cd=2     then eq5d=eq5d-0.036; 
if eqq3cd=3     then eq5d=eq5d-0.094; 
*****Pain/discomfort******; 
if eqq4cd=2     then eq5d=eq5d-0.123; 
if eqq4cd=3     then eq5d=eq5d-0.386; 
*****Anxiety/depression*****; 
if eqq5cd=2    then eq5d=eq5d-0.071; 
if eqq5cd=3    then eq5d=eq5d-0.236; 
 
if (eqq1cd ne 1 or eqq2cd ne 1 or eqq3cd ne 1 or eqq4cd ne 1 or eqq5cd ne 1)  
 
 
 
 
then eq5d=eq5d-0.081; 
if (eqq1cd=3 or eqq2cd=3 or eqq3cd=3 or eqq4cd=3 or eqq5cd=3)  
 
 
 
 
then eq5d=eq5d-0.269; 
if (eqq1cd=. or eqq2cd=. or eqq3cd=. or eqq4cd=. or eqq5cd=.)  
 
 
 
 
then eq5d=.; 
run; 
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10.5. 
Exposure-Adjusted Analyses 
To account for potentially differential exposure time, two types of exposure-adjusted analyses 
will be provided for analysis, namely, number of events per 100 patient-years and number of 
patients with at least one event per 100 patient-years. 
Number of events per 100 patient-years 
The number of events per 100 patient-years (NEPY) will be calculated as the number of events 
occurring in the population divided by the sum of the exposure over all patients (ie, total 
exposure) in the TEAE period.  
 
where ni is the number of events observed for patient i; ti is total TEAE exposure for patient i in 
person-year unit. 
Number of patients with at least one event per 100 patient-years 
The exposure-adjusted incidence rate (EAIR) is the expected number of patients with at least one 
specific adverse event per 100 patients taking the treatment for 1 year (52 weeks). The number of 
patients with at least one event per 100 patient-years will be calculated as the number of patients 
having a specific event divided by the total person-year among patients in the pool and at risk of 
an initial occurrence of the event. In particular, the EAIR is computed as follows: 
 
where n is the number of patients with the specific adverse event; it is a patient’s exposure time 
in person-year unit. For each of the adverse events of interest, the exposure time for patients who 
have experienced the adverse experience will be defined as the time to first adverse experience, 
whereas the exposure time for those who have not had this adverse experience will be total 
duration of exposure in the TEAE period. 
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10.6. 
Search Criteria for TEAE of Special Interest/TEAE Syndrome 
Below table is the search criteria for AESI under protocol amendment 4 and 5. 
AESI 
Search Criteria 
Anaphylactic reactions  
Narrow SMQ for “anaphylactic reaction” 
Acute allergic reactions that 
require treatment 
Narrow SMQ for “hypersensitivity” 
Action taken for AE="medication” or “surgery" 
Note: Blinded manual adjudication of relevant PTs will be 
required by the study medical monitor, before database locks 
Severe ISRs that last longer 
than 24 hours 
-HLT = Injection site reactions 
- Severity = “severe” 
- duration of AE > 24 hours 
Mycosis fungoides or other 
forms of cutaneous T cell 
lymphoma 
-HLT = “Mycosis fungoides” 
 Includes LLT = Sezary syndrome 
 Includes LLT = Cutaneous T-cell lymphoma 
-PT = “Cutaneous T-cell dyscrasia 
Any severe infection 
-SOC = Infections and infestations 
-Severity = “severe 
Any infection requiring 
treatment with parenteral 
antibiotics 
-SOC = Infection and infestations 
-Action taken for AE = “medication” 
-ConMed: ATC3= “Antiinfectives” during the TEAE course 
(between start and stop dates), Route = IV, IM 
Any infection requiring 
treatment with oral 
antibiotic/anti-viral/anti-
fungal for longer than 2 
weeks 
-SOC = Infection and infestations 
-Action taken for AE = “medication” 
-Check CM: ATC3= “Antiinfectives” during the TEAE course 
(between start and stop dates), Route = PO and Treatment 
duration >14 days 
Any clinical endoparasitosis 
-HLT = Cestode infections 
-HLT = Helminthic infections NEC 
-HLT = Nematode infections 
-HLT = Trematode infection 
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AESI 
Search Criteria 
Any opportunistic infectiona 
The following HLTs plus PTs 
-HLT = Pneumocystis infection 
-HLT* = Fungal infections NEC 
-HLT* = Pseudallescheria infections 
-HLT = Herpes viral infections 
-HLT = Paracoccidioides infections 
-HLT = Sporothrix infections 
-HLT = Cryptosporidia infections 
-HLT* = Trypanosomal infections 
-HLT* = Campylobacter infections 
-HLT* = Shigella infections 
-HLT* = Vibrio infections 
Plus the following PTs  
-Polyomavirus-associated nephropathy 
-BK virus infection 
-Cytomegalovirus infection 
-Post transplant lymphoproliferative disorder 
-Progressive multifocal leukoencephalopathy 
-*Bartonellosis 
-Blastomycosis 
-Toxoplasmosis 
-Coccidioidomycosis 
-Histoplasmosis 
-*Aspergillus infection 
-Systemic candida 
-Oropharyngeal candidiasis 
-Cryptococcosis 
-Listeriosis 
-Tuberculosis 
-Nocardiosis 
-Mycobacterial infection 
-*Salmonellosis 
-*Hepatitis B 
-Herpes zoster 
-*Strongyloidiasis 
-Microsporidia infection 
-Visceral leishmaniasis 
-*Hepatitis C 
-Eczema herpeticum  
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AESI 
Search Criteria 
-Kaposi's varicelliform eruption  
-Herpes zoster 
Note: *Blinded manual adjudication of relevant PTs under each 
of HLTs listed above will be required by the study medical 
monitor, before database locks 
Suicidal behavior 
Include the following PTs  
-Completed suicide 
-Suicidal ideation 
-Suicide attempt 
-Depression suicidal  
-Suicidal behavior 
a 
The definition of opportunistic infections is referring to the recent consensus guidance for opportunistic 
infections in the setting of biologic therapy (K L Winthrop et al, 2015) 
 
Below table is the search criteria for AESI under protocol amendment 6/7/8. 
AESI 
Search Criteria 
Anaphylactic reactions  
 
For SMQ “anaphylactic reaction” An algorithmic approach will be 
used. A case must include either:  
4. 
A narrow term (a term from Category A);  
5. Patient with both a term from Category B AND a term from 
Category C;  
6. Patient with a term from Category D AND { a term from Category B 
-  OR a term from Category C } 
For bullets 2 and 3, the search terms that are included under the SMQ for 
a particular event need to have the same start date (for e.g. if search 
shows cough (category B term) occurring at day 3 and urticaria (category 
C term) occurring at day 7, this event is not adjudicated as anaphylactic 
reaction as this is inconsistent with the clinical presentation of 
anaphylaxis as an acute event with simultaneous involvement of 2 or 
more body systems. 
Note:  manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
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AESI 
Search Criteria 
Systemic or severe 
hypersensitivity reactions  
 
Hypersensitivity: Narrow SMQ for hypersensitivity excluding preferred 
term equal to dermatitis atopic or eczema  
For systemic hypersensitivity, events in which 2 or more body systems 
are involved (as defined by System Organ Class) would be considered for 
adjudication based on further medical judgement 
For severe hypersensitivity, an additional search will be done; 
 HLT = Injection site reactions 
 Severity = “severe”  
Note:  manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
Malignancy 
 
SMQ “Malignant tumours” 
 
SMQ “Tumours of unspecified malignancy” 
Helminthic infections 
-HLT = Cestode infections 
-HLT = Helminthic infections NEC 
-HLT = Nematode infections 
-HLT = Trematode infection 
Suicidal behavior 
Include the following PTs 
 
Completed suicide 
 
Suicidal ideation 
 
Suicide attempt 
 
Depression suicidal 
 
Suicidal behavior 
Any type of conjunctivitis or 
blepharitis or keratitis (only 
events that are either severe 
or serious) 
broad CMQ conjunctivitis (Conjunctivitis, Conjunctivitis allergic, 
Conjunctivitis bacterial, Conjunctivitis viral, Atopic keratoconjunctivitis, 
Blepharitis, Dry eye, Eye irritation, Eye pruritus, Lacrimation increased, 
Eye discharge, Foreign body sensation in eyes, Photophobia, Ocular 
hyperaemia, Conjunctival hyperaemia, Xerophthalmia); 
 
Blepharitis PTs (Blepharitis, blepharitis allergic); 
 
Keratitis PTs (Keratitis, Allergic keratitis, Ulcerative keratitis, Atopic 
keratoconjunctivitis, Herpes ophthalmic, Ophthalmic herpes simplex);  
 
AND 
 
Serious AE= “Yes” OR Severity= “severe” 
Note: manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock. 
1 The search criteria are meant to assist the process of identification of TEAE of Special Interest/TEAE Syndrome.  
However, since these criteria might not be exhaustive in some cases or may not be specific in other cases. Hence an 
additional review of all PTs in the database may be performed by the Medical monitor, based on medical 
judgement, to identify any TEAE of Special Interest/TEAE Syndrome that might have been missed by the criteria 
or to identify any TEAE may been inaccurately assigned as AESI by the algorithmic search 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 100 of 107 
10.7. 
Process to Derive Data Cut-off for the First Step Analysis 
Database lock of the first step analysis for R668-AD-1225 study is planned for 05-May-2016 
with data cut-off date 11-Apr-2016. 
The data cutoff algorithm will be applied to the raw datasets extracted from Electronic Data 
Capture (EDC) and IVRS system. 
I. 
Patients to be included for the first step analysis 
1. Include enrolled patients with date of enrollment <=11Apr2016 inside ELIG1 raw dataset. 
2. Include screen failure patients with record date <=11Apr2016 inside ELIG raw dataset. 
Note: only these patients’ data will be included in the first step analysis. Hence patients who are 
under screening and do not enroll prior to the data cut-off date will not be included in the first 
step analysis.  
II. 
Data recorded during the screening period: 
The following data recorded during the screening period for patients identified in step (I) do not 
need data cut-off. All data for patients identified in step (I) included in the final locked data 
transfer will be used for the first step analysis. 
Informed consent 
Inclusion/exclusion 
Medical history 
Demographics 
Previous AD study information 
III. 
Data collected through IVRS  
1. All diary data collected on or before 11-Apr-2016 will be kept for the first step analysis. 
2. For the kit allocation dataset, all records will be kept for the first step analysis. 
IV. 
Visit dependent data:  
All visit dependent data on or before 11-Apr-2016 will be kept for the first step analysis. All visit 
dependent data collected later than 11-Apr-2016 will not be included in the first step analysis 
datasets. Unscheduled visits with a date on or before 11-Apr-2016 will be kept on the first step 
analysis.  
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 101 of 107 
V. 
Visit independent/Event based data:  
This includes adverse events, concomitant/prior medication and procedure:  
All event records with a start date later than 11-Apr-2016 will be censored (this includes 
incomplete dates when the incomplete date is without any doubts later than 11-Apr-2016, e.g. the 
incomplete date is May 2016). 
Records with a start date earlier or on 11-Apr-2016 will be kept (this includes incomplete dates 
when the incomplete date is earlier than 11-Apr-2016 or in case of doubts, e.g. the incomplete 
date for an event is April 2016, or only year 2016 or even a missing date). 
For the events included in the first step analysis cut-off, several adaptions to the data will be 
made:  
 Adverse Events: 
 If a stop date of adverse event is specified and earlier or equal to 11-Apr-2016 
then the record will not be changed. 
 If a stop date of adverse event is specified and later than 11-Apr-2016, then the 
stop date will be deleted (set to missing) and the outcome of the adverse event 
(SAS variable AEOUT/AEOUTN) will be set to missing, AE ongoing status will 
be set to Yes. 
 If no stop date is specified and the outcome is either not yet reported 
(AEOUT/AEOUTN is blank) or is reported (AEOUT in (recovering/resolving, not 
recovered/not resolved, unknown)), then the outcome will be set to missing 
(AEOUT/AEOUTN is blank) 
 Concomitant medication/procedure:  
 If a stop date is reported which is earlier than or on 11-Apr-2016, the record will 
not be changed.  
 If a stop date is reported which is later than 11-Apr-2016, the date will be set to 
missing and ongoing status will be set to Yes. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 102 of 107 
10.8. 
Process to Derive Data Cut-off for the Second Step Analysis 
Database lock of the second step analysis for R668-AD-1225 study is planned for 14-Feb-2019 
with data cut-off date 01-Dec-2018 for ongoing patients in Poland, Finland, Russia, 
New Zealand, and Singapore. All data for patients from remaining countries will be included for 
analysis. 
The data cutoff algorithm will be applied to the raw datasets extracted from Electronic Data 
Capture (EDC) and IVRS system. 
I. 
Patients to be included for the second step analysis 
All screened patients will be included for analysis.  
II. 
Data recorded during the screening period: 
All data recorded during the screening period will be included for analysis. 
III. 
Data collected through IVRS  
1. All diary data collected on or before 01-Dec-2018 for ongoing patients in Poland, 
Finland, Russia, New Zealand, and Singapore will be kept for the second step analysis. 
2. All diary data for patients from rest countries will be included for the second step 
analysis.  
3. For the kit allocation dataset, all records will be kept for the second step analysis. 
IV. 
Visit dependent data:  
All visit dependent data on or before 01-Dec-2018 for ongoing patients in Poland, Finland, 
Russia, New Zealand, and Singapore will be kept for the second step analysis. All visit 
dependent data collected later than 01-Dec-2018 will not be included in the second step analysis 
datasets. Unscheduled visits with a date on or before 01-Dec-2018 will be kept on the second 
step analysis.  
V. 
Visit independent/Event based data:  
This includes adverse events, concomitant/prior medication and procedure:  
All event records with a start date later than 01-Dec-2018 will be censored (this includes 
incomplete dates when the incomplete date is without any doubts later than 01-Dec-2018, e.g. the 
incomplete date is December 2018). 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 103 of 107 
Records with a start date earlier or on 01-Dec-2018 will be kept (this includes incomplete dates 
when the incomplete date is earlier than 01-Dec-2018 or in case of doubts, e.g. the incomplete 
date for an event is November 2018, or only year 2018 or even a missing date). 
For the events included in the first step analysis cut-off, several adaptions to the data will be 
made:  
 Adverse Events: 
 If a stop date of adverse event is specified and earlier or equal to 01-Dec-2018 
then the record will not be changed. 
 If a stop date of adverse event is specified and later than 01-Dec-2018, then the 
stop date will be deleted (set to missing) and the outcome of the adverse event 
(SAS variable AEOUT/AEOUTN) will be set to missing, AE ongoing status will 
be set to Yes. 
 If no stop date is specified and the outcome is either not yet reported 
(AEOUT/AEOUTN is blank) or is reported (AEOUT in (recovering/resolving, not 
recovered/not resolved, unknown)), then the outcome will be set to missing 
(AEOUT/AEOUTN is blank) 
 Concomitant medication/procedure:  
 If a stop date is reported which is earlier than or on 01-Dec-2018, the record will 
not be changed.  
 If a stop date is reported which is later than 01-Dec-2018, the date will be set to 
missing and ongoing status will be set to Yes. 
 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 104 of 107 
10.9. 
Algorithm to Add Not Reported Home Study Drug Injection 
Records Based on Drug Accountability Data for First Step analysis 
Background and Rationale:  
The R668-AD-1225 study is a multicenter, open-label extension study to assess the long-term 
safety and efficacy of repeat doses of dupilumab in adults with moderate-to-severe AD who have 
previously participated in controlled studies of dupilumab.  Study drug was dupilumab 300 mg, 
administered weekly via subcutaneous injections.  During the study, patients were provided the 
option to administer the study drug outside the clinic, in which case they were dispensed drug 
supplies for up to 4 weeks at monthly visits and up to 8 weeks at bimonthly visits.  Study drug 
administration and drug accountability were recorded in several sources: 
The weekly study drug injections were reported in two sources. 
 EDC where on-site injections were reported. 
 IVRS where patients reported their weekly injections taken at home. 
The dispensation and return of study drug supplies (used, partially used or unused) were reported 
in: 
 EDC where study drug kit dispense/return data was captured 
A considerable number of home-injections were not reported through IVRS system, but were 
actually taken by the patients.  This is supported by drug accountability records, which 
documented the administration of study drug via the dispensation of drug supplies and the return 
of used kits.  The purpose of this appendix to provide the algorithm for creating a more complete 
and accurate study drug administration record for the analysis by incorporating these data 
sources. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 105 of 107 
Algorithm: 
1. Between the scheduled on-site dispensing visit and next on-site return visit, identify all 
kits dispensed including the one(s) dispensed at the unscheduled visit(s) between, and all 
kits returned. 
2. Identify kits used between these 2 visits and count number of kits used.  
 If the question “If all vials are empty” from CRF was answered as “Yes”, then it was 
assumed that all returned kits were taken by the patient.  
 If the question “If all vials are empty” from CRF was answered as “No”, use the 
information from excel spreadsheet R668AD1225 Kit not empty.xls to identify which 
kits were not used. For each kit return record,  
I. If the column ‘Adjudicated by team, if total volume was injected’ was Yes, then it 
was assumed that all returned kits were taken by the patient.  
II. If column ‘Adjudicated by team, if total volume was injected’ was No, then kits 
identified starting from column “Kit number not used” were the returned kits not 
taken by the patient. 
3. Identify the dose injection records reported in EDC and IVRS satisfying condition: date 
of dispensing visit <= date of injection < date of next on-site return visit, then count 
number of injections between visits. 
4. If the number of injections in step #3 is less than the number of kits used in step #2, then 
add the not reported injections into SDTM.EX dataset. These not reported injections will 
be identified using variables in SUPPEX with QNAM=DATAORG and QVAL=”Added 
by drug accountability”. The Treatment variable (EXTRT) and dose variable (EXDOSE) 
will be populated for the newly added injections based on last observation carry forward 
(LOCF) method.  
5. If the number of injections in step #3 is equal to or larger than the number of kits used in 
step #2, then no new injection record will be added into SDTM.EX dataset. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 106 of 107 
10.10. 
Algorithm to Derive Treatment Exposure and Duration of 
Observational period 
The duration of treatment exposure period during the study in week is calculated as: 
[(Date of last study drug injection – date of first study drug injection) + 7]/7 
regardless of unplanned intermittent discontinuations. For the exposure calculation, below two 
treatment gaps will be excluded.        
1. For patients from Germany, France, Poland and Japan who completed the 3-year 
treatment period under protocol amendment 6 before resuming dupilumab treatment 
under amendment 7, the duration from the end of treatment under amendment 6 up to the 
first injection date under amendment 7 will be excluded from the duration of exposure 
calculation. 
2. For patients from Poland, Finland and France who completed the treatment period under 
protocol amendment 7 before resuming dupilumab treatment under amendment 8, the 
duration from the end of treatment under amendment 7 up to the first injection date under 
amendment 8 will be excluded from the duration of exposure calculation. 
The following duration of exposure will be summarized using number of patients, means, SD, 
minimums, medians, and maximums. A summary of the number of doses will also be provided: 
 The entire study treatment period 
 The treatment period prior to “treatment gap” 
 The treatment extension period under protocol amendment 7 for patients from Germany, 
France, Poland and Japan who completed 3-year treatment 
 The treatment extension period under protocol amendment 8 for patients from Poland, 
Finland and France who completed 3-year treatment and extension period under 
amendment 7 
The duration of observation period during the study in weeks is calculated as: 
[(Date of the last visit – date of the first study medication dose) +1]/7. 
For the duration of observation period calculation, below study gaps will be excluded. 
1. For patients from Germany, France, Poland and Japan who completed 3-year study under 
protocol amendment 6, then reentered the study after reconsenting to protocol amendment 
7, the duration from the end of study under amendment 6 up to date of reconsent to 
amendment 7 will be excluded from the duration of observation period calculation. 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
R668-AD-1225 
Statistical Analysis Plan 
 
February 01, 2019 
 
 
CONFIDENTIAL 
Page 107 of 107 
The following duration of observation periods will be summarized using number of patients, 
means, SD, minimums, medians, and maximums: 
 The entire study period 
 The study period prior to protocol amendment 7 
 The study extension period under protocol amendment 7 for patients from Germany, 
France, Poland and Japan who completed 3-year treatment 
 The study extension period under protocol amendment 8 for patients from Germany, 
Finland and France who completed 3-year treatment and extension period under 
amendment 7 
The number (%) of patients with observation periods will be presented by specific time periods. 
The time periods of interest is specified as: ≥ 1 week, ≥ 4 weeks, ≥ 12 weeks, ≥ 16 weeks, 
≥ 24 weeks, ≥ 52 weeks, ≥ 76 weeks, ≥ 100 weeks, ≥ 104 weeks, ≥ 124 weeks, ≥ 148 weeks, 
≥ 156 weeks, ≥ 164 weeks, ≥ 208 weeks, ≥ 260 weeks, ≥ 272 weeks.  
As of protocol amendment 2, the weekly dose of dupilumab was changed from 200 mg to 
300 mg. The number of patients exposed to 200 mg dose, the number of 200 mg doses and 
duration of treatment exposure with 200 mg and 300 mg in weeks will be calculated and 
summarized separately. 
The duration of treatment exposure with 200 mg dose during the study in weeks is calculated as: 
 [(Date of last 200 mg injection – date of first study drug injection) + 7]/7 for patients 
who did not receive 300 mg injection 
 [(Date of first 300 mg injection – date of first study drug injection)]/7 for patients 
who received 300 mg injection 
The duration of treatment exposure with 300 mg dose during the study in weeks is calculated as: 
[(Date of last 300 mg injection – date of first 300 mg injection) + 7]/7 
 
                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00


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-2019 15:00:16 GMT+0000
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                                        VV-RIM-00070032-1.0 Approved - 06 Feb 2019 GMT-5:00