An Open-label Study of Dupilumab in Patients With Atopic Dermatitis Who Participated in Previous Dupilumab Clinical Trials
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: Regeneron Pharmaceuticals

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 
 
 
 
 
 
 
 
 
.  
VV-RIM-00152209-1.0 Approved - 11 May 2021 GMT-5:00
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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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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Regeneron Pharmaceuticals, Inc. 
Page 4 of 124 
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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Clinical Study 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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Regeneron Pharmaceuticals, Inc. 
Page 6 of 124 
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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Clinical Study Protocol 
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Page 7 of 124 
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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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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Clinical Study Protocol 
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Regeneron Pharmaceuticals, Inc. 
Page 11 of 124 
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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• 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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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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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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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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