A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel- Group Study to Evaluate the Efficacy and Safety of Dupilumab in Adult and Adolescent Patients With Moderate-to-Severe Atopic Hand and Foot Dermatitis
Phase: PHASE3
Conditions: Moderate to Severe Atopic Hand and Foot Dermatitis
Sponsor: Regeneron Pharmaceuticals

Clinical Study Protocol 
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EudraCT: 2019-003088-22 
IND Number: 107969 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF DUPILUMAB IN ADULT AND 
ADOLESCENT PATIENTS WITH MODERATE-TO-SEVERE ATOPIC 
HAND AND FOOT DERMATITIS 
Compound: 
Dupilumab 
Study Name: 
Liberty-AD-HAFT 
Clinical Phase: 
3 
Protocol Number: 
R668-AD-1924 
Protocol Version 
R668-AD-1924 Amendment 2 
Amendment 2 Date of Issue: 
See appended electronic signature page
Amendment 1 Date of Issue: 
28 Apr 2020 
Original Date of Issue: 
03 Oct 2019 
Medical/Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
VV-RIM-00138022-1.0 Approved - 13 Jan 2021 GMT-5:00
NCT04417894

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
ACD 
Allergic contact dermatitis 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BL 
Baseline 
BSA 
Body Surface Area 
BUN 
Blood urea nitrogen 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
EASI 
Eczema Area and Severity Index 
EC 
Ethics Committee 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HECSI 
Hand eczema severity index 
HFD 
Hand and foot dermatitis 
Hep C Ab 
Hepatitis C antibody 
HIV 
Human immunodeficiency virus 
ICD 
Irritant contact dermatitis  
ICDRG 
International Contact Dermatitis Research Group 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IGA 
Investigator Global Assessment 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IL-4Rα 
IL-4 receptor alpha subunit 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System 
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JAK 
Janus kinase 
mTLSS 
Modified Total Lesion Sign Score 
NAb 
Neutralizing antibody 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NRS 
Numerical Rating Scale 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PUVA 
Psoralen and UVA 
PV 
Phone visit 
QoL 
Quality of life 
QOLHEQ 
Quality of Life in Hand Eczema Questionnaire 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis  
TCI 
Topical calcineurin inhibitors 
TCS 
Topical corticosteroids 
TEAE 
Treatment-emergent adverse event 
TRUE 
Thin Layer Rapid Use Epicutaneous 
UVB 
Ultraviolet B 
WBC 
White blood cell 
WPAI+CIQ 
Work Productivity and Activity Impairment plus Classroom Impairment 
Questionnaire 
WPCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................25 
1. 
INTRODUCTION ......................................................................................................33 
2. 
STUDY OBJECTIVES ..............................................................................................35 
2.1. 
Primary Objective .......................................................................................................35 
2.2. 
Secondary Objectives .................................................................................................35 
2.3. 
Exploratory Objectives ...............................................................................................35 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................36 
3.1. 
Hypotheses ..................................................................................................................36 
3.2. 
Rationale .....................................................................................................................36 
3.2.1. 
Rationale for Study Design .........................................................................................36 
3.2.2. 
Rationale for Dose Selection ......................................................................................38 
3.3. 
Risk-Benefit ................................................................................................................38 
4. 
ENDPOINTS ..............................................................................................................40 
4.1. 
Primary and Secondary Endpoints..............................................................................40 
4.1.1. 
Primary Endpoint ........................................................................................................40 
4.1.2. 
Secondary Endpoints ..................................................................................................40 
4.1.3. 
Other Endpoints and Assessments ..............................................................................41 
4.1.4. 
Exploratory Endpoints ................................................................................................41 
5. 
STUDY VARIABLES................................................................................................41 
5.1. 
Demographic and Baseline Characteristics ................................................................41 
5.2. 
Efficacy Variables ......................................................................................................41 
5.3. 
Safety Variables ..........................................................................................................41 
5.4. 
Pharmacokinetic Variables .........................................................................................41 
5.5. 
Immunogenicity Variables ..........................................................................................42 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................42 
6. 
STUDY DESIGN .......................................................................................................42 
6.1. 
Study Description and Duration .................................................................................42 
6.1.1. 
End of Study Definition ..............................................................................................46 
6.2. 
Planned Interim Analysis ............................................................................................46 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............46 
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7.1. 
Number of Patients Planned .......................................................................................46 
7.2. 
Study Population .........................................................................................................46 
7.2.1. 
Inclusion Criteria ........................................................................................................46 
7.2.2. 
Exclusion Criteria .......................................................................................................48 
7.3. 
Premature Withdrawal from the Study .......................................................................53 
7.4. 
Replacement of Patients .............................................................................................53 
8. 
STUDY TREATMENTS............................................................................................53 
8.1. 
Investigational and Reference Treatments ..................................................................53 
8.2. 
Background Treatment ...............................................................................................54 
8.3. 
Rescue Treatment .......................................................................................................54 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................55 
8.4.1. 
Dose Modification ......................................................................................................55 
8.4.2. 
Study Drug Discontinuation .......................................................................................55 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................55 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................56 
8.5. 
Management of Acute Reactions ................................................................................56 
8.5.1. 
Acute Injection Reactions ...........................................................................................56 
8.5.1.1. 
Systemic Injection Reactions ......................................................................................57 
8.5.1.2. 
Local Injection Site Reactions ....................................................................................57 
8.6. 
Method of Treatment Assignment ..............................................................................57 
8.7. 
Blinding ......................................................................................................................57 
8.8. 
Emergency Unblinding ...............................................................................................57 
8.9. 
Treatment Logistics and Accountability .....................................................................58 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................58 
8.9.2. 
Supply and Disposition of Treatments .......................................................................58 
8.9.3. 
Treatment Accountability ...........................................................................................58 
8.9.4. 
Treatment Compliance ................................................................................................59 
8.10. 
Concomitant Medications and Procedures .................................................................59 
8.10.1. 
Prohibited Medications and Procedures .....................................................................59 
8.10.2. 
Permitted Medications and Procedures ......................................................................60 
8.10.3. 
Skin Protection Measures ...........................................................................................60 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................61 
9.1. 
Schedule of Events .....................................................................................................61 
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9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................66 
9.1.2. 
Early Termination Visit ..............................................................................................69 
9.1.3. 
Unscheduled Visits .....................................................................................................69 
9.2. 
Study Procedures ........................................................................................................69 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................70 
9.2.1.1. 
Patch Testing ..............................................................................................................70 
9.2.2. 
Efficacy Procedures ....................................................................................................72 
9.2.2.1. 
Investigator Global Assessment of Hand and Foot ....................................................72 
9.2.2.2. 
Modified Total Lesion Sign Score for Hands and Feet ..............................................72 
9.2.2.3. 
Hand and Foot Pruritus Numerical Rating Scale ........................................................72 
9.2.2.4. 
Hand and Foot Skin Pain Numerical Rating Scale .....................................................73 
9.2.2.5. 
Sleep Numerical Rating Scale ....................................................................................73 
9.2.2.6. 
Hand and Foot Area Involvement of Atopic Dermatitis ............................................73 
9.2.2.7. 
Patient Global Impression of Severity ........................................................................73 
9.2.2.8. 
Patient Global Impression of Change .........................................................................73 
9.2.2.9. 
Hand Eczema Severity Index ......................................................................................73 
9.2.2.10. 
Quality of Life in Hand Eczema Questionnaire .........................................................74 
9.2.2.11. 
Eczema Area and Severity Index ................................................................................74 
9.2.2.12. 
Investigator’s Global Assessment ...............................................................................74 
9.2.2.13. 
Atopic Dermatitis Area Photographs ..........................................................................74 
9.2.2.14. 
Patient-Assessed EQ-5D .............................................................................................75 
9.2.2.15. 
Work Productivity and Activity Impairment Questionnaire Plus Classroom 
Impairment Questions .................................................................................................75 
9.2.3. 
Safety Procedures .......................................................................................................76 
9.2.3.1. 
Vital Signs ..................................................................................................................76 
9.2.3.2. 
Body Weight and height .............................................................................................76 
9.2.3.3. 
Physical Examination .................................................................................................76 
9.2.3.4. 
Laboratory Testing ......................................................................................................76 
9.2.4. 
Drug Concentration and Measurements .....................................................................77 
9.2.5. 
Immunogenicity Measurements and Samples ............................................................78 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................78 
9.2.7. 
Future Biomedical Research (Optional) .....................................................................78 
9.2.7.1. 
Pharmacogenomic Analysis (Optional) ......................................................................78 
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10. 
SAFETY EVALUATION AND REPORTING .........................................................79 
10.1. 
Recording and Reporting Adverse Events ..................................................................79 
10.1.1. 
General Guidelines .....................................................................................................79 
10.1.2. 
Reporting Procedure ...................................................................................................80 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................80 
10.2. 
Definitions ..................................................................................................................81 
10.2.1. 
Adverse Event .............................................................................................................81 
10.2.2. 
Serious Adverse Event ................................................................................................81 
10.2.3. 
Adverse Events of Special Interest .............................................................................81 
10.2.4. 
Severity .......................................................................................................................82 
10.2.5. 
Causality .....................................................................................................................82 
10.3. 
Safety Monitoring .......................................................................................................83 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .........................................................................................................84 
11. 
STATISTICAL PLAN................................................................................................84 
11.1. 
Statistical Hypothesis ..................................................................................................84 
11.2. 
Justification of Sample Size........................................................................................85 
11.3. 
Analysis Sets ...............................................................................................................85 
11.3.1. 
Efficacy Analysis Sets ................................................................................................85 
11.3.2. 
Safety Analysis Set .....................................................................................................85 
11.3.3. 
Pharmacokinetic Analysis Set ....................................................................................85 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................86 
11.4. 
Statistical Methods ......................................................................................................86 
11.4.1. 
Patient Disposition ......................................................................................................86 
11.4.2. 
Demography and Baseline Characteristics .................................................................86 
11.4.3. 
Efficacy Analyses .......................................................................................................86 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................86 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................87 
11.4.4. 
Control of Multiplicity ................................................................................................89 
11.4.5. 
Safety Analysis ...........................................................................................................89 
11.4.5.1. 
Adverse Events ...........................................................................................................89 
11.4.5.2. 
Other Safety ................................................................................................................90 
11.4.5.3. 
Treatment Exposure ....................................................................................................90 
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11.4.5.4. 
Treatment Compliance ................................................................................................90 
11.4.6. 
Pharmacokinetics ........................................................................................................91 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................91 
11.4.7. 
Analysis of Immunogenicity Data ..............................................................................91 
11.5. 
Timing and Operational Considerations of Statistical Analyses ................................91 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........92 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................92 
12.1. 
Data Management and Electronic Systems ................................................................92 
12.1.1. 
Data Management .......................................................................................................92 
12.1.2. 
Electronic Systems ......................................................................................................92 
12.2. 
Study Monitoring ........................................................................................................93 
12.2.1. 
Monitoring of Study Sites ...........................................................................................93 
12.2.2. 
Source Document Requirements ................................................................................93 
12.2.3. 
Case Report Form Requirements ................................................................................93 
12.3. 
Audits and Inspections ................................................................................................93 
12.4. 
Study Documentation .................................................................................................94 
12.4.1. 
Certification of Accuracy of Data ...............................................................................94 
12.4.2. 
Retention of Records ..................................................................................................94 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................95 
13.1. 
Good Clinical Practice Statement ...............................................................................95 
13.2. 
Informed Consent .......................................................................................................95 
13.3. 
Patients Confidentiality and Data Protection ..............................................................96 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................96 
13.5. 
Clinical Study Data Transparency ..............................................................................97 
14. 
PROTOCOL AMENDMENTS ..................................................................................97 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................97 
15.1. 
Premature Termination of the Study ...........................................................................97 
15.2. 
Close-out of a Site ......................................................................................................97 
16. 
CONFIDENTIALITY ................................................................................................98 
17. 
FINANCING AND INSURANCE .............................................................................98 
18. 
PUBLICATION POLICY ..........................................................................................98 
19. 
REFERENCES ...........................................................................................................99 
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20. 
INVESTIGATOR’S AGREEMENT ........................................................................102 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................62 
Table 2: 
Summary of Primary Estimand for Primary Endpoint ...............................................87 
Table 3: 
Summary of Primary Estimand for Key Secondary Endpoint ....................................88 
 
LIST OF FIGURES 
Figure 1: Study Flow Diagram ......................................................................................................45 
 
LIST OF APPENDICES 
APPENDIX 1. HANIFIN AND RAJKA DIAGNOSTIC CRITERIA FOR ATOPIC 
DERMATITIS – MAJOR AND MINOR CRITERIA .............................................103 
APPENDIX 2. INVESTIGATOR GLOBAL ASSESSMENT FOR HAND AND 
FOOT ATOPIC DERMATITIS ...............................................................................104 
APPENDIX 3. MTLSS: MODIFIED TOTAL LESION SIGN SCORE FOR HAND 
AND FOOT ATOPIC DERMATITIS ......................................................................105 
 
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AMENDMENT HISTORY 
Amendment 2 
The key changes implemented in this protocol amendment are a) Modification of the instrument 
used in assessment of primary endpoint (Investigator Global Assessment [IGA] for hands and 
feet) and b) Revision of the patch test series to be used to exclude patients with Allergic Contact 
Dermatitis (ACD).  
The following table outlines the changes made to the protocol and the affected sections: 
Description of Change 
Brief Rationale 
Section Number and Name 
IGA Instrument 
Modified the IGA for hands and feet 
instrument.  Major changes made to 
the IGA instrument were as follows: 
•
Consistent with atopic
dermatitis (AD) trials in the
dupilumab program, the revised
IGA instrument now will be
based on an overall impression of
disease severity of the hands and
feet (rather than assessment of
disease severity of individual
hand and foot separately).  The
investigator will be asked to
assign a single score to reflect this
clinical judgment (rather than
rating each individual hand and
foot separately to assign four
separate IGA scores).
•
The IGA score has been
de-coupled from the Modified
Total Lesion Sign Score
(mTLSS).  The IGA score will
now be based on a clinical
assessment rather than an
auto-calculation based upon
mTLSS score.
•
Multiple permutations for
different IGA severity levels have
been removed.  Each IGA
severity is associated with defined
morphological descriptors to
enable clinical interpretability.
In response to comments from a 
health authority which had 
requested that the IGA be a 
clinical assessment of overall 
disease severity of hands and 
feet and be easy to interpret 
clinically. 
Appendix 2 Investigator 
Global Assessment for Hand 
and Foot Atopic Dermatitis 
Appendix 3 mTLSS Modified 
Total Lesion Sign Score for 
Hand and Foot Atopic 
Dermatitis (added)  
Section 7.2.1 Inclusion 
Criteria, #3 and #4 
Section 9.2.2.2 Modified Total 
Lesion Sign Score for Hands 
and Feet 
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Description of Change 
Brief Rationale 
Section Number and Name 
Inclusion Criteria #3 and #4 (related 
to disease severity and IGA score) 
were revised accordingly to reflect the 
modified IGA scoring methodology. 
Patch Test 
Patch test series to be used in the 
study during screening period to 
exclude patients with ACD were 
changed as follows: 
• 
In the US, the American Contact 
Dermatitis Society (ACDS) core 
allergen series was changed to the 
TRUE (Thin layer Rapid Use 
Epicutaneous) test. 
• 
In the EU, the European Baseline 
Series (EBS) was changed to the 
TRUE test along with an 
additional panel of allergens 
which are missing in the TRUE 
test but are commonly implicated 
in causing ACD of hands and 
feet. 
• 
In Japan, the patch test panel was 
changed from the Japan standard 
series to the patch test panel (S). 
To use an allergen series which 
is approved by regulatory 
agencies in the corresponding 
geographical regions.  
Clinical Study Protocol 
Synopsis, Study Design 
Section 9.2.1.1 Patch Testing 
 
Updated the statistical power from 
>90% to >85% based on the revised 
assumption for treatment effect.  
The approved TRUE test has 
fewer number of allergens than 
a broader allergen panel such as 
ACDS, which is currently 
unapproved in the US.  The 
TRUE test has been reported to 
miss approximately 33% of 
cases with ACD that are 
detected by ACDS.  With the 
use of the TRUE test there is a 
risk that patients with ACD will 
be enrolled in this trial.  Based 
on the currently available 
clinical and scientific evidence, 
dupilumab is not expected to be 
effective in this patient group.  
Clinical Study Protocol 
Synopsis, Statistical Plan 
Section 11.2 Justification of 
Sample Size 
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Description of Change 
Brief Rationale 
Section Number and Name 
Accordingly, the assumption 
for treatment effect was 
lowered for the enrolled 
population, therefore, the power 
calculation was updated. 
Changes Related to Stratification Factors 
Clarified that the number of adult 
patients will be capped at 
approximately 100 to ensure that, at a 
minimum, approximately 
30 adolescents will be enrolled. 
In response to comments from a 
health authority. 
Clinical Study Protocol 
Synopsis, Sample Size 
Section 6 Study Design 
Figure 1 Study Flow Diagram 
Section 7.1 Number of Patients 
Planned 
Section 8.6 Method of 
Treatment Assignment 
Removed randomization stratification 
factor for presence of AD lesions 
outside hands and/or feet (yes/no).  
In response to comments from a 
health authority to limit the 
number of stratification factors 
to reduce the risk of having 
cells with small frequencies 
within strata.  This decision was
supported by further 
discussions with external 
experts who concluded that of 
the various stratification factors 
specified in the protocol, this 
one factor was least likely to 
influence response to treatment. 
Clinical Study Protocol 
Synopsis, Statistical Plan: 
Analysis Methods 
Section 3.2.1 Rationale for 
Study Design 
Figure 1 Study Flow Diagram 
Section 6.1 Study Description 
and Duration 
Section 8.6 Method of 
Treatment Assignment 
Section 11.4.3.1 Primary 
Efficacy Analysis 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Specified the stratification factor of 
geographic region is United States 
versus Japan versus other countries. 
In response to a health authority 
request. 
Clinical Study Protocol 
Synopsis, Statistical Plan: 
Analysis Methods 
Section 3.2.1 Rationale for 
Study Design 
Figure 1 Study Flow Diagram 
Section 6.1 Study Description 
and Duration 
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Description of Change 
Brief Rationale 
Section Number and Name 
Section 8.6 Method of 
Treatment Assignment 
Section 11.4.3.1 Primary 
Efficacy Analysis 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Changes Related to Endpoints 
In the Secondary Endpoints for 
Efficacy, moved the peak Pruritus 
NRS-related endpoints to before the 
mTLSS-related endpoint. 
To highlight the importance of 
pruritus endpoints, as pruritus is 
the most important symptom 
from a patient perspective. 
Clinical Study Protocol 
Synopsis, Secondary Endpoints 
for Efficacy 
Section 8.4.2 Secondary 
Endpoints 
Proportion of patients with 
NRS 4-point reduction from baseline 
to week 16 was promoted to key 
secondary endpoint.   
To highlight the importance of 
pruritus as a major symptom in 
hand and foot AD which is 
highly correlated with patient 
quality of life.  A reduction in 
4 points has previously been 
established as a clinically 
relevant change in patients with 
AD. 
Clinical Study Protocol 
Synopsis, Secondary Endpoints 
for Efficacy 
Section 4.1.2 Secondary 
Endpoints 
Section 11.4.3.2 Secondary 
Efficacy Analyses 
Changes to Statistical Analysis Plan 
Removed description of unblinded 
primary analysis of the study from 
Section 6.2 Planned Interim Analysis, 
as the primary analysis is not an 
interim analysis and the description 
already exists in Section 11.5. 
Changed Section 11.5 heading from 
“Interim Analysis” to “Timing and 
Operational Considerations of 
Statistical Analyses” as there is no 
interim analysis. 
For consistency and clarity.  
Section 6.2 Planned Interim 
Analysis 
Section 11.5 Timing and 
Operational Considerations of 
Statistical Analyses (revised 
heading) 
Specified important protocol 
deviations that will exclude patients 
from the per protocol set (PPS). 
In response to a health authority 
request. 
Clinical Study Protocol 
Synopsis, Statistical Plan: 
Efficacy Analysis Sets 
Section 11.3.1 Efficacy 
Analysis Sets 
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Description of Change 
Brief Rationale 
Section Number and Name 
Added primary estimand definition 
for the primary and key secondary 
efficacy endpoints based on 
ICH E9 (R1)  
To be compliant with 
ICH E9 (R1). 
Section 11.4.3.1 Primary 
Efficacy Analysis  
Table 2 Summary of Primary 
Estimand for Primary Endpoint 
(added) 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Table 3 Summary of Primary 
Estimand for Key Secondary 
Endpoint (added) 
Removal of Assessments 
Removed the following assessments 
from the protocol: Dermatology Life 
Quality Index (DLQI), Children’s 
Dermatology Life Quality Index 
(CDLQI), Hospital Anxiety and 
Depression Scale (HADS), Patient 
Oriented Eczema Measure (POEM), 
ophthalmological examination, body 
surface area (BSA) involvement of 
AD, thymus and activation-regulated 
chemokine (TARC), lactate 
dehydrogenase (LDH), 
immunoglobulin E (IgE), optional 
RNA sample, and research samples 
(serum/plasma). 
The frequency of vital signs, clinical 
laboratory, PK, and ADA assessments 
was decreased. 
To reduce patient burden and 
improve overall compliance 
with study 
procedures/assessments. 
 
Clinical Study Protocol 
Synopsis, Objectives, 
Endpoints, Procedures and 
Assessments 
Section 2.2 Secondary 
Objectives 
Section 4.1.2 Secondary 
Endpoints 
Section 5.2 Efficacy Variables 
Section 5.5 Pharmacodynamic 
and Other Biomarker Variables 
Section 8.7 Blinding 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #11, 
#19, and #28 deleted, and #3, 
#4, #14, #21, and #22 revised. 
Footnotes were renumbered. 
Section 9.2.2.7 Dermatology 
Life Quality Index (deleted) 
Section 9.2.2.10 Hospital 
Anxiety and Depression Scale 
(deleted) 
Section 9.2.2.13 Patient 
Oriented Eczema Measure 
(deleted) 
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Description of Change 
Brief Rationale 
Section Number and Name 
Section 9.2.2.16 Body Surface 
Area Involvement of Atopic 
Dermatitis (deleted) 
Section 9.2.3.5 
Ophthalmological Examination 
(deleted) 
Section 9.2.6 . 
Pharmacodynamic and 
Exploratory Biomarker 
Procedures 
Section 9.2.7.1 
Pharmacogenomic Analysis 
(Optional) 
Section 11.4.8 Analysis of 
Pharmacodynamic and 
Exploratory Biomarker Data 
(deleted) 
Section 19 References 
COVID-related Changes 
Added footnote * for In-Clinic Visits 
and footnote ** for Laboratory 
Testing in the Schedule of Events 
table, and revised footnote #15 (which 
became #14 with this amendment) to 
indicate the following, respectively, in 
case of lack of availability of site staff 
and/or patients to come to site for 
in-clinic visits due to COVID-19 
pandemic: 
• 
Phone visits/virtual 
visits/telemedicine visits/home 
visits by skilled staff should be 
considered for conducting 
certain assessments. 
• 
Alternate measures may be used 
for clinical lab testing.  
• 
The sponsor may implement 
processes for direct-to-patient 
shipment of study drug. 
To mitigate the risk to patient 
safety and data integrity 
resulting from COVID-19 
restrictions/lockdowns. 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, 
footnote * added, footnote ** 
added, footnote #15 (which 
became #14) revised 
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Description of Change 
Brief Rationale 
Section Number and Name 
Changes Made for Completeness and Clarity 
The definition of patient population 
was corrected to make it consistent 
with the eligibility criteria by 
changing ‘high potency’ to ‘medium-
to-high potency’ TCS, which now 
reads:  “The proposed study 
population is patients with chronic, 
moderate-to-severe hand and foot AD 
inadequately responsive to 
medium-to-high-potency TCS or in 
whom medium-to-high-potency TCS 
are inadvisable.” 
The study population was 
always intended to be patients 
with chronic, 
moderate-to-severe hand and 
foot AD inadequately 
responsive to 
medium-to-high-potency TCS 
from the beginning. The words 
‘medium to’ were 
inadvertently left out in the 
previous version of the protocol 
in the study population section, 
although the eligibility criteria 
did specify 
medium-to-high-potency TCS. 
Clinical Study Protocol 
Synopsis, Population: Target 
Population 
Section 7.2 Study Population 
Added UVB to the list of treatments 
that require a 4-week washout period 
prior to the patch testing.  Added 
localized PUVA or narrow band UVB 
on hands and/or feet to the list of 
prohibited medications. 
For completeness and clarity. 
Section 7.2.2 Exclusion 
Criteria, #6c 
Section 8.10.1 Prohibited 
Medications and Procedures 
Section 9.2.1.1 Patch Testing 
Added topical and systemic 
JAK inhibitors to prohibited 
medications. 
For completeness and clarity. 
Section 7.2.2 Exclusion 
Criteria, #8 
Section 8.3 Rescue Treatment 
Section 8.10.1 Prohibited 
Medications and Procedures 
Section 9.2.1.1 Patch Testing 
Added that latex should be avoided. 
For completeness and clarity. 
Section 8.10.3 Skin Protection 
Measures 
Corrected footnote designation in the 
Schedule of Events for “Optional 
DNA, RNA sample” from #3 to #4.  
Separated the “Optional DNA and 
RNA sample” into 2 separate rows. 
Correction of a typo. 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events 
Added eCOA instruments, eDiaries, 
and tablet devices for 
For completeness. 
Section 12.1.2 Electronic 
Systems 
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Description of Change 
Brief Rationale 
Section Number and Name 
collecting/recording some of the 
efficacy assessment data. 
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Amendment 1 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Added information regarding the “Coronavirus Disease 
2019” (COVID-19) pandemic and its impact on clinical 
trials. 
Section 3.3 Risk-Benefit 
Section 9.1 Schedule of Events 
Section 11 Statistical Plan 
Details were added regarding injection sites. 
Section 8.1 Investigational and Reference 
Treatments 
Added instruments for IGA and Modified Total Lesion 
Sign Score (mTLSS). These instruments incorporate the 
written feedback received from a health authority. 
Section 9.2.2.1 Investigator Global Assessment 
of Hand and Foot 
Section 9.2.2.2 Modified Total Lesion Sign 
Score for Hands and Feet 
Appendix 2 Modified Total Lesion Sign Score 
and Investigator Global Assessment 
Added statement that a responder threshold (currently 
unknown) for mTLSS in the study population will be 
determined using data gathered from this study.  
Analyses using this responder threshold will be 
conducted to help interpretation of the prespecified 
endpoints for the mTLSS. The methodology to be used 
for determining this responder threshold and the analyses 
will be specified in the SAP. 
Section 9.2.2.2 Modified Total Lesion Sign 
Score for Hands and Feet 
 
Added major criteria for the Hanifin and Rajka 
Diagnostic Criteria for AD. 
Appendix 1 Hanifin and Rajka Diagnostic 
Criteria for Atopic Dermatitis- Major and Minor 
Criteria 
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Change 
Section Changed 
Removed randomization stratification factor for disease 
morphology and added stratification for geographic 
region (pooled countries set by interactive voice response 
system/interactive web response system [IVRS/IWRS]).  
Sub-group analysis for treatment effect in patients with 
hands only involvement vs involvement of hands and feet 
or feet only were requested by the health authority. The 
number of patients with hands only involvement will be 
capped at approximately 100. 
In parallel, the stratification factor for disease 
morphology was removed to limit the total number of 
factors. On further discussions with external experts, it 
was felt that disease morphology should not impact 
response to treatment with study drug. Furthermore, data 
from a prospective observational study with dupilumab 
in patients with AD of hands suggests that disease 
morphology does not impact response to treatment. 
Clinical Study Protocol Synopsis: Population,
Statistical Plans 
Section 3.2.1 Rationale for Study Design 
Section 6 Study Design 
Section 6.1 Study Description and Duration 
Figure 1 Study Flow Diagram 
Section 7.1 Number of Patients Planned 
Section 8.6 Method of Treatment Assignment 
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.4.3.2 Secondary Efficacy Analysis 
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Change 
Section Changed 
Changed inclusion criterion #2 to:  Patients with chronic 
hand and/or foot dermatitis diagnosed at least 3 years 
prior to the screening visit for patients ≥18 years old and 
at least 1 year prior to the screening visit for patients 12 
to <18 years old. Previously, this criterion was:  Patients 
with chronic hand and/or foot dermatitis diagnosed at 
least 6 months prior to the screening visit. 
This modification will ensure that the disease duration to 
define chronicity is consistent with that used in the 
dupilumab phase 3 global AD trials and allow sufficient 
time to demonstrate inadequate response to the current 
standard-of-care (topical corticosteroids) for hand and 
foot dermatitis. 
Added inclusion criteria:  Patients with involvement of at 
least 2 anatomical areas with moderate to severe disease 
(IGA score of 3 or 4, separately for 2 anatomical areas) 
at screening and baseline (both hands, one hand and one 
foot, or both feet) AND Patients need to have an overall 
IGA hand and foot or hand or foot   score of 3 or 4 at 
screening and baseline. 
This will ensure that patients will have extent of disease 
that is sufficient to justify treatment with a biologic. 
Added clarification to criterion #5 regarding inadequate 
AD treatment response to topical medications. 
Added inclusion criterion #9: Treatment with an 
investigational drug within 8 weeks or within 5 half-lives 
(if known), whichever is longer, before the baseline visit. 
Section 7.2.1 Inclusion Criteria, #2, #3, #4, #5,
#9 
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Change 
Section Changed 
Added a note that patients with a documented diagnosis 
of allergic contact dermatitis of hands and/or feet, who 
have a positive patch test reaction at screening will also 
be excluded from the study, regardless of whether history 
of current skin exposure to products containing this 
allergen (current relevance) is present. 
Previously, only patients with a clinically relevant 
positive patch test were excluded from the trial; clinical 
relevance to positive patch testing was based upon 
reporting of exposure to allergen by the patient. 
However, patients might not be able to recall such 
exposure leading to failure to exclude patients whose 
hand and foot dermatitis is caused by allergic contact 
dermatitis, rather than AD.  
Added exclusion criterion: Patients with a known 
diagnosis of protein contact dermatitis of hands and/or 
feet. These are patients with occupational or non-
occupational contact to proteins such as food (eg, wheat, 
milk, fish), latex etc. with positive prick test who present 
with lesions of contact urticaria or dermatitis on 
hands/feet. 
Patients with protein contact dermatitis are spelled out 
separately from the broad group of allergic contact 
dermatitis as these patients typically have a negative 
patch test. Patients with protein contact dermatitis are not 
expected to benefit from the study drug based upon the 
available scientific and clinical evidence.  The study 
population has been limited to patients with AD of hand 
and foot.   
For clarification, combined exclusion criteria #s 2 and 3 
regarding exposure to irritants.  Added guidelines to be 
used in screening to evaluate patient exposure to irritants.  
Section 7.2.2 Exclusion Criteria, #1, #2, #3, #4,
#13 
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Change 
Section Changed 
Added further text to skin protection measures. Added a 
row ‘skin protection measures’ to the Schedule of events.  
Also added the following inclusion criterion:  Patients 
need to have been compliant with the skin protection 
measures (as outlined in Section 8.10.3) through the 
entire duration of the screening period (minimum of 4 
weeks but lasting to a maximum of 8 weeks).  This 
includes avoidance of irritants that are identified as 
causing exacerbation of hand and foot AD.   
These additions will ensure that patients whose disease 
can be managed by simple skin protection measures are 
not un-necessarily enrolled in a clinical trial with a 
biologic. Moreover, compliance with these skin 
protection procedures throughout the duration of the trial 
will prevent confounding of effect of study drug.  
Section 7.2.1 Inclusion Criteria, #12 
Section 6.1 Study Description and Duration 
Section 8.10.3 Skin Protection Measures 
Table 1 Schedule of Events 
Reduced the frequency of assessments for patient-
reported outcome measures to reduce patient burden and 
increase compliance.  
Added rows for ‘assign disease morphology’ and ‘assign 
anatomical area of involvement’ to the Schedule of 
Events as these were inadvertently omitted in the original 
protocol.  Added footnotes to provide details for these 
assessments. 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of 
Events, #9, #10 
Added a sentence in protocol and corresponding row in 
the Schedule of Events that detailed history of exposure 
to irritants in occupational as well as non-occupational 
setting will be elicited to rule out irritant hand and foot 
dermatitis.  This will lead to informed avoidance of such 
irritants during the screening period and will ensure that 
patients whose disease can be managed by simply 
avoiding irritants are not un-necessarily enrolled in a 
clinical trial with a biologic. 
Table 1 Schedule of Events  
Section 9.2.1 Procedures Performed Only at 
the Screening/Baseline Visit 
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Change 
Section Changed 
Added a window for the second reading for patch test: 
day 3-day 7 assessment (previously only allowed at day 
4). This will provide more flexibility to sites to schedule 
in-patient clinic visits as per patient convenience.  
Removed the extended European baseline series for 
contact allergens for patch testing and changed it to the 
European baseline series as the testing concentration for 
certain allergens in extended EU baseline series has not 
been finalized.  
Removed North American Contact Dermatitis Group 
(NACDG) patch test series. as the sponsor is having 
difficulty in sourcing this patch test series.  
A Japan specific patch test series (Patch test panel S) was 
added. 
Added the Australian baseline series in Australia. 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of 
Events, #7 
Section 9.2.1.1 Patch Testing 
Removed Pruritus Categorical Scale to reduce patient 
burden.  
Section 9.2.2.4 Hand and Foot Pruritus 
Categorical Scale – section removed from 
protocol body 
Added Work Productivity and Activity Impairment plus 
Classroom Impairment Questionnaire (WPAI+CIQ) and 
removed the assessment of missed work/school days. 
Clinical Study Protocol Synopsis: Endpoints,
Study Procedures and Assessments 
Section 4.1.2 Secondary Endpoints 
Section 5.2 Efficacy Variables 
Table 1 Schedule of Events  
Section 9.2.2.19 Work Productivity and 
Activity 
Impairment 
Plus 
Classroom 
Impairment Questions  
Section 
9.2.2.11 
Assessment 
of 
Missed 
Work/School Days – section removed from 
protocol body 
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Change 
Section Changed 
Made the following clarifications: 
• 
Details were added regarding moisturizers. 
• 
Specified that data from patients who receive 
rescue treatment as per adjudication during the 
study will be treated for efficacy analysis 
purposes as outlined in Section 11.4.3. 
• 
Clarified criteria for temporary discontinuation 
to ALT or AST >3 times ULN. 
• 
Clarified in the Schedule of Events and 
procedures that vital signs at baseline week 2 and 
week 4 will be done additionally at 30 minutes 
post-injection. 
• 
Added details regarding research samples and 
future biomedical research (FBR) samples. 
• 
Changed heart rate to pulse rate under vital signs 
assessment. 
• 
Removed alcohol and drug screens. 
• 
Changed Patient Global Assessment of Disease 
(PGAD) to Patient Global Impression of 
Severity (PGIS) and Patient Global Assessment 
of Treatment (PGAT) to Patient Global 
Impression of Change (PGIC) and corrected the 
description to make it specific for hand and foot 
AD. 
• 
Added sections to describe the Patient Oriented 
Eczema Measure (POEM) and Body Surface 
Area (BSA) involvement of AD to match 
assessments in the Schedule of Events.  
• 
Specified that the Eczema Area and Severity 
Index 
(EASI) 
and 
Investigator’s 
Global 
Assessment (IGA) will only be performed in 
patients who have AD lesions outside their hands 
and feet. 
Clinical Study Protocol Synopsis: Procedures 
and Assessments 
Section 8.2 Background Treatment 
Section 8.3 Rescue Treatment 
Section 8.4.2.2 Reasons for Temporary 
Discontinuation of Study Drug 
Table 1 Schedule of Events  
Section 9.1.1 Footnotes for the Schedule of 
Events, #11, #21, and #28 
Section 9.2.2.7 Patient Global Impression of 
Severity  
Section 9.2.2.8 Patient Global Impression of 
Change   
Section 9.2.2.10 Quality of Life in Hand 
Eczema Questionnaire 
Section 9.2.2.13 Patient Oriented Eczema 
Measure 
Section 9.2.2.14 Eczema Area and Severity 
Index 
Section 
9.2.2.15 
Investigator’s 
Global 
Assessment  
Section 
9.2.2.16 
Body 
Surface 
Area 
Involvement of AD 
Section 9.2.3.1 Vital Signs 
Section 9.2.3.4 Laboratory Testing 
Corrected minor typographical and formatting issues. 
Throughout protocol. 
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CLINICAL STUDY PROTOCOL SYNOPSIS  
Title 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study to Evaluate the Efficacy and Safety of Dupilumab in Adult and 
Adolescent Patients with Moderate-to-Severe Atopic Hand and Foot 
Dermatitis 
Site Locations 
 
Principal Investigator 
This is a global, multicenter study. 
To be determined 
Objectives 
The primary objective of the study is to assess the efficacy of dupilumab 
on skin lesions in patients with atopic hand and foot dermatitis. 
The secondary objectives of the study are: 
• 
To assess the efficacy of dupilumab on various other domains 
(pruritus, pain, sleep loss, health related quality of life (QoL), work 
life impairment) in patients with atopic hand and foot dermatitis 
• 
To evaluate the safety and tolerability of dupilumab administered 
to patients with atopic hand and foot dermatitis 
• 
To evaluate systemic exposure and immunogenicity of dupilumab 
in patients with atopic hand and foot dermatitis 
The exploratory objectives of the study are: 
• 
To study dupilumab’s mechanism of action (related to efficacy 
and/or safety), why some patients respond better than others (safety 
and/or efficacy), IL4R pathway, atopic hand and foot dermatitis 
and related diseases 
• 
To assess the concordance between treatment effect of dupilumab 
on a) atopic hand and foot dermatitis lesions and b) concomitant 
AD lesions on other parts of the body 
• 
To evaluate exposure-response relationships 
Study Design 
This is a global, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study investigating the efficacy and safety of dupilumab 
monotherapy in adult and adolescent patients with moderate-to-severe 
atopic hand and foot dermatitis as defined by a specific Investigator Global 
Assessment (IGA) assessment focused on these areas of the body.  Eligible 
patients must have a documented history of inadequate response or 
intolerance to treatment of hand and foot dermatitis with topical AD 
medications. 
At the screening visit, adult patients will provide informed consent before 
any other study procedures are conducted.  For adolescent patients, parents 
or legal guardians will provide informed consent and the patients will 
provide assent.  After providing informed consent/assent, the patients will 
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be assessed for study eligibility at the screening visit.  During the screening 
period, systemic treatments for AD will be washed out, as applicable, 
according to the eligibility requirements.  Topical treatments for AD of 
hands and feet will also be washed out, according to the eligibility 
requirements.  However, patients will be allowed to use topical treatments 
for treatment of AD on other parts of the body with certain restrictions. 
Patients may be re-screened once if they fail the screening evaluation for 
reasons related to incidental transitory conditions, unless the reason for the 
screen failure is related to failing the disease severity inclusion criteria.  
Patch testing with a standard series of allergens will also be carried out 
during the screening period to exclude patients with predominantly allergic 
contact dermatitis (ACD) of hand and foot.  The standard series used will 
vary based upon the region of conduct of the study.  Examples of the 
country-specific series based on countries the study is conducted include 
TRUE test for US, TRUE test and an additional panel of allergens which are 
missing in TRUE test but are commonly implicated in causing ACD of 
hands and feet for patients in the EU, and patch test panel (S) for Japan.  
Patients will need to be discontinued from topical/systemic medications for 
AD prior to the patch testing. 
Patients who meet the eligibility criteria will be randomized (1:1) to 
dupilumab subcutaneously (SC) every 2 weeks (Q2W) or matching placebo 
(see details of dosing regimens in the Treatments section). 
During the treatment period, patients will have in-clinic visits at week 2 and 
week 4, and then in-clinic visits every 4 weeks (Q4W) through week 16 with 
bi-weekly phone visits in between the in-clinic visits.  Patients and/or 
parents/caregivers will be trained on injecting study drug during in-clinic 
visit 2 (day 1) to visit 6 (week 4).  During weeks in which no in-clinic visit 
is scheduled, patients will either self-inject study drug or the 
parent/caregiver will administer study drug to the patient.  In case patients 
do not want to self-inject and the parents/caregivers do not want to 
administer study drug to patient, patients may have the clinic staff 
administer all the study drug injections in the clinic.  Safety laboratory tests, 
collection of samples for study drug concentrations and immunogenicity, 
and clinical assessments will be performed at specified clinic visits. 
The end of treatment visit will occur at week 16, 2 weeks after the last dose 
of study drug.  The primary endpoint will be assessed at this visit.  If patients 
prematurely discontinue study drug, the patients will be encouraged to stay 
in the study to have data collected at all remaining scheduled visits until 
completion of the planned end of study visit. 
Post-treatment follow-up period: Upon completing the 16-weeks 
randomized treatment period, patients will enter a 12-week follow-up 
period.  The end of study visit will occur at week 28. 
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Study Duration 
The duration of the study for each patient is approximately 28 weeks, 
excluding the screening period. 
End of Study Definition 
The end of study is defined as the date of the last visit of the last patient in 
the study. 
Population 
 
 
Sample Size: 
Approximately 130 patients (65 patients per arm) will be enrolled at 
approximately 50 global sites.  The number of adult patients will be capped 
at approximately 100 to ensure that, at a minimum, approximately 
30 adolescents will be enrolled.  The number of patients with hands only 
involvement will be capped at approximately 100. 
 
Target Population: 
The proposed study population is patients with chronic, moderate-to-severe 
atopic 
hand 
and 
foot 
dermatitis 
inadequately 
responsive 
to 
medium-to-high-potency topical corticosteroids (TCS) or in whom 
medium-to-high-potency TCS are inadvisable.  Only patients meeting the 
diagnostic criteria for AD will be included in this study.  Patients with a 
confirmed diagnosis of irritant contact dermatitis or ACD as the 
predominant cause of hand and foot dermatitis will be excluded from the 
study. 
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
• 
Dupilumab, administered SC Q2W 
− 
In adults: dupilumab 300 mg, after a loading dose of 600 mg on 
day 1, irrespective of body weight 
− 
In adolescents: Body weight ≥60 kg, dupilumab 300 mg, after a 
loading dose of 600 mg on day 1, body weight <60 kg, dupilumab 
200 mg, after a loading dose of 400 mg on day 1 
 
Placebo 
 
Route/Schedule: 
• 
Matching placebo, administered SC Q2W 
Endpoints 
 
 
Primary: 
• 
Proportion of patients achieving an IGA (hand and foot) score of 0 or 1 
at week 16 
 
Secondary: 
Key Secondary Endpoint for Efficacy: 
• 
Proportion of patients with improvement (reduction) of weekly average 
of daily hand and foot peak Pruritus NRS ≥4 from baseline to week 16 
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Secondary Endpoints for Efficacy: 
• 
Proportion of patients with improvement (reduction) of weekly average 
of daily hand and foot peak Pruritus Numeric Rating Scale (NRS) ≥3 
from baseline to week 16 
• 
Percent change from baseline to week 16 in weekly average of daily 
hand and foot peak Pruritus NRS 
• 
Percent change in Modified Total Lesion Sign Score (mTLSS) for 
hand/foot lesions from baseline to week 16  
• 
Percent change from baseline to week 16 in weekly average of daily 
hand and foot peak Pain NRS 
• 
Percent change from baseline to week 16 in weekly average of daily 
Sleep NRS 
• 
Change from baseline to week 16 in percent surface area of hand and 
foot involvement with AD 
• 
Percent change from baseline to week 4 in weekly average of daily hand 
and foot peak Pruritus NRS 
• 
Proportion of patients with improvement (reduction) of weekly average 
of daily hand and foot peak Pruritus NRS ≥4 from baseline to week 4 
• 
For patients with hand dermatitis, percent change from baseline to week 
16 in Hand Eczema Severity Index (HECSI) score  
• 
For patients with hand dermatitis, proportion of patients with HECSI-
75 at week 16 
• 
For patients with hand dermatitis, proportion of patients with HECSI-
50 at week 16 
• 
For patients with hand dermatitis, proportion of patients with HECSI-
90 at week 16 
• 
For patients with hand dermatitis, change from baseline to week 16 in 
Quality of Life in Hand Eczema Questionnaire (QOLHEQ) 
• 
Change from baseline to week 16 in Work Productivity and 
Impairment (WPAI) and Classroom Impairment Questionnaire (CIQ) 
Secondary Endpoints for Safety: 
• 
Incidence of treatment-emergent adverse events (TEAEs) through 
week 16 
Secondary Endpoints for Clinical Pharmacology and Immunogenicity: 
• 
Trough concentration of functional dupilumab in serum at various time 
points 
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• 
Incidence of treatment-emergent anti-drug antibodies (ADA) over time 
Procedures and Assessments 
Efficacy will be assessed during the study at specified clinic visits using 
patient reported assessments (including Daily hand and foot peak Pruritus 
NRS, Daily hand and foot peak Pain NRS, Daily Sleep NRS, QOLHEQ, 
Patient Global Impression of Severity [PGIS], Patient Global Impression of 
Change 
[PGIC], 
EQ-5D, 
WPAI+CIQ) 
and 
investigator-reported 
assessments (including IGA for hands and feet, mTLSS, percent surface area 
of hand and foot involvement with AD, HECSI, IGA [global], and Eczema 
Area and Severity Index [EASI]).  Safety will be assessed by vital signs, 
physical examinations, clinical laboratory tests, and clinical evaluations.  
Patients will be asked to monitor all adverse events (AEs) experienced from 
the time of informed consent/assent until their last study visit.  Laboratory 
testing will include hematology, blood chemistry, urinalysis, pregnancy 
testing, human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody 
(HBcAb), hepatitis C antibody (Hep C Ab), tuberculosis (TB), DNA.  
Samples for drug concentration and ADA assay will be collected.   
Statistical Plan 
The planned sample size is approximately 130 patients (65 patients in each 
treatment arm).  This sample size will yield >85% power to detect a 
treatment difference of 24% in the proportion of patients achieving 
IGA hand and foot (0, 1) at week 16 between placebo (10%) and dupilumab 
(34%) at a 2-sided significant level of 5% using Chi-square test and 
assuming a dropout rate of 10%. The assumed treatment difference of 24% 
is based on the effect of 26% observed in dupilumab phase 3 monotherapy 
studies in adult patients with AD, and adjusted to account for the potential 
inclusion of some patients with ACD who would be missed with certain 
patch testing (ie,, TRUE test) at screening. It is reasonable to assume that 
the effect size of dupilumab on AD of hands and feet would be similar to 
that seen in in previously conducted phase 3 trials in generalized AD, as the 
underlying pathophysiology is the same. Moreover, a recent observational 
study to compare the effect of dupilumab on hand lesions vs. lesions on other 
parts of the body found a high degree of concordance in terms of onset of 
effect and overall effect at week 16.  
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients.  Efficacy 
analyses will be based on the treatment allocated at randomization (as 
randomized). 
The per protocol set (PPS) includes all patients in the FAS except for those 
who are excluded because of specified important protocol deviations. 
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All efficacy variables will be evaluated on the FAS; the primary endpoint 
will also be evaluated on the PPS.  Analysis on the FAS will be considered 
to be primary. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received 
any study drug; it is based on the treatment received (as treated).  Treatment 
compliance/administration and all clinical safety variables will be analyzed 
using the SAF. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all patients/subjects who received any 
study drug and who had a at least 1 non-missing result following the first 
dose of study drug. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received any study drug and 
had at least 1 non-missing ADA result following the first study dose.  
The neutralizing antibody (NAb) analysis set includes all patients who 
received any study drug and who are negative in the ADA assay or with at 
least 1 non-missing result in the NAb assay (patients who are ADA negative 
are set to negative in the NAb analysis set). 
Analysis Methods: 
Primary Efficacy Analyses 
The primary endpoint of proportion of patients achieving an IGA score of 0 
or 1 on hand and foot at week 16 will be analyzed using the Cochran-Mantel-
Haenszel (CMH) test to assess the difference in the proportion of responders 
in the FAS adjusting for the randomization stratification factors (age [adults 
vs. adolescents], disease severity of IGA hand and foot [3 vs. 4], and 
geographic region [United States versus Japan versus other countries]).  
To account for use of rescue treatment, patients will be considered as 
non-responders for all time points subsequent to the use of rescue treatment 
in the primary analysis.  If a patient has missing value with any reason for 
IGA on hand and foot assessment at week 16, the patient will be classified 
as a non-responder at week 16.  
Sensitivity analysis using the last observation carried forward (LOCF) 
approach or the worst observation carried forward (WOCF) approach to 
determine patient’s status at week 16 will be conducted to assess the 
robustness of the primary efficacy analysis with regards to handling of 
missing data.  The efficacy data will be set to missing after rescue treatment 
is used, then the LOCF or WOCF method will be used to determine patients’ 
status at week 16.  
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In addition, the CMH method adjusted by randomization strata will also be 
performed on all observed data regardless if rescue treatment is used.  A 
patient with missing data will be counted as a non-responder.  Other 
sensitivity analyses may be conducted. 
Subgroup analysis (eg, by age group, by anatomical area of involvement 
[hand involvement only vs. involvement of hand and foot or foot 
involvement only]) will also be performed. 
Secondary Efficacy Analyses 
Secondary efficacy endpoints that measure binary responses (eg, 
improvement of weekly average of daily peak Pruritus NRS ≥4 from 
baseline to week 16) will be analyzed in the same fashion as the primary 
analysis. 
Continuous secondary efficacy endpoints (eg, percent change mTLSS for 
hand/foot lesions from baseline to week 16) will be analyzed using an 
analysis of covariance (ANCOVA) model for the FAS with treatment group, 
randomization stratification factors (age [adults vs. adolescents], disease 
severity of IGA hand and foot [3 vs. 4], and geographic region [United States 
versus Japan versus other countries]), and relevant baseline measurement 
included in the model.  Similarly, to account for the impact of rescue 
treatment on the efficacy effect, patients' efficacy data through week 16 after 
the rescue treatment use will be set to missing.  The missing data for 
continuous endpoints will be imputed by the pattern-mixture approach 
where the WOCF approach will be used for the missing due to rescue 
treatment, AE, and lack of efficacy and the multiple imputation (MI) 
approach will be used for the missing due to other reasons.  The MI 
Statistical Analysis Software (SAS) procedure with Markov Monte Carlo 
algorithm will be applied in the MI for multiple times.  The complete 
datasets created based on the pattern-mixture approach will be analyzed 
using the ANCOVA model defined previously, and the SAS MIANALYZE 
procedure will be used to generate valid statistical inferences by combining 
results from these multiple analyses using Rubin’s formula. 
All efficacy data will be used for analysis regardless of whether the patient 
is on study treatment or discontinues the study treatment but remains in the 
study.  In addition, the MI with the ANCOVA model and the ANCOVA 
model based on LOCF or WOCF imputation method will be performed as 
sensitivity analyses.  Other sensitivity analysis such as the MI approach with 
ANCOVA model on all observed data regardless of rescue treatment use 
will also be conducted.  Additional details on sensitivity analyses will be 
provided in the SAP. 
Control of Multiplicity 
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Type I error rate will be controlled using a hierarchical testing procedure for 
the primary and secondary efficacy endpoints at the 2-sided 0.05 level.  The 
hierarchy order will be specified in the SAP prior to database lock. 
Safety Analysis 
Safety analysis will be based on the SAF.  This includes reported TEAEs, 
AESIs, and other safety information (eg, clinical laboratory evaluations, 
vital signs).  A summary of safety results for each treatment group will be 
presented. 
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1. 
INTRODUCTION 
Hand and foot dermatitis is an umbrella term that includes irritant contact dermatitis (ICD), allergic 
contact dermatitis (ACD) and patients with a history of, or presence of concurrent atopic dermatitis 
(AD), which is also known as atopic hand and foot dermatitis (Agner, 2015).  The morphological 
types that have been described in this condition include the following: vesicular (dyshidrotic), 
hyperkeratotic, fissured, and nummular (Menne, 2011). 
Patients with AD are at increased risk of hand dermatitis of any etiology as compared to the general 
population with a 3 to 4-fold increase of prevalence as compared to controls (Ruff, 2018).  The 
prevalence of hand dermatitis in patients with AD has been reported to be approximately 60% 
(Simpson, 2006).  Similarly, the prevalence of foot dermatitis in patients with AD has been 
reported to be approximately 30% (Holm, 2016).  Atopic dermatitis is a known risk factor for 
development of hand dermatitis with approximately 28% of patients with hand dermatitis having 
a history of AD (Petersen, 2014).  Similarly, a history of AD is present in approximately 14% of 
patients with foot dermatitis (Agner, 2015).  Atopic conditions apart from AD, such as allergic 
rhinitis and asthma, have also been associated with atopic hand and foot dermatitis 
(Scalone, 2015). 
Atopic hands and feet dermatitis (also known as atopic hand and foot eczema)1 presents with 
redness, infiltration, scaling, vesicles, areas of hyperkeratosis, and cracks (fissures) 
(Coenraads 2012).  Lesions are associated with significant itching and pain.  The morphology 
tends to evolve over time and many patients can have a mixed presentation.  In the majority of 
patients, the same morphological subtype is found on the hands and feet (Brans, 2015).  
The disease tends to be chronic and recalcitrant with a substantial impact on quality of life (QoL), 
comparable with other skin diseases like psoriasis (Agner, 2008).  Chronic hand dermatitis has 
also been associated with significant detrimental effect on work productivity, activity impairment, 
and heath care costs (Fowler, 2006).  It has been shown that 65% of patients with severe hand 
dermatitis reported loss of productivity at work, with an average of 10.1 days per patient per month 
(Politiek, 2016).  Moreover, in certain occupations like hairdressers, bakers, and machine workers, 
up to 18% of patients had to change jobs due to hand dermatitis (Meding, 2005). 
Atopic hand and foot dermatitis has the same underlying pathophysiology as in other parts of the 
body and is caused by a complex interaction of genetics, defects in skin barrier function, 
environmental exposure to irritants, and immunologic responses.  In addition, it has been suggested 
that abnormal cholinergic responses in the form of palmar and plantar hyperhidrosis specifically 
contribute to the development of H-F dermatitis of AD (Lee, 2001) Type 2 helper T cell (Th2) 
mediated immune response is believed to play a central role in the pathogenesis of AD, including 
that of hands and feet.  The skin lesions of AD are characterized by increased expression of 
proinflammation type 2 cytokines, such as interleukin (IL)-4 and IL-13, and by skin infiltration of 
Th2 and other inflammatory cells.  The elevated immunoglobulin E (IgE) responses and 
eosinophilia observed in the majority of patients with AD reflects an increased expression of the 
type 2 cytokines IL-4 and IL-13 (Leung, 1999)  
                                                 
1 For the purpose of this protocol, atopic hands and feet dermatitis refers to involvement of either hands only, feet 
only, or both hands and feet.   
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The other 2 major causes for hand and foot dermatitis, apart from AD, are ICD and ACD.  It should 
be noted that the morphological presentation of all these etiologies can be very similar, and it is 
hard to delineate the etiology just based on clinical examination.  Recently there has been a trend 
to obtain further disease classification in hand and foot dermatitis to focus on etiology rather than 
morphology as this approach offers the advantage of targeting prevention and, in some cases, also 
providing more specific treatment (Johansen, 2011).  These 2 forms of dermatitis are unlike AD; 
these forms are not primarily driven by type 2 immune responses (Gittler, 2013). 
The management of AD of hand and foot is based upon prevention and avoidance strategies using 
gloves, reducing exposure to irritants and regular use of emollients.  Step therapy is used with an 
approach to initiate treatment with topicals and then progress to systemics in case of inadequate 
response to topicals (Diepgen, 2007).  Short courses of topical corticosteroids (TCS) are 
recommended as first line treatment to control flares.  Long term application of TCS comes with 
risk of skin atrophy, dyspigmentation, acneiform eruptions, and risks associated with systemic 
absorption (eg, growth retardation, hypothalamic-pituitary axis effects, etc).  Treatment guidelines 
for hand dermatitis of any etiology recommend continuous long-term treatment beyond 6 weeks 
be performed only when necessary and under careful medical supervision (Diepgen, 2007).  
Topical calcineurin inhibitors may be considered for patients with AD of hand and foot who 
require long-term need for treatment, although evidence for their efficacy is limited.  The low 
penetration/permeation of topical agents through the skin of the hands and feet explains the limited 
efficacy of topical anti-inflammatory agents.  Overnight occlusion may be advocated to allow for 
sufficient penetration of topical anti-inflammatory drugs.  However, in the long-term, such 
measures are frequently unpractical and cumbersome for patients. 
There is no Food and Drug Administration (FDA) approved systemic therapy for localized atopic 
hand and foot dermatitis.  Alitretinoin (oral retinoid) is the only approved systemic therapy in the 
European Union (EU), for severe chronic hand dermatitis (including AD of hands) but has 
significant side effects (Ruzicka, 2008).  Most common adverse events (AEs) seen in phase 3 trials 
were headache, dry skin, conjunctivitis, hypercholesterolemia, and flushing.  Significant known 
side effects are psychiatric effects such as depression, mood changes and suicidal ideation, changes 
in bone mineralization, and benign intracranial hypertension.  Alitretinoin also requires strict 
contraception measures in women of childbearing potential due to high teratogenic potential.  
Although systemic corticosteroids can be effective symptomatic treatment in acute hand eczema 
or acute flares of chronic hand eczema, chronic use is not recommended due to potentially serious 
long-term side effects.  Systemic immunomodulators such as cyclosporine, azathioprine and 
methotrexate have very little evidence from randomized controlled trials to support their use in 
AD of hand and foot and are associated with significant side effects. 
Dupilumab (brand name DUPIXENT®) is approved in over 40 countries worldwide including the 
United States (US), EU, and Japan for the treatment of moderate-to-severe AD in adults.  
Dupilumab was also authorized in the US and EU recently for use in adolescent patients 
(≥12 years) with inadequately controlled moderate-to-severe AD.  Dupilumab is a novel targeted 
immunoregulatory agent that selectively and simultaneously inhibits IL-4 and IL-13 signaling by 
blocking the obligate shared component of the IL-4/IL-13 receptor complex.  It is intended to 
inhibit key disease drivers to achieve clinical benefit without the side effects commonly observed 
with existing non-selective systemic immunosuppressants.  Additional background information on 
the study drug and development program can be found in the Investigator’s Brochure. 
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It is known that severe atopic hand and foot dermatitis can be particularly difficult to treat.  
Although dupilumab is efficacious in AD more broadly, its effect specifically in treating localized 
atopic hand and foot dermatitis has not been studied.  Several case reports have recently 
demonstrated efficacy of dupilumab in atopic hand and foot dermatitis (Zirwas, 2018).  This is not 
surprising given the lesions of AD share the same underlying type 2 driven pathophysiology, 
irrespective of body location.  However, atopic hand and foot dermatitis can be difficult to 
distinguish clinically from allergic or irritant eczema.  This study, by generating data on the effect 
of dupilumab on AD lesions of the hand and feet and providing an algorithm to identify patients 
who are candidates for dupilumab therapy, is intended to facilitate access to a promising new 
therapy for patients with a recalcitrant and debilitating form of AD. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to assess the efficacy of dupilumab on skin lesions in patients 
with atopic hand and foot dermatitis. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To assess the efficacy of dupilumab on various other domains (pruritus, pain, sleep 
loss, health related QoL, work life impairment) in patients with atopic hand and foot 
dermatitis 
• To evaluate the safety and tolerability of dupilumab administered to patients with 
atopic hand and foot dermatitis 
• To evaluate systemic exposure and immunogenicity of dupilumab in patients with 
atopic hand and foot dermatitis 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To study dupilumab’s mechanism of action (related to efficacy and/or safety), why 
some patients respond better than others (safety and/or efficacy), IL4R pathway, atopic 
hand and foot dermatitis and related diseases 
• To assess the concordance between treatment effect of dupilumab on a) atopic hand 
and foot dermatitis lesions and b) concomitant AD lesions on other parts of the body 
• To evaluate exposure-response relationships 
 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Signs and symptoms of AD of hands and feet, like other parts of the body, are driven by type 2 
inflammation.  Dupilumab monotherapy, by blocking type 2 inflammation, will result in an 
improvement in various domains of disease in adult and adolescent patients with moderate-to-
severe atopic hand and foot dermatitis inadequately responsive to topical corticosteroids.  This 
includes effect on various measures of intensity and extent of skin lesions on hand and foot, 
symptoms such as pruritus, sleep loss and pain, QoL, work life impairment, and mental health. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
Dupilumab is the first globally approved therapy for moderate-to severe AD.  Its efficacy, both as 
monotherapy and in conjunction with corticosteroids, has been demonstrated in multiple double-
blind, randomized, clinical trials (Simpson, 2016) (Thaci, 2016).  In all the reported trials inclusion 
criteria mandated that AD must affect greater than 10% of the Body Surface Area (BSA).  Because 
the palm including the fingers comprises 1% of the BSA, the studies specifically excluded patients 
with AD limited to the hands.  Similarly, the feet represent a small BSA much lower than 10%.  
These trials evaluated the global effect of dupilumab on AD lesions on the whole body without 
discrimination by body regions such as hands and feet.  Similarly, these trials did not evaluate the 
effect of dupilumab on symptoms such as pruritus and pain resulting specifically from hand and 
foot disease.  A dedicated clinical study using investigator assessments and patient reported 
outcomes focused on disease in hand and feet is needed to evaluate such effects. 
Atopic hand and foot dermatitis can be significantly debilitating and can cause unique problems 
such as reduced work productivity, prolonged sick leave and ultimately job loss (Fowler, 2006).  
The impact on QoL of hand dermatitis has been found to be comparable to that with moderate-to-
severe AD (generalized) and psoriasis (Agner, 2008).  This study, by generating data on the effect 
of dupilumab on AD lesions of the hand and feet, is intended to facilitate access to a promising 
new therapy for patients with a recalcitrant and debilitating form of AD. 
Hand and foot dermatitis has multiple underlying etiologies with AD, ACD, and ICD recognized 
as the major causes.  The pathophysiology of hand and foot dermatitis varies depending upon the 
underlying etiology (Gittler, 2013).  Atopic hand and foot dermatitis is believed to be classically 
type 2 inflammation-mediated.  Allergic contact dermatitis is classically believed to be Th1 
mediated disorder.  Irritant contact dermatitis is primarily caused due to damage to skin barrier 
and is believed to be mediated by innate immunity (IL-1, TNFα).  
Several case reports have recently demonstrated efficacy of dupilumab in AD of hand and foot 
(Nanda, 2019) (Oosterhaven, 2018) (Zirwas, 2018).  These patients had previously failed treatment 
with various topical and systemic therapies used in hand and foot dermatitis.  In the case series 
published by Zirwas et al, all 3 patients met the diagnostic criteria for AD and had total BSA<10%.  
All 3 patients underwent comprehensive patch testing and no relevant allergens were detected.  In 
contrast to these case reports, dupilumab has been shown to have a variable effect on ACD, with 
many patients reporting no improvement with use of dupilumab (Stout, 2019).  Moreover, there 
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have been case reports of patients with AD in whom failure of resolution of lesions in certain parts 
of the body was caused due to concomitant presence of ACD (Suresh, 2018). 
Given the unclear scientific rationale for dupilumab in forms of hand and foot dermatitis other than 
atopic hand and foot dermatitis, as well as the variable results reported in the literature of the effect 
of dupilumab on ACD, the patient population in this study will exclude patients with these other 
dermatides. 
Limiting the study population with moderate-to-severe forms of disease (Investigator Global 
Assessment [IGA] hands and feet of 3 or 4), chronic disease (disease present for at least 6 months 
prior to screening visit) and with disease inadequately responsive to TCS or in patients in whom 
TCS are inadvisable, will ensure that the patients with highest unmet medical need will be enrolled 
in this study.  Moreover, should the study demonstrate adequate safety and efficacy, the approach 
used in this study can be applied in clinical practice as an algorithm to identify patients for 
dupilumab therapy. 
A blinded, randomized, placebo-controlled design is chosen to minimize bias in data collection 
and result interpretation.  The presence of a placebo arm is appropriate for the objectives of this 
study as this will allow for the most robust assessment of the efficacy and safety of dupilumab. 
A monotherapy design has been chosen to allow a true estimate of the effect size of dupilumab 
without any confounding by use of topical or systemic therapies.  This is especially pertinent to 
hand and foot dermatitis as due to thicker skin of palms and soles, higher potency TCS or TCS 
under occlusion might be needed which have potential to confound study results.  Patients will be 
allowed to be rescued with topical/systemic therapies in case of intolerable symptoms. 
The primary endpoint used in the study is based on the endpoint used in previous phase 3 
dupilumab AD trials (IGA), which is adapted to assess hand and feet involvement only.  A similar 
instrument was used in the phase 3 trial for alitretinoin for hand dermatitis.  Moreover, there is 
precedence of adapting the IGA to measure outcomes in localized forms of disease for scalp and 
nail psoriasis in phase 3 trials for biologics (secukinumab for scalp psoriasis and adalimumab for 
nail psoriasis) (Bagel, 2017) (Elewski, 2018). 
The 16-week treatment duration is similar to that used in previous adult phase 3 trials in AD.  
Moreover, the selected dupilumab dose regimens will have achieved steady-state concentration by 
the end of this period.  A recent observational study to compare effect of dupilumab on hand lesions 
vs. lesions on other parts of the body found a high degree of concordance in terms of onset of 
effect and overall effect at week 16 (Oosterhaven, 2018).  The only drug approved for hand 
dermatitis, alitretinoin, is a slow acting drug showing modest efficacy after 24 weeks.  The 
response of hand dermatitis to systemic immunomodulatory agents used in AD is rapid.  As an 
example, oral cyclosporine has shown efficacy in hand dermatitis in a 6-week randomized 
controlled trial (Granlund, 1996). 
The 12-week follow-up period is based on the expected pharmacokinetics (PK) of dupilumab after 
the last dose, ie, the time for serum concentrations to decline to nondetectable levels (below the 
lower limit of quantification) in most patients. 
Randomization will be stratified to control for potential confounding variables which could impact 
efficacy (age [adults vs. adolescents], disease severity [IGA hand and foot 3 vs. 4], and geographic 
region [United States versus Japan versus other countries]).  
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3.2.2. 
Rationale for Dose Selection 
The dose regimen of dupilumab selected for this study is an initial (loading) dose of 600 mg 
administered subcutaneously (SC), followed by 300 mg administered SC every 2 weeks (Q2W) in 
adults and a fixed dose tiered by body weight in adolescent patients (body weight ≥60 kg, an initial 
[loading] dose of 600 mg administered SC, followed by 300 mg administered SC Q2W; body 
weight <60 kg, an initial [loading] dose of 400 mg administered SC, followed by 200 mg 
administered SC Q2W).  The respective dose regimens have proven to be effective and have 
demonstrated an acceptable safety profile in adult and adolescent patients with moderate-to-severe 
AD.  Given the substantial evidence gathered regarding dose selection with dupilumab in AD and 
considering that pathophysiology of AD elsewhere is identical to that of atopic hand and foot 
dermatitis, the dose of dupilumab approved in the US, EU, and other countries globally for use in 
AD will be tested in this study.  This is especially relevant as atopic hand and foot dermatitis tends 
to co-exist with AD on other parts of the body in majority of the patients (Agner, 2015). 
The case reports published in the literature that showed substantial benefit for dupilumab in 
patients with AD of hands and feet used the approved dupilumab dosing regimen, thus provide 
further support for this dosing regimen (Nanda, 2019) (Oosterhaven, 2018) (Zirwas, 2018).  The 
observational study cited in the previous section, which showed a high degree of concordance 
between effect on lesions of atopic hand dermatitis vs. lesions on other parts of the body, also used 
the approved dupilumab dosing regimen providing further credence to this approach  
(Oosterhaven, 2018). 
The administration of the loading dose of dupilumab will allow systemic concentrations to reach 
steady-state faster, and potentially reduce the time to onset of clinical effect.  
3.3. 
Risk-Benefit 
Benefits 
The efficacy of dupilumab in AD was evaluated in multiple randomized, double-blind, placebo-
controlled studies in adults and in a separate study with a similar study design in adolescents.  In 
all studies, dupilumab demonstrated clinically meaningful and statistically significant 
improvements compared to placebo in disease activity measures assessing objective AD signs 
(IGA, Eczema Area and Severity Index [EASI], SCORing AD [SCORAD], BSA affected by AD), 
subjective symptoms (eg, Pruritus Numeric Rating Scale [NRS], Patient Oriented Eczema Measure 
[POEM]), and quality of life (Dermatology Life Quality Index [DLQI] in adults, Childrens’ 
Dermatology Life Quality Index [CDLQI] in adolescents).  These results formed the basis for 
approval of dupilumab for moderate-to-severe AD in adults worldwide, and in adolescents in US 
and EU. 
Although the above trials did not specifically look at the effect of dupilumab on hand and foot 
dermatitis, post hoc analyses from phase 3 trials showed that dupilumab works equally well across 
different anatomical regions (upper limbs/lower limbs/trunk/head and neck) (Blauvelt, 2017).  In 
the post approval setting, multiple case reports have shown that patients with atopic hand and foot 
dermatitis receive substantial clinical benefit from treatment with dupilumab (Nanda, 2019) 
(Oosterhaven, 2018) (Zirwas, 2018)This is consistent with the known pathophysiology of AD 
which is driven primarily by type 2 inflammation, irrespective of the site of location. 
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Risks 
The most common adverse drug reactions identified in the dupilumab adult AD clinical program 
were injection site reactions common (≥10%).  Other common adverse reactions (≥1% and <10%) 
included conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, eye pruritus, dry eye, 
blepharitis, oral herpes, herpes simplex (primarily mucocutaneous in nature) and eosinophilia.  In 
the completed adolescent AD studies, the safety profile was consistent with that reported in adults 
and there were no new safety signals detected with dupilumab in the adolescent population. 
Overall, systemic hypersensitivity has been established an important identified risk with 
dupilumab.  As protein therapeutics, all monoclonal antibodies (mAbs) are potentially 
immunogenic.  Rare serious and systemic hypersensitivity reactions have been observed in the 
dupilumab program including serum sickness/serum sickness-like reaction in the adult AD and 
anaphylaxis related to dupilumab in the adult asthma clinical trials.  No event of serum 
sickness/serum sickness-like reaction or anaphylaxis related to dupilumab has been reported in the 
adolescent AD program. 
In study R668-AD-1924, patients will be monitored at the study center for 30 minutes post-dose 
for the first 3 visits at which study drug is administered to facilitate detection and treatment of any 
immediate hypersensitivity reactions to the study drug. 
An important potential risk “Eosinophilia associated with clinical symptoms” has been observed 
in the asthma clinical trials (few cases of eosinophilic granulomatosis with polyangiitis and 
eosinophilic pneumonia) but not in AD clinical studies. 
Risk/Benefit Conclusion 
The safety data available to date, in conjunction with the risk monitoring and mitigation strategies 
in the study protocol, and the clinical benefit of dupilumab demonstrated in multiple AD studies 
in adult and adolescent patients, support a favorable benefit-risk profile for dupilumab. 
A risk-benefit statement with respect to the overall development program is provided in the 
Investigator’s Brochure. 
Study Conduct in Response to COVID-19 
Recognizing that “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on the 
conduct of clinical trials, the Sponsor does not intend to screen any patient in this study until the 
COVID-19 pandemic is deemed manageable and no longer interfering with the conduct of trials 
at individual sites, and patients can safely participate in the study. Until then, the Sponsor plans to 
obtain approvals from Health Authorities/Ethics Committees to enable initiation of study sites for 
this study, as allowed by local laws and regulations. 
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4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
• Proportion of patients achieving an IGA (hand and foot) score of 0 or 1 at week 16 
4.1.2. 
Secondary Endpoints  
Key Secondary Endpoint for Efficacy: 
• Proportion of patients with improvement (reduction) of weekly average of daily hand 
and foot peak Pruritus NRS ≥4 from baseline to week 16 
Secondary Endpoints for Efficacy: 
• Proportion of patients with improvement (reduction) of weekly average of daily hand 
and foot peak Pruritus NRS ≥3 from baseline to week 16 
• Percent change from baseline to week 16 in weekly average of daily hand and foot peak 
Pruritus NRS 
• Percent change in mTLSS for hand/foot lesions from baseline to week 16  
• Percent change from baseline to week 16 in weekly average of daily hand and foot peak 
Pain NRS 
• Percent change from baseline to week 16 in weekly average of daily Sleep NRS 
• Change from baseline to week 16 in percent surface area of hand and foot involvement 
with AD 
• Percent change from baseline to week 4 in weekly average of daily hand and foot peak 
Pruritus NRS 
• Proportion of patients with improvement (reduction) of weekly average of daily hand 
and foot peak Pruritus NRS ≥4 from baseline to week 4 
• For patients with hand dermatitis, percent change from baseline to week 16 in Hand 
Eczema Severity Index (HECSI) score 
• For patients with hand dermatitis, proportion of patients with HECSI-75 at week 16 
• For patients with hand dermatitis, proportion of patients with HECSI-50 at week 16 
• For patients with hand dermatitis, proportion of patients with HECSI-90 at week 16 
• For patients with hand dermatitis, change from baseline to week 16 in Quality of Life 
in Hand Eczema Questionnaire (QOLHEQ) 
• Change from baseline to week 16 in Work Productivity and Impairment (WPAI) and 
Classroom Impairment Questionnaire (CIQ) 
Secondary Endpoint for Safety: 
• Incidence of treatment-emergent adverse events (TEAEs) through week 16 
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Secondary Endpoints for Clinical Pharmacology and Immunogenicity: 
• Trough concentration of functional dupilumab in serum at various time points 
• Incidence of treatment-emergent anti-drug antibody (ADA) and titer over time 
4.1.3. 
Other Endpoints and Assessments 
Other endpoints and assessments, as applicable, will be specified in the Statistical Analysis Plan 
(SAP). 
4.1.4. 
Exploratory Endpoints 
• In patients with AD lesions on other parts of the body in addition to hands and feet; 
− Percent change in EASI score from baseline to week 16 
− Proportion of patients with IGA score of 0/1 at week 16 
− Proportion of patients with EASI-75 at week 16  
5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
disease characteristics including medical history, and medication history for each patient.   
5.2. 
Efficacy Variables 
The efficacy variables include measurements or scores for individual patients for the following: 
• Patient-reported outcome measures: Daily hand and foot peak Pruritus NRS, Daily 
hand and foot peak Pain NRS, Daily Sleep NRS, QOLHEQ, Patient Global Impression 
of Severity (PGIS), Patient Global Impression of Change (PGIC), WPAI+CIQ, and 
EQ-5D 
• Investigator-reported outcomes: IGA for hands and feet, mTLSS, percent surface area 
of hand and foot involvement with AD, HECSI, IGA (global), and EASI 
5.3. 
Safety Variables 
The safety variables include recordings, measurements or laboratory test results for individual 
patients for the following: AEs, vital signs, physical examinations, hematology, blood chemistry, 
and urinalysis. 
5.4. 
Pharmacokinetic Variables 
The PK variable is the concentration of dupilumab at each time point.  These sampling timepoints 
are specified in Table 1 . 
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5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, neutralizing antibody (NAb) status, and time 
point/visit.  Samples in this study will be collected at the clinic visits specified in Table 1 . 
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Not applicable. 
6. 
STUDY DESIGN 
This is a global, multicenter, randomized, double-blind, parallel-group, placebo-controlled study 
investigating the efficacy and safety of dupilumab monotherapy in adult and adolescent patients 
with moderate-to-severe atopic hand and foot dermatitis.  Eligible patients must have a 
documented history of inadequate response or intolerance to treatment of hand and foot dermatitis 
with topical AD medications.  Approximately 130 patients will be enrolled for the study.  The 
number of adult patients will be capped at approximately 100 to ensure that, at a minimum, 
approximately 30 adolescents will be enrolled.  The number of patients with hands only 
involvement will be capped at approximately 100.  
6.1. 
Study Description and Duration 
The study consists of 3 periods: 
• Screening period (minimum duration of 4 weeks and maximum up to 8 weeks) 
• Randomized treatment period (16 weeks) 
• Post treatment follow-up period (12 weeks) 
At the screening visit, adult patients will provide informed consent before any other study 
procedures are conducted.  For adolescent patients, parents or legal guardians will provide 
informed consent and the patients will provide assent.  After providing informed consent/assent, 
the patients will be assessed for study eligibility at the screening visit.  During the screening period, 
systemic treatments for AD will be washed out, as applicable, according to the eligibility 
requirements.  Topical treatments for AD of hands and feet will also be discontinued, according to 
the eligibility requirements.  However, patients will be allowed to use topical treatments for 
treatment of AD on other parts of the body with certain restrictions (Section 8.10.2 ).  
A detailed history of exposure to irritants relevant to hand and foot dermatitis in the occupational 
as well as non-occupational setting will be elicited at screening.  During the screening period, 
patients will be provided instructions on skin protection measures.  Patients will need to follow 
these measures throughout the screening period in order to remain eligible for the study.  It is 
recommended that patients continue with these measures during the remaining duration of the 
study (for details of skin protection measures refer to Section 8.10.3 ). 
Patients may be re-screened once if they fail the screening evaluation for reasons related to 
incidental transitory conditions (eg, inability to conduct patch testing during the screening period, 
medication use, intercurrent illness, transient medical condition), unless the reason for the screen 
failure is related to failing the disease severity inclusion criteria.  
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Patch testing with a standard series of allergens will also be carried out during the screening period 
to exclude patients with predominantly ACD of hand and foot.  Patients will need to be 
discontinued from topical/systemic medications for AD prior to the patch testing.  Patients will be 
called to the site for multiple visits during the screening period for conducting these patch tests 
(refer to Section 9.2.1.1 for further details on the patch testing procedure). 
Patients who meet the eligibility criteria will be randomized (1:1) to one of the following treatment 
groups:  
• Dupilumab, administered SC Q2W 
− in adults; dupilumab 300 mg, after a loading dose of 600 mg on day 1, irrespective 
of body weight  
− in adolescents; Body weight ≥60 kg, dupilumab 300 mg, after a loading dose of 
600 mg on day 1, body weight <60 kg, dupilumab 200 mg, after a loading dose of 
400 mg on day 1. 
• Matching placebo with the above respective dupilumab doses, administered SC Q2W 
Randomization will be stratified by age (adults vs. adolescents), disease severity (IGA hand and 
foot 3 vs. 4), and geographic region (United States versus Japan versus other countries).  
Randomization will be capped for the adults at approximately 100 to ensure that, at a minimum, 
approximately 30 adolescents will be enrolled. 
Information on the anatomical area of involvement (hands only vs. hands and feet vs. feet only) 
will be collected at baseline prior to randomization.  The number of patients with hands only 
involvement will be capped at approximately 100. 
During the treatment period, patients will have in-clinic visits at week2 and week4, and then in-
clinic visits every 4 weeks through week 16 with bi-weekly phone visits in between the in-clinic 
visits.  Patients and/or parents/caregivers (in case of adolescents as deemed appropriate based on 
age of patient) will be trained on injecting study drug during in-clinic visits when study drug is 
administered (day 1, week 2, and week 4).  During weeks in which no in-clinic visit is scheduled, 
patients will either self-inject study drug or the parent/caregiver will administer study drug to the 
patient.  In case patients do not want to self-inject and the parent/caregiver do not want to 
administer study drug to patient, patients may have the clinic staff administer all the study drug 
injections in the clinic.  Safety laboratory tests, collection of samples for study drug concentrations, 
immunogenicity, and clinical assessments will be performed at specified clinic visits, as noted in 
Table 1. 
The use of topical and systemic medications for the treatment of atopic chronic hand and foot 
dermatitis will be prohibited during the treatment period.  However, patients will be allowed to 
use topical medications for AD on parts of the body other than hand and foot.  These topical 
medications will be limited to low to medium potency TCS creams.  Moreover, patients will be 
advised to either a) use gloves or use tongue depressors while applying these creams if self-
applying or b) have a caregiver apply these treatments.  If medically necessary (ie, to control 
disease flares), rescue treatment in the form of high potency TCS on hand/foot and/or systemic 
immunosuppressants may be provided to study patients at the discretion of the investigator.  
Patients may continue study treatment if they received rescue treatment. 
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The end of treatment visit will occur at week 16, 2 weeks after the last dose of study drug.  The 
primary endpoint will be assessed at this visit.  If patients prematurely discontinue study drug, the 
patients will be encouraged to stay in the study to have data collected at all remaining scheduled 
visits until completion of the planned end of study visit. 
Post-treatment follow-up period: Upon completing the 16-week randomized treatment period, 
patients will enter a 12-week follow-up period.  The end of study (EOS) visit will occur at week 28. 
An overview of the study is provided in the study schematic below (Figure 1). 
 
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Figure 1: Study Flow Diagram 
 
D=Day; DB=Double-blind; EOS=End of study; EOT=End of treatment; F/U=Follow-up; OCS=oral corticosteroid; R=Randomization; W=Week. 
 
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6.1.1. 
End of Study Definition 
The end of study is defined as the date of the last visit of the last patient in the study. 
6.2. 
Planned Interim Analysis 
No interim analysis with alpha spending is planned for this study.   
Timing of data analyses are described in Section 11.5. 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately 130 patients (65 patients per arm) will be enrolled at approximately 50 global sites.  
The number of adult patients will be capped at approximately 100 to ensure that, at a minimum, 
approximately 30 adolescents will be enrolled.  The number of patients with hands only 
involvement will be capped at approximately 100. 
7.2. 
Study Population 
The proposed study population is patients with chronic, moderate-to-severe atopic hand and foot 
dermatitis 
inadequately 
responsive 
to 
medium-to-high-potency 
TCS 
or 
in 
whom 
medium-to-high-potency TCS are inadvisable.  Only patients meeting the diagnostic criteria for 
AD will be included in this study.  Patients with a confirmed diagnosis of irritant contact dermatitis 
or ACD as the predominant cause of hand and foot dermatitis will be excluded from the study. 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female ≥12 years old at time of the screening visit. 
2. Patients with chronic hand and foot dermatitis diagnosed at least 3 years prior to the 
screening visit for patients ≥18 years old, and at least 1 year prior to the screening visit for 
patients ≥12 to <18 years old. 
3. Patients with involvement of at least 2 anatomical areas at screening and baseline.  These 
2 anatomical areas could be both hands, 1 hand and 1 foot, or both feet. 
4. Patients need to have an IGA hand and foot score of 3 or 4 (moderate-to-severe disease) 
at screening and baseline. 
Note:  The investigators should assign a single IGA score based on their overall 
impression of disease severity of hands and feet.  Patients need to have overall 
moderate-to-severe disease in hands/feet and involvement of at least 2 anatomical areas 
to be eligible. 
5. Patients with documented recent history (within 6 months before the screening visit) of 
inadequate response of atopic hand and foot dermatitis to topical medication(s) or for 
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whom topical treatments of atopic hand and foot dermatitis is medically inadvisable 
(eg, intolerance, because of important side effects or safety risks).  If documentation is 
inadequate, potential patients may be offered a course of treatment with a daily regimen 
of TCS of medium or higher potency (±TCI as appropriate), applied for at least 28 days 
during the screening period, or for the maximum duration recommended by the product 
prescribing information, whichever is shorter.  Patients who demonstrate inadequate 
response during this period, as defined above, will be eligible for inclusion in the study 
following appropriate washout. 
NOTES: 
• Inadequate response is defined as failure to achieve and maintain remission or a low 
disease activity state as per clinical judgment of treating physician despite treatment 
with a daily regimen of TCS of medium to higher potency (± topical calcineurin 
inhibitor [TCI] as appropriate), applied for at least 28 days or for the maximum duration 
recommended by the product prescribing information (eg, 14 days for super-potent 
TCS), whichever is shorter. 
• Important side effects or safety risks from treatment of atopic hand and foot dermatitis 
are those that outweigh the potential treatment benefits and include intolerance to 
treatment, hypersensitivity reactions, significant skin atrophy of hand and feet, and 
systemic effects, as assessed by the investigator or by the patient’s treating physician. 
• Acceptable documentation includes contemporaneous chart notes that record topical 
medication prescription and treatment outcome, or investigator documentation based 
on communication with the patient’s treating physician.   
• Patients with documented systemic treatment (systemic immunosuppressant drugs like 
cyclosporine, methotrexate, corticosteroids, alitretinoin, etc) for atopic hand and foot 
dermatitis in the past 6 months are also considered as inadequate responders to topical 
treatments and are potentially eligible for treatment with dupilumab after appropriate 
washout.  However, this does not apply to patients who used these systemic treatments 
for generalized AD lesions throughout the body.  Moreover, this also does not apply to 
cases in which a determination cannot be made with reasonable certainty that the 
systemic treatment was used in the past specifically for atopic hand and foot dermatitis. 
6. Patients need to meet the Hanifin and Rajka criteria for diagnosis (Hanifin, 1980). 
NOTES: 
The diagnosis of AD requires the presence of at least 3 of 4 major criteria: 
a. Pruritus 
b. Dermatitis affecting flexural surfaces in adults and the face and extensors in infants 
(criterion: criterion quoted verbatim, infants will not be included in this study) 
c. Chronic or relapsing dermatitis 
d. Personal or family history of cutaneous or respiratory atopy 
In patients who do not have AD lesions present on parts of the body other than hands 
and feet at time of screening, the study investigator should check for any prior history 
of presence of AD lesions in typical age specific distribution patterns for eg, flexural 
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areas (cutaneous atopy).  Prior history of respiratory atopic diseases (for eg, asthma, 
allergic rhinitis) should also be elicited. 
In addition, 3 out of 23 minor criteria need to be met (refer to Appendix 1 for a list of the minor 
criteria). 
7. Baseline hand and foot peak Pruritus NRS score for maximum itch intensity ≥4. 
8. At least 11 (of a total of 14*) applications of a topical emollient (moisturizer) during the 
7 consecutive days immediately before the baseline visit (not including the day of 
randomization). 
* Based on application of moisturizer twice daily for 7 days leading up to randomization.  
Application of emollient more than twice in a day is permitted but the additional 
applications will not be counted in the 11 required applications to fulfil eligibility for 
the study. 
9. Willing and able to comply with clinic visits and study-related procedures. 
10. Provide informed consent/assent signed by study patient or legally acceptable 
representative. 
11. Able to understand and complete study-related questionnaires. 
12. Patients need to have been compliant with the skin protection measures (as outlined in 
Section 8.10.3) through the entire duration of the screening period (minimum of 4 weeks 
but lasting to a maximum of 8 weeks).  This includes avoidance of known irritants that 
are identified as causing exacerbation of one’s hand and foot AD.  
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Patients with a positive patch test reaction to one or more allergens (a score of 1+ or above 
according to International Contact Dermatitis Research Group [ICDRG] grading scale) in 
either  
a. the baseline patch test series OR  
b. extended baseline or supplemental patch test allergens if such additional testing is 
conducted by the investigator OR 
c. Personal products if testing with such products is conducted by the investigator 
AND  
Which is deemed to be clinically relevant in the view of the investigator as the current 
cause of the hand and foot dermatitis. 
NOTES: 
• Patch testing with extended baseline series, supplemental series and/or personal 
products will only be carried out if deemed necessary as per clinical judgment of 
investigator 
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• The results of the patch tests conducted in the past can be used to determine eligibility 
for a patient as long as ALL of the following are met: 
− the patch testing was conducted no more than 3 years prior to screening visit AND  
− patch testing was conducted with the same battery of allergens as the baseline Patch 
test series or even if conducted with a different series included all the allergens 
included in the baseline patch test series AND 
− the investigator does not deem patch testing with an extended baseline series, 
supplemental series or with patient’s personal products necessary based on clinical 
judgment. 
• Patients with a documented diagnosis of ACD of hands and/or feet, who have a 
positive patch test reaction at screening will also be excluded from the study, 
regardless of whether history of current skin exposure to products containing this 
allergen (current relevance) is present. 
• Patients with positive reactions which are interpreted as irritant reactions based upon 
morphology, timing (eg, 1 +ve at day 2 followed by a decrescendo pattern) will still 
be eligible for study as long as they meet other eligibility criteria for the study. 
2. Patients with a documented diagnosis of protein contact dermatitis of hands and/or feet. 
These are patients with occupational or non-occupational contact to proteins such as food, 
latex etc. with positive prick test who present with lesions of contact urticaria or dermatitis 
on hands/feet. 
3. Patients in whom patch testing cannot be conducted due to any reason (these include but 
are not limited to refusal of patient to have patch testing, inability to take patient off 
systemic immunosuppressants/topical AD medications for the required washout period 
prior to patch testing, lack of clear skin (free of lesions) on upper back and /or upper arm 
on which to apply patch tests, etc). 
4. Patients with documented exposure to irritants in the occupational or non-occupational 
(household/recreational) setting that is believed to be a predominant cause of the current 
hand and foot dermatitis as per the judgment of the investigator. A detailed history of 
exposure to irritants in the occupational as well as non-occupational setting will be 
elicited at screening. The site staff will complete a CRF containing a list of irritants 
commonly implicated in causing irritant contact dermatitis at screening.  
NOTES: 
• It is recognized that patients with atopic hand and foot dermatitis may have identified 
irritants which are known to exacerbate their disease.  As long as the irritants are a) 
neither the primary nor the predominant cause for their disease as per clinical 
judgment of investigator and b) the patients are willing to avoid these irritants during 
the entire duration of the study, such patients can be enrolled into the study.  
• Patients whose hand dermatitis, in the clinical judgment of investigator, is 
predominantly irritant contact dermatitis caused due to household or occupational wet 
work exposure will also be excluded. As a guide, investigators can use the following 
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wet work criteria; (a) activities where workers have to immerse their hands in liquids 
for >2 hours per shift, b) wear waterproof (occlusive) gloves for a corresponding 
amount of time, or c) wash their hands >20 times per shift (Behroozy et al. 2014) to 
make this determination.  
5. Treatment with dupilumab in the past. 
6. Patients who have used any the following treatments within 4 weeks before the baseline 
visit 
a. Systemic corticosteroids 
b. Immunosuppressive/immunomodulating 
drugs 
(eg, 
alitretinoin, 
cyclosporine, 
mycophenolate mofetil, IFN-γ, systemic Janus kinase inhibitors, azathioprine or 
methotrexate) 
c. Phototherapy (including localized psoralen and UVA [PUVA] or narrow band 
ultraviolet B [UVB] on hands and/or feet). 
7. Treatment with biologics, other than dupilumab, as follows: 
a. Any cell-depleting agents including but not limited to rituximab: within 6 months 
before the baseline visit, or until lymphocyte and CD 19+ lymphocyte count returns to 
normal, whichever is longer 
b. Other biologics: within 5 half-lives (if known) or 16 weeks prior to the baseline visit, 
whichever is longer 
8. Treatment with TCS or TCI or crisaborole or topical Janus kinase (JAK) inhibitor within 
2 weeks before the baseline visit on the hand and foot. 
9. Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), 
whichever is longer, before the baseline visit. 
10. Treatment with a live (attenuated) vaccine within 4 weeks before the baseline visit. 
11. Planned or anticipated use of any prohibited medications and procedures during study 
treatment. 
12. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections (eg, tuberculosis [TB], histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent 
infections of abnormal frequency as judged by the investigator. 
13. Known history of human immunodeficiency virus (HIV) infection or HIV seropositivity. 
14. With a current diagnosis of hepatitis B viral infection at the time of screening as evidenced 
by 
a. Positive hepatitis B surface antigen (HBsAg) or  
b. Positive total hepatitis B core antibody (HBcAb) confirmed by positive HBV DNA 
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NOTE: 
Patients who have gained immunity for hepatitis B virus infection after vaccination 
(patients who are HBsAg negative, hepatitis B surface antibody [HBsAb] positive, and 
HBcAb negative) or after natural infection (patients who are HBsAg negative, HBsAb 
positive, and HBcAb positive) are eligible for the study.  These patients will be allowed to 
enroll into the study but will be followed using routine clinical and liver function tests. 
In case of results showing HBsAg negative, HBsAb negative, and HBcAb positive, a HBV 
DNA testing will be performed prior to randomization to rule out a false positivity and to 
confirm current infection.  Patients who are HBcAb positive and HBV DNA negative will 
be eligible to enroll in the trial.   
15. With a current diagnosis of hepatitis C viral infection at the time of screening as evidence 
by 
a. Positive HCV Ab AND 
b. Positive HCV RNA 
16. On current treatment for hepatic disease including but not limited to acute or chronic 
hepatitis, cirrhosis, or hepatic failure, or has evidence of liver disease as indicated by 
persistent (confirmed by repeated tests ≥2 weeks apart) elevated transaminases (alanine 
aminotransferase [ALT] and/or aspartate aminotransferase [AST]) more than 3 times the 
upper limit of normal (ULN) during the screening period. 
17. Presence of any 1 or more of the following abnormalities in laboratory test results at 
screening: 
a. Platelets ≤100 × 103/μL 
b. Neutrophils <1.5 × 103/μL 
18. Diagnosed active endoparasitic infections.  Patients with suspected or high risk of 
endoparasitic infection will be excluded, unless clinical and (if necessary) laboratory 
assessment have ruled out active infection before randomization. 
19. Presence of skin comorbidities on hand and foot that may interfere with study assessments.  
This includes, but is not limited to palmoplantar psoriasis, palmoplantar keratoderma, 
lichen planus, pityriasis rubra pilaris, herpes simplex, erythema multiforme, tinea 
mannum/tinea pedis, scabies, granuloma annulare. 
20. 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. 
21. Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect 
the patient’s participation in the study.  Examples include, but are not limited to patients 
with short life expectancy, patients with uncontrolled diabetes (HbA1c ≥9%), patients with 
cardiovascular conditions (eg, stage III or IV cardiac failure according to the New York 
Heart Association classification), severe renal conditions (eg, patients on dialysis), 
neurological conditions (eg, demyelinating diseases), active major autoimmune diseases 
(eg, Eosinophilic granulomatosis with polyangitis (EGPA), lupus, inflammatory bowel 
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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. 
22. Any other medical or psychological condition (including relevant laboratory 
abnormalities at screening) that, in the opinion of the investigator, may suggest a new 
and/or insufficiently understood disease, may present an unreasonable risk to the study 
patient as a result of his/her participation in this clinical trial, may make patient’s 
participation unreliable, or may interfere with study assessments.  The specific 
justification for patients excluded under this criterion will be noted in study documents. 
23. History of alcohol or drug abuse within 2 years before the screening visit. 
24. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities. 
25. Patient is a member of the investigational team or his/her immediate family. 
26. Pregnant or breastfeeding women or planning to become pregnant or breastfeed during the 
patient’s participation in this study. 
27. Women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to the initial dose/start of the first treatment, during the 
study, and for at least 12 weeks after the last dose.  Highly effective contraceptive 
measures include:  
a. stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening 
b. intrauterine device; intrauterine hormone-releasing system  
c. bilateral tubal ligation  
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual 
partner of the WOCBP study participant and that the vasectomized partner has obtained 
medical assessment of surgical success for the procedure) 
e. and/or sexual abstinence†, ‡. 
*Women of childbearing potential are defined as women who are fertile following 
menarche until becoming postmenopausal, unless permanently sterile.  Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy.  However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a 
postmenopausal state.  The above definitions are according to Clinical Trial Facilitation 
Group guidance.  Pregnancy testing and contraception are not required for women with 
documented hysterectomy or tubal ligation. 
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†Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs.  The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. 
f. ‡Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are 
not acceptable methods of contraception.  Female condom and male condom should 
not be used together. 
7.3. 
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/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures).  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patient who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.4.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from study or study drug will not be replaced. 
8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
• Dupilumab, administered SC Q2W 
− in adults; dupilumab 300 mg, after a loading dose of 600 mg on day 1, 
irrespective of body weight  
− in adolescents; Body weight ≥60 kg, dupilumab 300 mg, after a loading dose of 
600 mg on day 1, body weight <60 kg, dupilumab 200 mg, after a loading dose of 
400 mg on day 1. 
• Matching placebo, administered SC Q2W 
Randomization is discussed in Section 8.6. 
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Study drug will be administered by SC injections.  Subcutaneous injection sites of study drug 
should be alternated among the different quadrants of the abdomen (avoiding navel and waist 
areas), upper thighs, and upper arms so that the same site is not injected for 2 consecutive 
administrations. 
Instructions on dose preparation are provided in the pharmacy manual. 
8.2. 
Background Treatment 
All patients are required to apply moisturizers on their hands and feet at least twice daily during 
the screening period.  It is recommended that patients continue the use of moisturizers throughout 
the study (all 28 weeks where applicable).  All types of moisturizers are permitted, but patients 
may not initiate treatment with prescription moisturizers or moisturizers containing additives 
during the screening period or during the study.  Patients may continue using stable doses of such 
moisturizers if initiated before the screening visit.  It is recommended that the moisturizers used 
be free of additives, fragrances, perfumes, and other potentially sensitizing agents.  Moreover, it 
is recommended that the moisturizers not contain any compound with known anti-itch effect (such 
as pramoxine, lidocaine, prilocaine, capsaicin etc.). 
NOTE:  In patients with lesions of AD on parts of the body other than hands and feet, emollients 
are permitted but are not required as background medication for other body regions. 
8.3. 
Rescue Treatment 
Rescue treatment for worsening of AD of hands and feet may be provided to study patients at the 
discretion of the investigator in the study.  The use of rescue treatment is only allowed after day 
14 of the study.  Investigators will be required to perform an IGA for hands and feet assessment 
prior to starting rescue treatment and initiate rescue treatment only in patients who have an IGA 
hand and foot score ≥3.  If possible, investigators are encouraged to consider rescue initially with 
topical treatment (high potency or ultra-high potency TCS, TCIs, crisaborole, topical 
JAK inhibitors) and to escalate to systemic medications only for patients who do not respond 
adequately after at least 7 days of topical treatment.  Rescue treatment for the topical therapies 
should be used as per prescribing information and local guidelines.  Patients may continue study 
treatment if rescue consists of topical medications. 
Investigators can also use systemic corticosteroids or non-steroidal systemic immunosuppressive 
drugs 
(alitretinoin, 
cyclosporine, 
methotrexate, 
mycophenolate-mofetil, 
azathioprine, 
JAK inhibitors etc) for rescue in patients with worsening of AD of hands and feet.  Patients may 
continue study treatment if rescue consists of these systemic therapies, based upon discretion of 
investigator.  All patients will be asked to complete the scheduled study visits and assessments 
whether or not they complete study treatment and whether or not they receive rescue treatment for 
AD.  Investigators should make every attempt to conduct efficacy and safety assessments (eg, 
disease severity scores, safety laboratory tests) immediately before administering any rescue 
treatment.  An unscheduled visit may be used for this purpose, if necessary.  For the purpose of 
the efficacy responder analysis, a pre-specified algorithm will be used to classify rescue (details in 
the SAP).  In addition, a blinded review of all post-baseline medications to adjudicate rescue 
treatment, based on medical judgment, will be performed to adjudicate rescue.  Data from patients 
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who receive rescue treatment as per this adjudication during the study will be treated for efficacy 
analysis purposes as outlined in Section 11.4.3. 
Note: During the study, patients might also experience flare of AD lesions on parts of the body 
other than hands and feet.  Rescue treatment (in addition to low to medium TCS that are permitted 
during the study) will be allowed after day 14 of the study.  It is recommended that investigators 
manage these flares using topical therapies, unless the use of systemic therapies is deemed 
necessary based on severity and extent of flare as determined by the investigator.  High/ultra-high 
potency TCS/TCIs/crisaborole can be used in such situations.  The hands and feet should be spared 
from the use of these topical therapies, unless there is evidence of exacerbation of lesions on hands 
and feet as per clinical judgment of the investigator.  In case systemic corticosteroids or non-
steroidal systemic immunosuppressive drugs are used for controlling flare in AD lesions on parts 
of the body other than hands and feet, the study drug may be continued, based upon discretion of 
investigator. 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules 
8.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
8.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study.  Those who agree and do not withdraw from the study will be asked to return to the clinic 
for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 9.1.2 . 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Serious or severe allergic reactions considered related to study drug 
• Specific types of liver dysfunction [eg, Hy’s law is met (FDA, 2009)] 
• Patient or parent/legal guardian withdraws assent or consent 
• Diagnosis of a malignancy during study other than non-melanoma skin cancer or 
carcinoma in situ that is considered curable by local surgery 
• Any infection that is opportunistic, such as TB and other infections whose nature or 
course may suggest an immunocompromised status 
• Severe laboratory abnormalities assessed as related to study drug: 
− Neutrophil count ≤0.5 × 103/µL 
− Platelet count ≤50 × 103/µL 
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− ALT and/or AST values >3 × ULN with total bilirubin >2 × ULN, excluding 
confirmed Gilbert’s Syndrome 
− Confirmed AST and/or ALT >5 × ULN (for more than 2 weeks) 
NOTE: 
If the laboratory abnormality is considered causally related to study drug, study treatment will be 
permanently discontinued.  In cases in which a causal relationship to study drug can be reasonably 
excluded, (ie, an alternative cause is evident), study treatment will be suspended but it may be 
resumed when the laboratory abnormality is sufficiently normalized.  A decision to resume study 
treatment will be made jointly by the investigator and medical monitor (medical monitor’s written 
approval is required). 
• Treatment with a live attenuated vaccine (refer to Section 8.10.1 for details) 
• Treatment with an investigational drug  
The investigator may discontinue study treatment at any time, even without consultation with the 
medical monitor if the urgency of the situation requires immediate action and if this is determined 
to be in the patient’s best interest.  However, the medical monitor should be contacted as soon as 
possible in any case of study drug discontinuation.  
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
• Clinically important laboratory abnormalities, such as: 
− ALT or AST >3 × ULN 
− Neutrophil count <1.5 × 103/μL but >0.5 × 103/μL 
− Platelet count ≤100 × 103/μL but >50 × 103/μL 
After the condition leading to suspension of dosing resolves, study treatment may resume at the 
discretion of the investigator in consultation with the medical monitor.  A decision to temporarily 
discontinue study drug and/or to reinstitute study treatment should be discussed with the medical 
monitor. 
The investigator may suspend study treatment at any time, even without consultation with the 
medical monitor if the urgency of the situation requires immediate action and if this is determined 
to be in the patient’s best interest.  However, the medical monitor should be contacted as soon as 
possible in any case of study drug discontinuation. 
8.5. 
Management of Acute Reactions  
8.5.1. 
Acute Injection Reactions 
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8.5.1.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use.  All injection reactions must be reported as AEs (as defined in Section 10.2.1) 
and graded using the grading scales as instructed in Section 10.2.4 . 
Acute systemic reactions following injection of study drug (SC) should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
8.5.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.4  
8.6. 
Method of Treatment Assignment 
Approximately 130 patients will be randomized in a 1:1 ratio to receive either dupilumab or 
placebo according to a central randomization scheme provided by an interactive voice response 
system (IVRS)/interactive web response system (IWRS) to the designated study pharmacist (or 
qualified designee).   
Randomization will be stratified by age (adults vs. adolescents), disease severity (IGA hand and 
foot 3 vs. 4), and geographic region (United States versus Japan versus other countries).  
Randomization will be capped for the adults at approximately 100. 
Information on the anatomical area of involvement (hands only vs. hands and feet vs. feet only) 
will be collected at baseline prior to randomization.  The number of patients with hands only 
involvement will be capped at approximately 100.   
8.7. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study.  The Regeneron Medical/Study Director, Study 
Monitor, and any other Regeneron and contract research organization (CRO) personnel who are 
in regular contact with the study site will remain blinded to all patient randomization assignments. 
Blinded study drug kits coded with a medication numbering system will be used.  In order to 
maintain the blind, lists linking these codes with product lot numbers will not be accessible to 
individuals involved in study conduct. 
Anti-drug antibody and drug concentration results will not be communicated to the sites, and the 
sponsor’s blinded operational team will not have access to results associated with patient 
identification until after the database is locked. 
8.8. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy) and when a treatment decision is contingent 
on knowing the patient's treatment assignment.  Study drug will be discontinued for patients whose 
treatment has been unblinded (Section 8.4.2). 
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• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator.  If there is no study pharmacist, the 
investigator for the site will unblind the patient.  
− The IVRS/IWRS will provide the treatment assignment to the investigator and 
will notify Regeneron of the unblinding transaction.   
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient's treatment 
assignment.  In the event that there is no study pharmacist, the individual at the site fulfilling that 
role will be the only unblinded member of the site personnel. 
8.9. 
Treatment Logistics and Accountability 
8.9.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug.  Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging/clinical drug supply.  In order to maintain the 
blind, these lists will not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.9.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed or returned to the 
sponsor or designee. 
8.9.3. 
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 
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• 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. 
8.9.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.10. 
Concomitant Medications and Procedures 
Any treatment administered from the time of informed consent/assent to final study visit will be 
recorded.  Any treatment administered from the time of first dose of study drug to the final study 
visit will be considered concomitant medication.  This includes medications that were started 
before the study and are ongoing during the study. 
8.10.1. 
Prohibited Medications and Procedures  
Treatment with the following concomitant medications is prohibited during the study treatment 
period (through week 16):   
• Topical corticosteroids on hand and foot (may be used as rescue) 
• Topical calcineurin inhibitors on hand and foot (may be used as rescue) 
• Topical crisaborole on hand and foot (may be used as rescue) 
• Topical JAK inhibitors on hand and foot (may be used as rescue) 
• Systemic immunosuppressive/immunomodulating drugs (including, but not limited to 
alitretinoin, cyclosporine, mycophenolate-mofetil, azathioprine, methotrexate, IFN-γ, 
systemic JAK inhibitors, or other biologics) (may be used as rescue) 
• Systemic corticosteroids (may be used as rescue) 
• Treatment with an investigational drug  
• Treatment with a live (attenuated) vaccine 
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Chickenpox (varicella) 
FluMist-Influenza 
Intranasal influenza 
Measles (rubeola) 
Measles-mumps-rubella combination 
Measles-mumps-rubella-varicella 
combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rubella 
Smallpox (vaccinia) 
Yellow fever 
Bacille Calmette-Guerin 
Rotavirus 
Varicella zoster (shingles) 
(use of Zostavax is prohibited 
as it is live attenuated; use of 
Shingrix is allowed as it is 
non-live) 
Note:  If at screening visit, there is an anticipated need for use of live vaccines during the study, 
the patient should receive the vaccine during the screening period at least 4 weeks prior to baseline 
visit. 
The following concomitant procedures are prohibited during study treatment through week 16: 
• Major elective surgical procedures 
• Phototherapy (ultraviolet A [UVA], UVB, narrowband UVB [nbUVB], high dose 
UVA, and PUVA), localized PUVA or narrow band UVB on hands and/or feet  
• Tanning in bed/booth 
8.10.2. 
Permitted Medications and Procedures 
Other than the prohibited medications listed in Section 8.10.1, treatment with concomitant 
medications are permitted during the study.  Topical treatments used for AD lesions on parts of 
the body other than the hands and feet will be permitted.  This includes low to medium potency 
TCS (high potency/ultra-high TCS are prohibited), TCIs and crisaborole.  In order to avoid 
confounding of assessment of AD lesions on the hands, patients will be asked to either a) use 
gloves or tongue depressors if applying themselves or b) have a caregiver apply topical treatments 
on these lesions.  In addition, use of contraceptives and basic skin care (cleansing and bathing 
including bleach baths) as well as treatment with emollients, topical anesthetics, antihistamines, 
topical and systemic anti-infective medications for any duration are permitted. 
Medications used to treat chronic disease such as diabetes and hypertension are also permitted.  If 
there is any question regarding whether a concomitant medication may be used during the study, 
the study site should contact the medical monitor. 
In patients with lesions of AD on parts of the body other than hands and feet, emollients are 
permitted but are not required as background medication for other body regions. 
8.10.3. 
Skin Protection Measures 
Patients will be required to follow routine skin protection measures throughout the duration of the 
screening period in order to be eligible for the study.  It is recommended that patients continue 
with these measures during the duration of the study.  These measures will include the following: 
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• Avoidance of identified irritants for hand and foot dermatitis.  
• Using protective gloves when performing wet work.  It should be ensured that 
protective gloves should be intact and clean and dry inside.  When protective gloves 
are used for a long period of time, cotton gloves should be worn underneath.  Latex is 
best avoided for risk of contact urticaria and/or ACD. 
• Washing hands in lukewarm (not hot) water and to rinse and dry hands thoroughly 
after washing.  
• Minimize excessive hand washing with soaps and substitute with alcohol disinfection 
when hands are not visibly dirty.   
• Application of moisturizers, preferably those which are free from fragrances and with 
preservatives having the lowest allergen potential. 
The site staff will instruct the patients on further skin protection measures, if applicable. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
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 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 
Study Period 
Screening  
Treatment Period   
Follow-up  
  
 
Study Milestone 
  
BL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EOT 
  
  
EOS 
  
In-Clinic Visit (V)* or 
Phone Visit (PV) 
V1 
V1a 
V2 
V3 
V4 
PV51 
V6 
PV71 
V8 
PV91 
V10 
V11 
Unsched
uled 
visit2 
ET visit 
Week (W) 
 
  
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W28 
 
 
Study Day (D) 
D-56 to  
D-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D197 
 
 
Visit Window in Days 
 
  
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
 
 
Screening/ Baseline 
 
  
  
  
  
  
  
  
  
 
 
 
 
Informed consent/assent 
X 
  
 
 
 
  
  
 
  
 
  
 
 
Informed consent/assent 
for optional genomic sub-
study3 
X 
 
  
 
 
 
  
 
  
 
  
 
 
Informed consent/assent 
for optional future 
biomedical research sub-
study4 
X 
 
Informed 
consent/assent for 
optional use 
of photographs for 
educational/marketing 
purposes 
(selected study 
sites only) 
X 
 
Inclusion/Exclusion 
criteria 
X 
 
X  
 
  
 
  
  
 
  
 
  
 
 
Patch testing5,6,7,8  
 
X 
Medical History 
X 
 
 
  
  
 
  
  
 
  
 
 
 
 
History of exposure to 
irritants relevant to hand 
and foot dermatitis 
X 
 
Assign disease 
morphology9 
 
 
X 
Assign anatomical area 
of involvement10 
 
 
X 
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Study Period 
Screening  
Treatment Period   
Follow-up  
  
 
Study Milestone 
  
BL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EOT 
  
  
EOS 
  
In-Clinic Visit (V)* or 
Phone Visit (PV) 
V1 
V1a 
V2 
V3 
V4 
PV51 
V6 
PV71 
V8 
PV91 
V10 
V11 
Unsched
uled 
visit2 
ET visit 
Week (W) 
 
  
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W28 
 
 
Study Day (D) 
D-56 to  
D-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D197 
 
 
Visit Window in Days 
 
  
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
 
 
Demographics 
X 
  
  
  
  
 
  
  
 
 
 
 
 
Randomization 
  
 
X  
  
 
  
 
 
  
  
 
  
 
 
Patient diary training11 
X 
 
X  
  
   
 
  
  
  
  
 
 
 
 
Treatment 
 
 
  
  
  
  
  
  
 
 
  
 
 
Injection training/ 
observation12 
  
 
X  
X  
X  
  
X  
  
X  
  
  
 
  
  
  
Administration of study 
drug 
  
 
X13  
X  
X  
X  
X  
X  
X  
X  
  
  
  
  
Patient dosing diary 
completion 
  
 
  
   
  
X  
  
X  
   
X  
  
  
  
  
Patient counseling for 
diary completion 
  
 
X  
X  
X  
   
X  
   
X  
  
  
   
  
  
Study drug dispensation14 
  
 
   
  
X  
   
X  
   
X  
  
  
   
X 
X 
Study drug 
accountability14 
  
 
  
  
  
  
X 
   
X  
  
X 
   
  
  
Con meds/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Skin protection measures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy15 
 
 
 
 
 
 
 
 
 
 
 
Patient assessment of 
hand and foot pruritus 
intensity using NRS via 
diary (daily) 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
Patient assessment of 
hand and foot skin pain 
and sleep NRS16 
X 
X 
X 
X 
X 
  
 
   
  
   
X 
X  
  
  
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Study Period 
Screening  
Treatment Period   
Follow-up  
  
 
Study Milestone 
  
BL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EOT 
  
  
EOS 
  
In-Clinic Visit (V)* or 
Phone Visit (PV) 
V1 
V1a 
V2 
V3 
V4 
PV51 
V6 
PV71 
V8 
PV91 
V10 
V11 
Unsched
uled 
visit2 
ET visit 
Week (W) 
 
  
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W28 
 
 
Study Day (D) 
D-56 to  
D-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D197 
 
 
Visit Window in Days 
 
  
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
 
 
IGA (hand and foot), 
mTLSS, hand and feet 
area involvement, 
HECSI17 
X 
 
X 
X 
X  
  
X  
   
X  
  
X 
X 
X 
X 
EQ-5D18, WPAI+CIQ18  
X 
 
X  
  
X  
   
  
   
   
 
  
X 
X 
  
X 
PGIS18, QOLHEQ17,18 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
PGIC18 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
IGA (global)19, EASI19 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
Photograph areas of 
atopic hand or foot 
dermatitis (select sites) 
  
 
X  
   
  
   
   
  
  
   
X 
X 
  
X 
Safety 
  
 
  
  
   
   
  
   
  
  
  
   
  
  
Weight 
X 
 
X  
   
  
  
  
   
   
   
X 
X 
  
X 
Height 
X 
 
  
   
  
   
   
   
   
  
 X 
  
  
  
Vital signs 
X 
 
X13 
 
  
   
  
  
 
 
X 
X 
X 
X 
Physical examination 
X 
 
   
  
   
  
   
   
   
   
X 
 X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing20** 
  
 
  
   
   
   
   
  
  
   
  
  
  
  
Hematology 
X 
 
X  
  
  
   
   
  
  
   
X 
 X 
X 
X 
Chemistry 
X 
 
X  
  
  
  
  
  
  
   
X 
 X 
X 
X 
Urinalysis 
X 
 
X  
  
  
   
   
   
  
  
X 
X 
X 
X 
Pregnancy test, WOCBP 
only 
Serum 
 
Urine  
  
  
  
Urine  
  
Urine  
  
Urine 
Urine 
Urine 
Urine 
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Study Period 
Screening  
Treatment Period   
Follow-up  
  
 
Study Milestone 
  
BL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EOT 
  
  
EOS 
  
In-Clinic Visit (V)* or 
Phone Visit (PV) 
V1 
V1a 
V2 
V3 
V4 
PV51 
V6 
PV71 
V8 
PV91 
V10 
V11 
Unsched
uled 
visit2 
ET visit 
Week (W) 
 
  
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W28 
 
 
Study Day (D) 
D-56 to  
D-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D197 
 
 
Visit Window in Days 
 
  
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±4 
 
 
HIV, HBsAg, HBsAb, 
HBcAb21, HBV DNA22, 
Hep C Ab23, HCV 
RNA24, TB25 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
Optional DNA sample3  
  
 
X 
   
  
   
   
  
   
   
  
  
  
  
PK and ADA Sample20 
  
 
  
  
  
  
  
 
  
  
   
  
   
  
  
Functional dupilumab PK 
sample 
  
 
X  
  
 
 
 
 
 
  
X 
X 
X 
X 
Anti-dupilumab antibody 
sample 
  
 
X  
  
  
  
  
  
  
  
X 
X 
X 
X 
ADA=anti-drug antibody; BL=baseline; D= Day;  EASI=Eczema Area and Severity Index; EOS=end of study; EOT=end of treatment; ET=early termination; FBR 
= future biomedical research HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; HECSI=Hand Eczema Severity Index; HIV=human 
immunodeficiency virus; IGA=Investigator Global Assessment; mTLSS=Modified Total Lesion Sign Score; NRS=Numerical Rating Scale; PGIC=Patient Global 
Impression of Change; PGIS=Patient Global Impression of Severity; PK=pharmacokinetic; PV=phone visit; TB=tuberculosis; V=visit; W=week; 
WPAI+CIQ=WPAI plus Classroom Impairment Questionnaire; WOCBP=women of childbearing potential. 
 
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9.1.1. 
Footnotes for the Schedule of Events Table 
*Phone visits/virtual visits/telemedicine visits/home visits by skilled staff should be considered 
in case of lack of availability of site staff and/or patients to come to site for in-clinic visits due to 
COVID-19 pandemic. The following investigator-performed assessments, if feasible, should be 
performed using telemedicine/virtual visits/home visits by skilled staff: 
i. 
IGA (hand and foot) 
ii. 
mTLSS 
iii. 
Hand and feet area involvement 
iv. 
HECSI 
Site staff should make every effort to conduct telephone interviews to complete the following 
questionnaires: 
i. 
EQ-5D 
ii. 
WAPI + CIQ 
iii. 
PGIS 
iv. 
QOLHEQ 
v. 
PGIC 
Site staff should also collect information on AEs and concomitant medications. 
Site staff should conduct the telephone interviews on the date of scheduled site visit by following 
an interview guide provided by the sponsor. Patient responses from the interviewer-administered 
questionnaires will be captured by the site staff directly into the tablet OR onto a paper-copy 
printout of the questionnaire screenshots. In case telephone interviews cannot be conducted, the 
questionnaires may be sent by mail/email to the patient’s home. Questionnaires should be 
completed by patients and returned to the site. 
1. The site will contact the patient by telephone to conduct these visits.  The patient or 
caregiver (in case of adolescents, if applicable) may administer study drug on these days.  
Patients who receive study drug outside the study center will complete a dosing diary to 
document compliance with study drug administration and to document any related issues.  
Site staff will also remind the patients to either a) use gloves or tongue depressors if 
applying themselves or b) have a caregiver apply, when patients are using TCS treatment 
on lesions of AD other than hands and feet. 
2. Unscheduled visits may be necessary to repeat testing following abnormal laboratory 
results, for follow-up of AEs, or for any other reason (eg, before a rescue).  The assessments 
and procedures performed during an unscheduled visit will depend upon the reason for the 
visit.  During an unscheduled visit, any of the study procedures noted may be performed, 
but not all are required.  If the unscheduled visit is due to an AE, collect samples for PK 
and ADA analysis 
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3. For patients who decide to participate and provide a specific written informed 
consent/assent for the optional genomics sub-study (DNA sample collection).  DNA 
sample should be collected at the day 1 visit (predose) but can be collected at any visit 
during the study.   
4. FBR samples will be optional.  No additional samples are collected for patients who sign 
the FBR consent. FBR analyses will be performed on leftover biological samples (PK and 
ADA).    
5. Patch testing with a standard series of allergens will be carried out in all patients unless 
there is documented evidence that patient has been previously patch tested with the same 
series (or an expanded series which contains all the allergens in the standard series tested 
in this study) within last 3 years and the investigator determines from clinical judgment 
that further patch testing is unnecessary.  In that case, the results from the previous patch 
test will be used for determining eligibility 
6. In addition to standard baseline series, additional patch testing with expanded series and/or 
patient personal products may be carried out if deemed necessary by the investigator 
7. Patients will need to visit the site at least 3 times during the screening period for the conduct 
of patch tests (day of application, reading of results at day 2, reading of results at day 3 to 
day 7).  In some patients a reading after 7 to 10 days may be taken when the clinical history 
strongly supports sensitization 
8. Patients will need to discontinue topical and systemic therapies for AD for a certain period 
prior to patch testing.  Please refer to Section 9.2.1.1 for further details on patch testing 
9. Investigators will assign patients to the following disease morphology for each 
anatomical area of hand and foot involvement:  
• Hyperkeratotic 
• Dyshidrotic 
• Pulpitis 
• Nummular eczema 
• Chronic dry fissured forms of eczema 
• Unspecified 
It is acknowledged that a mixed pattern might be present in some patients.  Investigators should 
identify the predominant morphology in such cases and assign patients accordingly. 
Investigators will also assign an overall disease morphology which will be based upon the disease 
morphology of the anatomical area with most severe disease (in some cases, a different 
morphology may be present in hands vs. feet).  In these scenarios, investigators should assign 
morphology based on the region with higher severity of involvement (hands or feet). 
10. Investigators will assign patients to the following anatomical areas of involvement: 
• Hands only 
• Hands and feet 
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• Feet only 
11. Training of patients regarding completion of diary to record a) administration of each dose 
of drug outside the clinic by patient, b) completion of assessment of pruritus using NRS 
scale, c) completion of assessment of pain using NRS scale, d) completion of assessment 
of sleep loss using NRS scale, and e) twice daily application of emollients 
12. Patients or caregivers (in case of adolescents, if applicable) will be trained on how to 
administer study drug under observation by site staff to ensure correct administration 
technique.  This would enable administration at home in between clinic visits. 
13. Patients will be monitored at the study site at visit 2 for a minimum of 30 minutes after 
study drug administration.  Vital signs (blood pressure, respiratory rate and pulse rate) and 
AE assessments will also be assessed at 30 minutes (+/- 10 minutes) post-injection, in 
addition to pre-dose assessment.   
14. Starting at visit 4, study drug will be dispensed to the patient for the dose that will be 
administered at home before the next clinic visit.  Patients will return the study kit box (for 
prefilled syringes) at each subsequent clinic visit.  At these in-clinic visits, sites will 
perform accountability assessment for the study drug that the patients have returned to the 
site.  In case of lack of availability of site staff and/or patients to come to the site for 
in-clinic visits due to the COVID-19 pandemic, the sponsor may implement processes for 
direct-to-patient shipment of study drug. 
15. Assessments/procedures should be conducted in the following order: patient-reported 
outcomes, investigator assessments, safety and laboratory assessments, administration of 
study drug. 
16. Pain and sleep quality will be assessed daily throughout the screening period, the 7 days 
leading up to the week 2 visit, the 7 days leading up to the week 4 visit, the 7 days leading 
up to the week 16 visit, and 7 days leading up to the week 28 visit.  Patients will complete 
a daily diary on these days to record skin pain and sleep quality NRS. 
17. The HECSI and QOLHEQ will only be performed in patients with presence of hand 
dermatitis at baseline  
18. The questionnaires will be administered only to the subset of patients who speak fluently 
the language in which the questionnaire is presented (based on availability of validated 
translations in participating countries). 
19. Standard assessments for AD lesions over the whole body, not just limited to hands and 
feet. As part of these assessments, sites will answer the question: Does the patient have AD 
lesions outside the hands and/or feet? These assessments will only be performed in patients 
who have AD lesions outside their hands and feet. 
20. Samples will be collected before the injection of study drug.  Serum samples will be 
collected for the determination of dupilumab concentration in and for the immunogenicity 
assessment of dupilumab.  In the event of suspected serious adverse events (SAEs), such 
as anaphylaxis or hypersensitivity, additional PK and ADA samples may be collected at or 
near the event.  Samples positive in the ADA assay will be analyzed in the NAb assay. 
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** Alternate measures for laboratory testing should be considered in case of lack of availability 
of site staff and/or patients to come to the site for in-clinic visits due to the COVID-19 
pandemic. Assessments, including but not limited to, which can be performed are as follows: 
a. Hematology 
b. Chemistry 
c. Urinalysis 
d. Pregnancy test 
21. In case of results showing HbsAg negative, HbsAb negative and HbcAb positive, 
HBV DNA testing will be performed prior to randomization to rule out a false positivity 
and to confirm current infection. 
22. Only performed in patients whose serology results show HbsAg negative, HbsAb 
negative and HbcAb positive. 
23. In case of results showing positive hepatitis C antibody (Hep C Ab), an HCV RNA will 
be performed to rule out a false positivity and to confirm current infection. 
24. Only performed in patients whose serology results show positive Hep C Ab. 
25. TB testing will be performed on a country-by-country basis, according to local guidelines 
if required by regulatory authorities or ethics boards. 
9.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study before the primary endpoint visit (week 16) will be 
asked to return to the clinic for an early termination visit consisting of the early termination 
assessments described in Table 1.  
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
9.2. 
Study Procedures 
Assessments/procedures the clinic visit should be performed in the following order:  
1. Patient Reported Outcomes  
2. Investigator assessments (performed only by adequately trained and qualified investigators 
or sub-investigators; it is recommended that the same investigator or sub-investigator 
perform all the evaluations for a given patient throughout the entire study period)  
3. Safety and laboratory assessments (including sample collection for ADA, PK, and optional 
DNA). 
4. Administration of study drug  
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9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:   
• Medical History 
• Detailed occupational, social, and personal history relevant to hand and foot 
dermatitis  
• Demographics 
• Inclusion/Exclusion criteria, including hepatitis and HIV serology, and TB (if 
required per local regulation) 
• Patch Testing 
• Patient diary training 
9.2.1.1. 
Patch Testing 
Patch testing with a standard series of allergens will be conducted during the screening period for 
determining eligibility.  Patch testing should normally be conducted after other screening 
procedures (eg, lab testing) have been completed and eligibility for the study confirmed.  Patients 
need to discontinue therapies for AD before the patch testing is conducted.  The wash out period 
will be as follows: 
1. 1 week for TCS/TCI /topical JAK inhibitor/crisaborole application (this application will 
not be allowed only on the region of the body where patch testing is planned which in 
most cases would be the upper back) 
2. 4 weeks for UVA and UVB 
3. 4 weeks for oral corticosteroids 
4. 4 weeks for other systemic immunomodulators such as cyclosporine (CsA), 
mycophenolate mofetil (MMF), methotrexate (MTX), Alitretinoin, systemic 
JAK inhibitors etc.  
The standard series used will vary based upon the region of conduct of the study, eg, TRUE test 
in the US, The TRUE test and an additional panel of allergens (provided in the study manual) 
which are not included in TRUE test but are commonly implicated in causing ACD of hands and 
feet in patients in the EU, and patch test panel (S) in Japan. In case other countries/regions are 
added to the study, country specific patch test series may be used as applicable. In case of patients 
who have had patch testing with the same country-specific series of allergens within 3 years prior 
to screening visit, the patch testing does not need to be repeated and results from the previous patch 
test can be used for study purposes. 
In addition, patch testing with extended baseline series, supplemental series and/or personal 
products may be carried out as per clinical judgment of investigator.  
Patients will be called to the site for 3 visits for the patch testing 
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1. Appointment 1 (day 0): Application of patch tests 
2. Appointment 2 (reading of results at day 2): the patches will be removed, and reading 
will be taken 20 to 30 minutes after removal of the patches. 
3. Appointment 3 (reading of results at day 3 to day 7): A second reading will be taken 
In some patients a reading after day 7 may be taken when the clinical history strongly supports 
sensitization.  This is especially relevant for contactants such as metals (nickel sulfate, gold sodium 
thiosulfate, palladium chloride, potassium dichromate, cobalt chloride), some antibiotics 
(neomycin), TCS (tixocortol-21-pivalate, budesonide), and dyes (para-phenylenediamine). 
The patch test should be applied on normal appearing skin free from skin diseases such as AD.  
The upper back is preferred site for the application of patch tests.  In case not suitable for patch 
testing, or is fully used already, the upper parts of the arm may be used.  
The patch tests will be read using the globally recognized the ICDRG criteria: 
Symbol 
Morphology  
Assessment 
- 
No reaction 
Negative reaction 
?+ 
Faint erythema only 
Doubtful reaction 
+ 
Erythema, infiltration, 
possibly 
papules 
Weak positive 
reaction 
++ 
Erythema, infiltration, 
papules, 
vesicles 
Strong positive 
reaction 
+++ 
Intense erythema, infiltrate, 
coalescing vesicles 
Extreme positive 
reaction 
For the purpose of this study, a score of 1+ and above will be considered a positive result.  The 
investigators should be careful to exclude irritant reactions which typically appear within the first 
48 hours and tend to disappear (decrescendo effect) by 96 hours, whereas allergic reactions tend 
to increase (crescendo effect).  Moreover, the morphology of these irritant reactions can differ 
from allergic reactions with presence of necrosis and bullae. 
The history and physical examination must be correlated with the result of the PT to establish 
clinical relevance.  A positive PT may be clinically relevant depending on current or past 
exposures. 
Current relevance will be defined as definite if the PT or use test with the suspected material is 
positive This occurs if an allergen is found in the patient’s environment (example: fragrance in the 
patient’s personal care products), the dermatitis corresponds to the point of contact with allergen 
(face), and the dermatitis improves with avoidance or recurs with rechallenge.  Relevance is 
probable if the antigen is present in known skin contactants and the clinical presentation is 
consistent with that exposure.  This can occur if the allergen is found in the patient’s environment 
and the dermatitis corresponds to the point of contact with allergen but follow-up information on 
improvement with avoidance or rechallenge not available.  Relevance is possible if skin contact 
with materials known to contain the allergen was likely.  Past relevance is considered if the PT is 
positive but the exposure was in the past, and not the present. 
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Further instructions on patch testing and guidance to the patients will be provided in the study 
manual. 
9.2.2. 
Efficacy Procedures 
9.2.2.1. 
Investigator Global Assessment of Hand and Foot 
The IGA for hands and feet is an adaptation of the physician global assessment instrument which 
has been previously used in registrational studies in hand dermatitis (Ruzicka, 2008).  The global 
IGA for generalized AD lesions throughout the body has been previously used in dupilumab 
studies in patients with AD (Simpson, 2016). 
Investigators will be asked to assess the severity of signs of disease on hands and feet on this scale.  
It is important that this assessment be limited to only the hands and feet and not be influenced by 
severity of AD lesions on other parts of the body.  The IGA score will be assessed at time points 
according to Section 9.1 . 
The IGA is provided in Appendix 2 . 
9.2.2.2. 
Modified Total Lesion Sign Score for Hands and Feet 
The Modified Total Lesional Sign Score is adapted for hands and feet; which has been previously 
used in registrational studies in hand dermatitis (Ruzicka, 2008).  A similar instrument, Global 
Individual Sign Score, has been previously used for assessment of severity of generalized AD 
lesions in dupilumab studies in patients with AD (Simpson, 2016). 
It is important that this assessment be limited to only the hands and feet and not be influenced by 
severity of AD lesions on other parts of the body.  The mTLSS for hands and feet will be assessed 
at time points according to Section 9.1 . 
The mTLSS for hands and feet is provided in Appendix 3  
A responder threshold (currently unknown) for mTLSS in the study population will be determined 
using blinded interim data gathered from this study utilizing an anchor-based approach. Both 
dynamic responder definition (eg, change scores) and static severity bands (eg, none, mild, 
moderate, severe) will be explored. Treatment arms will be pooled to perform the analysis in a 
blinded fashion. Analyses using this responder threshold will be conducted to help interpretation 
of the prespecified endpoints for the mTLSS.  The methodology to be used for determining this 
responder threshold will be specified in the psychometric analysis plan and the determined 
responder threshold will be specified in the SAP. 
9.2.2.3. 
Hand and Foot Pruritus Numerical Rating Scale 
The Pruritus NRS is a simple assessment tool that patients will use to report the intensity of their 
hand and foot pruritus (itch) during a 24-hour recall period.  
Patients will be instructed on using the patient diary to record their Pruritus NRS score at the 
screening and baseline visits.  Patients will complete the rating scale DAILY according to the time 
points in Table 1.  Clinical sites will check and remind patient to complete the diary at each visit.  
The pruritus NRS score will be calculated as the average of the last 7 days with a minimum of 
4 daily scores. 
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9.2.2.4. 
Hand and Foot Skin Pain Numerical Rating Scale 
Hand and foot skin pain will be measured using a skin pain NRS.   
Clinical sites will check and remind the patient to complete the scale according to the time points 
in Table 1.  Patients will be instructed on using the scale to record their skin pain score at the 
screening visit.  Patients will complete the rating scale DAILY throughout the screening period, 
for the 7 days prior to the week 2 visit, for the 7 days prior to the week 4 visit, and for the 7 days 
prior to the week 16 visit.  Clinical sites will check patient data collected using an e-diary for 
protocol compliance and remind patients to complete their e-diary throughout the study. 
9.2.2.5. 
Sleep Numerical Rating Scale 
Sleep quality will be measured using a sleep quality NRS.  This is an 11-point scale (0 to 10) in 
which 0 indicates worst possible sleep while 10 indicates best possible sleep.  The patients will be 
asked to select the number that best describes the quality of their sleep during the previous night. 
Clinical sites will check and remind the patients to complete the scale according to the time points 
in Table 1.  Patients will be instructed on using the scale to record their sleep quality score at the 
screening visit.  Patients will complete the rating scale DAILY throughout the screening period, 
for the 7 days prior to the week 2 visit, for the 7 days prior to the week 4 visit, and for the 7 days 
prior to the week 16 visit.  Clinical sites will check patient data collected using an e-diary for 
protocol compliance and remind patients to complete their e-diary throughout the study. 
9.2.2.6. 
Hand and Foot Area Involvement of Atopic Dermatitis 
This assessment will be performed at time points according to Section 9.1 .  The hand and foot 
area assessment tool is provided in the study reference manual. 
9.2.2.7. 
Patient Global Impression of Severity  
The PGIS will be assessed at time points according to Table 1.  This instrument is provided in 
the study reference manual. 
9.2.2.8. 
Patient Global Impression of Change  
The PGIC will be assessed at time points according to Table 1.  This instrument is provided in 
the study reference manual 
9.2.2.9. 
Hand Eczema Severity Index 
The HECSI is similar to scoring systems in AD (EASI) and Psoriasis vulgaris (PASI) in 
incorporating both the extent and the intensity of the disease.  Each hand is divided into 5 areas 
[fingertips, fingers (except the tips), palms, back of hands and wrists].  For each of these areas the 
intensity of the 6 following clinical signs: erythema, induration ⁄papulation, vesicles, fissuring, 
scaling and oedema is graded on the following scale: 0, no skin changes; 1, mild disease; 2, 
moderate, and 3, severe.  For each location (total of both hands) the affected area is given a score 
from 0 to 4 (0, 0%; 1, 1 to 25%; 2, 26 to 50%; 3, 51 to 75%, and 4, 76 to 100%) for the extent of 
clinical symptoms.  Finally, the score given for the extent at each location is multiplied by the total 
sum of the intensity of each clinical feature, and the total sum called the HECSI score is calculated, 
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varying from 0 to a maximum severity score of 360 points.  The HECSI has been previously 
validated in patients with hand dermatitis (Held, 2005).  
The HECSI will only be performed in patients with presence of hand dermatitis at baseline.  This 
assessment will be performed at time points according Section 9.1 .  The HECSI is provided in the 
study reference manual. 
The HECSI will be assessed at time points according to Table 1. 
The HECSI assessment tool is provided in the study reference manual. 
9.2.2.10. Quality of Life in Hand Eczema Questionnaire 
The QoLHEQ will be assessed at time points according to Table 1 
The QoLHEQ is provided in the study reference manual. 
9.2.2.11. Eczema Area and Severity Index 
This assessment is not limited to just evaluation of hands and feet lesions, but will assess severity 
of AD lesions across the body. This assessment will only be performed in patients who have AD 
lesions outside their hands and feet. 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin, 2001).  The EASI is a composite index with scores ranging from 0 to 
72.  Four AD disease characteristics (erythema, thickness [induration, papulation, edema], 
scratching [excoriation], and lichenification) will each be assessed for severity by the investigator 
or designee on a scale of “0” (absent) through “3” (severe).  In addition, the area of AD 
involvement will be assessed as a percentage by body area of head, trunk, upper limbs, and lower 
limbs, and converted to a score of 0 to 6.  In each body region, the area is expressed as 0, 1 (1% to 
9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). 
The EASI will be assessed at time points according to Table 1. 
The EASI assessment tool is provided in the study reference manual. 
9.2.2.12. Investigator’s Global Assessment  
This assessment is not limited to just evaluation of hands and feet lesions, but will assess severity 
of AD lesions across the body. This assessment will only be performed in patients who have AD 
lesions outside their hands and feet. 
The IGA is an assessment instrument used in clinical studies to rate the severity of AD globally, 
based on a 5-point scale ranging from 0 (clear) to 4 (severe). 
The IGA score will be assessed at time points according to Table 1. 
The IGA assessment tool is provided in the study reference manual. 
9.2.2.13. Atopic Dermatitis Area Photographs 
At select study sites, photographs will be taken of a representative area of atopic hand and foot 
dermatitis involvement.  Subsequent photographs of the same area will be taken at time points 
according to Table 1. 
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Instructions for taking the photographs are provided in the photography reference manual. 
9.2.2.14. Patient-Assessed EQ-5D 
This assessment is based on general AD, not only of atopic hand and foot dermatitis. 
The EQ-5D is a standardized measure of health status developed by the EuroQOL Group in order 
to provide a simple, generic measure of health for clinical and economic appraisal.  The EQ-5D 
consists of 2 parts: the descriptive system and the EQ Visual Analogue Scale (EQVAS).  The 
EQ-5D descriptive system comprises the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression.  Each dimension has 3 levels of perceived 
problems: “no problem” (level 1), “some problems” (level 2), “extreme problems” (level 3).  The 
respondent is asked to indicate his/her health state by ticking (or placing a cross) in the box against 
the most appropriate statement (ie, no problems, some problems, or severe problems) in each of 
the 5 dimensions; this results in a 1-digit number expressing the level for that dimension.  The 
digits for 5 dimensions can be combined in a 5-digit number describing the respondent’s health 
state.  
The EQVAS records the respondent’s self-rated health on a vertical, visual analogue scale where 
the endpoints are labeled “best imaginable health state (100)” and “worst imaginable health state 
(0)”.  This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents.  
The questionnaire will be administered only to the subset of patients who fluently speak a language 
in which the questionnaire is presented (based on availability of validated translations in 
participating countries), at time points according to Table 1. 
The EQ-5D is provided in the study reference manual.  
9.2.2.15. Work Productivity and Activity Impairment Questionnaire Plus Classroom 
Impairment Questions  
The WPAI+CIQ is a self-administered instrument used to assess the impact of disease on 
productivity. An adaptation of WPAI, the WPAI+CIQ incorporates classroom impairment 
questions in the original WPAI to assess classroom impairment.  The WPAI+CIQ measures 
work/classroom productivity loss due to general health or a specified health problem in past 7 days. 
The question can be adapted based on the specific condition of study.  For this study, WAPI+CIQ-
AHFD will be used to capture the impairment to work productivity/classroom impairment and 
activity due to atopic hand and foot dermatitis. The WPAI+CIQ yields 4 types of scores: 
absenteeism (work/classroom time missed), presenteeism (impairment at work/classroom or 
reduced on-the-job/classroom effectiveness), work/classroom productivity loss (overall 
work/classroom impairment divided by absenteeism plus presenteeism), and activity impairment. 
All scores range from 0 to 100% with 100% indicating total work/classroom productivity 
impairment and 0 no impairment at all.  
The WPAI+CIQ will be administered to every patient.  Depending on whether the patients are 
currently employed or attending classes, the patients will answer the applicable questions in WAPI 
components or CIQ components or both. 
The WPAI+CIQ will be administered at time points according to Table 1  
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9.2.3. 
Safety Procedures 
9.2.3.1. 
Vital Signs 
Vital signs (including pulse rate, sitting blood pressure, body temperature, and respiratory rate) 
will be collected pre-dose at time points according to Table 1. 
At the first 3 administrations of study drug, sitting blood pressure, respiratory rate and pulse rate 
will also be assessed at 30 minutes (+/- 10 minutes) post-injection.  
9.2.3.2. 
Body Weight and height 
Body weight and height will be measured at time points according to Table 1. 
9.2.3.3. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to  
Table 1.  Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the patient’s medical history. 
9.2.3.4. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory.  Detailed instructions for blood sample collection are in the laboratory manual provided 
to study sites. 
Samples for laboratory testing will be collected at visits according to Table 1.  Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin1 
 
Potassium 
Creatinine 
Total cholesterol2 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK)3 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
1 Direct and indirect bilirubin will be measured when the total bilirubin is above the ULN  
2 Low-density lipoprotein and high-density lipoprotein  
3 CPK isoenzymes will be measured when CPK >5× the ULN  
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Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
Serum and urine pregnancy testing will be performed for all female patients of childbearing 
potential at time points according to Table 1 . 
The following tests will be performed at screening: HIV, HBsAg, HBsAb, HBcAb, HBV DNA 
(only in patients who are HBsAg negative, HBsAb negative, and HBcAb positive), hepatitis C 
antibody, HCV RNA (only in patients who are HCV Ab positive), and tuberculosis (will be 
performed on a country-by-country basis according to local guidelines if required by regulatory 
authorities or ethics boards). 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment 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/Study Director 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 10.1.1. 
9.2.4. 
Drug Concentration and Measurements 
Serum samples for measuring functional dupilumab concentrations will be collected at time points 
according to Table 1. 
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9.2.5. 
Immunogenicity Measurements and Samples 
Serum samples for ADA and NAb assessment will be collected at time points according to  
Table 1. 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
Not applicable. 
9.2.7. 
Future Biomedical Research (Optional)  
Patients who agree to participate in the future biomedical research sub-study will be required to 
consent to this optional sub-study before samples are banked in long-term storage.  The unused 
PK and ADA samples will be stored for up to 15 years after the final date of the database lock.  
The unused samples may be utilized for future biomedical research of AD and related diseases, 
dupilumab and related pathways.  After 15 years, any residual samples will be destroyed.  The 
results of these future biomedical research analyses will not be presented in the CSR. 
9.2.7.1. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples.  Whole blood samples for DNA extraction 
should be collected on day 1/baseline (predose) but can be collected at a later study visit.  
DNA samples will be collected for pharmacogenomics analyses to understand the genetic 
determinants of efficacy and safety associated with the treatments in this study and the molecular 
basis of AD and related diseases.  These samples will be single-coded as defined by the 
International Council on Harmonisation (ICH) guideline E15.  Samples will be stored for up to 
15 years after the final date of the database lock.  If there are specific site or country requirements 
involving the pharmacogenomic analyses which the sponsor is unable to comply with, samples 
will not be collected at those sites.   
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker responses to dupilumab, other AD clinical outcome measures and possible AEs.  In 
addition, associations between genomic variants and prognosis or progression of AD as well as 
related diseases may also be studied.  These data may be used or combined with data collected 
from other studies to identify and validate genomic markers related to the study drug, target 
pathway, or AD and related diseases. 
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions.  Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, may also be performed.  The 
list of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period.  Results from the genomic analyses will not be 
reported in the CSR. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data collection 
period from the time of signing the ICF to the end of study.  Medical conditions that existed or 
were diagnosed prior to the signing of the Informed Consent will be recorded as part of medical 
history.  Abnormal laboratory values and vital signs observed at the time of Informed Consent 
should also be recorded as medical history.  Any subsequent worsening (ie, any clinically 
significant change in frequency and/or intensity) of a pre-existing condition that is temporally 
associated with the use of the study drug should also be recorded as an AE.  
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient.  Adverse events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit.  Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms.  The investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2.  
The investigator’s assessment must be clearly documented in the site’s source documentation with 
the investigator’s signature.  The investigator should follow up on SAEs (and AESIs) until they 
have resolved or are considered clinically stable; AEs should be followed until they are resolved 
or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE.   
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported 
as AEs if they are symptomatic, lead to study drug discontinuation, dose reduction, require 
corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization).  A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to 
signing the Informed Consent Form) procedures, treatments requiring hospitalization for pre-
existing conditions that do not worsen in severity, and admission for palliative or social care should 
not be reported as SAEs (see Section 10.2 for Definitions). 
For deaths, the underlying or immediate cause of death should always be reported as an SAE. 
Any SAE that may occur subsequent to the reporting period (end of the study) that the investigator 
assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3 . 
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10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the blinded study drug.  For SAEs and AESIs, a detailed 
narrative summarizing the course of the event, including its evaluation, treatment, and outcome 
should be provided on the AE CRF.  Specific or estimated dates of event onset, treatment, and 
resolution should be included, when available.  Medical history, concomitant medications, and 
laboratory data that are relevant to the event should also be summarized in the narrative.  For fatal 
events, the narrative should state whether an autopsy was or will be performed and include the 
results, if available.  Information not available at the time of the initial report must be documented 
in a follow-up report.  Source documents (including hospital or medical records, diagnostic reports, 
etc.) will be summarized in the narrative on the AE CRF and retained at the study center and 
available upon request. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up. 
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of 
learning of the event: 
• SAEs 
• Adverse Events of Special Interest (serious and nonserious):  Adverse events of 
special interest for this study include the following:   
• Anaphylactic reaction 
• Systemic hypersensitivity reactions 
• Helminthic infections 
• Any severe type of conjunctivitis or blepharitis  
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms)  
• 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  during the study or within 12 weeks 
of the last dose of study drug.  Any complication of pregnancy affecting a female study 
patient and/or fetus and/or newborn that meets the SAE criteria must be reported as an 
SAE.  Outcome for all pregnancies should be reported to the sponsor. 
Refer to the study reference manual for the procedures to be followed. 
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10.2. 
Definitions 
10.2.1. 
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 (ICH 
E2A Guideline.  Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
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 a hospital admission (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 one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical interest specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate.  Such an event might warrant further investigation in order to 
characterize and understand it.   
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10.2.4. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient 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 subject’s health.  Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade: 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires ER 
visit or hospitalization; necrosis or exfoliative dermatitis 
10.2.5. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions.  The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs. time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
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• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration 
and is a known reaction to the drug under study or its class of drugs or is 
predicted by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified 
procedure or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient 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/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Pharmacovigilance; Risk Management; Biostatistics and Data Management).  
Safety monitoring will be performed on an ongoing basis and on a periodic cumulative aggregate 
basis. 
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10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, IECs/IRBs, and the 
participating investigators of any SUSARs (Suspected Unexpected Serious Adverse Reactions) 
occurring in other study centers or other studies of the active study drug (dupilumab), as 
appropriate per local reporting requirements.  In addition, the sponsor and/or CRO will comply 
with any additional local safety reporting requirements.  All notifications to investigators will 
contain only blinded information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the Institutional Review Board (IRB)/Ethics Committee (EC) unless 
delegated to the sponsor. 
Event expectedness for study drug (dupilumab) is assessed against the Reference Safety 
Information section of the Investigator’s Brochure that is effective for expedited safety reporting. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the Clinical Study Report to health authorities and IECs/IRB as appropriate. 
11. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study.  The SAP will be revised prior to the end 
of the study to accommodate amendments to the clinical study protocol and to make changes to 
adapt to unexpected issues in study execution and data that may affect the planned analyses.  The 
final SAP will be issued before the first database lock. 
Endpoints are listed in Section 4 Analysis variables are listed in Section 5. Handling of missing 
data due to the COVID-19 pandemic and any additional analyses required to investigate the impact 
of COVID-19 to understand estimated treatment effect and safety will be detailed in the SAP. 
11.1. 
Statistical Hypothesis  
For comparison of dupilumab treatment to placebo, the following hypothesis of the primary 
endpoint will be tested:  
• Null hypothesis: the success rate (where success is proportion of patients achieving an 
IGA score of 0 or 1 on hand and foot at week 16) is equal between dupilumab and 
placebo  
• Alternative hypothesis: the success rate differs at week 16 between dupilumab and 
placebo. 
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11.2. 
Justification of Sample Size 
The planned sample size is approximately 130 patients (65 patients in each treatment arm).  This 
sample size will yield >85% power to detect a treatment difference of 24% in the proportion of 
patients achieving IGA hand and foot (0, 1) at week 16 between placebo (10%) and dupilumab 
(34%) at a 2-sided significant level of 5% using Chi-square test and assuming a dropout rate of 
10%. The assumed treatment difference of 24% is based on the effect of 26% observed in 
dupilumab phase 3 monotherapy studies in adult patients with AD and adjusted to account for the 
potential inclusion of some patients with ACD who would be missed with certain patch testing (ie, 
TRUE test) at screening.  
It is reasonable to assume that the effect size of dupilumab on AD of hands and feet would be 
similar to that seen in global AD lesions in previously conducted phase 3 trials as the underlying 
pathophysiology is same.  Moreover, a recent observational study to compare effect of dupilumab 
on hand lesions vs. lesions on other parts of the body found a high degree of concordance in terms 
of onset of effect and overall effect at week 16 (Oosterhaven, 2018). 
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients.  Efficacy analyses will be based on 
the treatment allocated at randomization (as randomized).  
The per protocol set (PPS) includes all patients in the FAS except for those who are excluded 
because of specified important protocol deviations.  A preliminary list of such important protocol 
deviations is provided below and the final list will be specified in the SAP prior to database lock.   
• Entered study even though entry criteria not satisfied 
• Received an excluded concomitant treatment 
• Received wrong treatment or incorrect dose 
• Other treatment compliance  
All efficacy variables will be evaluated on the FAS; the primary endpoint will also be evaluated 
on the PPS.  Analysis on the FAS will be considered to be primary. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
11.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result following the first dose of study drug. 
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11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received any study drug and had at least 1 non-
missing ADA result following the first study dose.  
The NAb analysis set includes all patients who received any study drug and who are negative in 
the ADA assay or with at least 1 non-missing result in the NAb assay (patients who are ADA 
negative are set to negative in the NAb analysis set). 
11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients 
• The total number of randomized patients:  received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
11.4.3. 
Efficacy Analyses 
For all efficacy variables, the analysis will be comparisons of the dupilumab treatment group with 
the placebo group. 
11.4.3.1. Primary Efficacy Analysis 
The primary endpoint of proportion of patients achieving an IGA score of 0 or 1 on hand and foot 
at week 16 will be analyzed using the Cochran-Mantel-Haenszel (CMH) test to assess the 
difference in the proportion of responders in the FAS adjusting for the randomization stratification 
factors (age [adults vs. adolescents], disease severity of IGA hand and foot [3 vs. 4], and 
geographic region [United States versus Japan versus other countries]).  
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The primary estimand of interest, the intercurrent event(s) strategy, and missing data handling 
methods for the primary endpoint (binary response) are described in Table 2.  
Table 2: 
Summary of Primary Estimand for Primary Endpoint 
Endpoint 
Intercurrent Event(s) 
Strategy 
Missing Data 
Handling Method  
Primary efficacy 
endpoint (proportion of 
patients achieving an 
IGA score of 0 or 1 on 
hand and foot at 
week 16) 
Rescue treatment 
Composite strategy: 
Patients will be 
considered as 
non-responders after 
such events. 
Patient will be 
considered as 
non-responder if 
patient’s IGA on hand 
and foot is missing at 
week 16 due to patient 
discontinuation from 
study or other reasons. 
Treatment 
discontinuation 
Treatment policy 
strategy: Data collected 
after the patient 
discontinued treatment 
will be included in the 
analysis. 
To account for use of rescue treatment, patients will be considered as non-responders for all time 
points subsequent to the use of rescue treatment in the primary analysis.  If a patient has missing 
value with any reason for IGA on hand and foot assessment at week 16, the patient will be 
classified as a non-responder at week 16.  
Sensitivity analysis using the last observation carried forward (LOCF) approach or the worst 
observation carried forward (WOCF) approach to determine patient’s status at week 16 will be 
conducted to assess the robustness of the primary efficacy analysis with regards to handling of 
missing data.  The efficacy data will be set to missing after rescue treatment is used, then the LOCF 
or WOCF method will be used to determine patients’ status at week 16.  
In addition, the CMH method adjusted by randomization strata will also be performed on all 
observed data regardless if rescue treatment is used.  A patient with missing data will be counted 
as a non-responder.  Other sensitivity analyses may be conducted. 
Subgroup analysis (eg, by age group, by anatomical area of involvement [hand involvement only 
vs. involvement of hand and foot or foot involvement only]) will also be performed. 
11.4.3.2. Secondary Efficacy Analysis 
The primary estimand of interest, the intercurrent event(s) strategy, and missing data handling 
methods for the key secondary endpoint (binary response) are described in Table 3. 
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Table 3: 
Summary of Primary Estimand for Key Secondary Endpoint 
Endpoint 
Intercurrent Event(s) 
Strategy 
Missing Data 
Handling Method  
Key secondary efficacy 
endpoint (proportion of 
patients with 
improvement 
(reduction) of weekly 
average of daily hand 
and foot peak 
Pruritus NRS ≥4 from 
baseline to week 16) 
Rescue treatment 
Composite strategy: 
Patients will be 
considered as 
non-responders after 
such events. 
Patient will be 
considered as 
non-responder if 
patient’s weekly 
average of daily hand 
and foot peak 
Pruritus NRS is missing 
at week 16 due to 
patient discontinuation 
from study or other 
reasons. 
Treatment 
discontinuation 
Treatment policy 
strategy: Data collected 
after the patient 
discontinued treatment 
will be included in the 
analysis. 
Secondary efficacy endpoints that measure binary responses (eg, improvement of weekly average 
of daily peak Pruritus NRS ≥4 from baseline to week 16) will be analyzed in the same fashion as 
the primary analysis. 
Continuous secondary efficacy endpoints (eg, percent change mTLSS for hand/foot lesions from 
baseline to week 16) will be analyzed using an analysis of covariance (ANCOVA) model for the 
FAS with treatment group, randomization stratification factors (age [adults vs. adolescents], 
disease severity of IGA hand and foot [3 vs. 4], and geographic region [United States versus Japan 
versus other countries]), and relevant baseline measurement included in the model.  To account 
for the impact of rescue treatment on the efficacy effect, patients' efficacy data through week 16 
after the rescue treatment use will be set to missing.  The missing data for continuous endpoints 
will be imputed by the pattern-mixture approach where the WOCF approach will be used for the 
missing due to rescue treatment, AE, and lack of efficacy and the multiple imputation (MI) 
approach will be used for the missing due to other reasons.  The MI Statistical Analysis Software 
(SAS) procedure with Markov Monte Carlo algorithm will be applied for multiple times.  The 
complete datasets created based on the pattern-mixture approach will be analyzed using the 
ANCOVA model defined previously, and the SAS MIANALYZE procedure will be used to 
generate valid statistical inferences by combining results from these multiple analyses using 
Rubin’s formula. 
For the endpoint of percent change in mTLSS for hand/foot lesions from baseline to week 16, the 
empirical cumulative distribution function (CDF) curves showing response in dupilumab and 
placebo groups for different responder thresholds will be provided. 
All efficacy data will be used for analysis regardless of whether the patient is on study treatment 
or discontinues the study treatment but remains in the study.  In addition, the MI with the 
ANCOVA model and the ANCOVA model based on LOCF or WOCF imputation method will be 
performed as the sensitivity analyses.  Other sensitivity analysis such as the MI approach with 
ANCOVA model on all observed data regardless of rescue use will be conducted.  Additional 
details on sensitivity analyses will be provided in the SAP. 
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11.4.4. 
Control of Multiplicity 
Type I error rate will be controlled using a hierarchical testing procedure for the primary and 
secondary efficacy endpoints at the 2-sided 0.05 level.  The hierarchy order will be specified in 
the SAP prior to database lock. 
11.4.5. 
Safety Analysis 
Safety analysis will be based on the SAF.  This includes reported TEAEs, AESIs, and other safety 
information (eg, clinical laboratory evaluations, vital signs).  A summary of safety results for each 
treatment group will be presented. 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The treatment-emergent period is defined as the day from first dose of study drug to 
end of study.  The treatment-emergent period includes the 16-week treatment period 
and 12-week follow-up period.  
− Treatment period: date of the first dose of study drug to week 16 visit date (study 
day 113 starting from the first dose of study drug if week 16 visit date is 
unavailable) or early termination date, whichever comes first.  
− Follow-up period: date after week 16 visit date (study day 113 starting from first 
dose of study drug if week 16 visit date is unavailable) to end of study. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing 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 
preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group for overall during the treatment-emergent period, 
during the 16-week treatment period, and during the follow-up period will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.4 ), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
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Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
11.4.5.2. 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. 
The number and percentage of patients with a treatment-emergent potentially clinically significant 
value (PCSV) will be summarized for each vital sign variable.  The criteria for treatment-emergent 
PCSV will be defined in the SAP. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a treatment-emergent PCSV will be summarized for each 
clinical laboratory test.  The criteria for treatment-emergent PCSV will be defined in the SAP.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
11.4.5.3. Treatment Exposure 
The duration of exposure during the study will be presented by treatment group and calculated as:  
(Date of last study drug injection – date of first study drug injection) + 14 days 
The number (%) of patients randomized and exposed to double-blind study drug will be presented 
by specific time periods for each treatment group.  The time periods of interest will be specified 
in the SAP.  In addition, duration of exposure during the study will be summarized for each 
treatment group using number of patients, means, standard deviation, minimums, Q1, medians, 
Q3, and maximums.  A summary of the number of doses by treatment group will be provided as 
well. 
11.4.5.4. Treatment Compliance 
The compliance with study treatment will be calculated as follows: 
Treatment Compliance = (Number of study drug injections during exposure 
period)/(Number of planned study drug injections during exposure period) × 100% 
The treatment compliance will be presented by specific ranges for each treatment group.  The 
ranges of interest will be specified in the SAP. 
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11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The concentrations of functional dupilumab over time will be summarized by descriptive statistics.  
No formal statistical hypothesis testing will be performed. 
11.4.7. 
Analysis of Immunogenicity Data  
Immunogenicity will be characterized by the ADA and NAb response observed:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 4-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative or missing 
• Treatment boosted ADA response, defined as any post-dose positive ADA assay 
response that is 4-fold over baseline titer levels when baseline is positive in the ADA 
assay  
• Maximum ADA titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
• NAb status for samples that are positive in the ADA assay  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
and NAb positivity presented by patient, time point, and dose group will be provided.  Incidence 
of treatment-emergent ADA and NAb will be assessed as absolute occurrence (N) and percent of 
patients (%), grouped by dose group and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated.  Assessment of impact of ADA and NAbs on safety and efficacy may be 
provided. 
11.5. 
Timing and Operational Considerations of Statistical Analyses 
No interim analysis is planned for this study.  The unblinded primary analysis may be performed 
once all patients in the study have completed the 16-week treatment period.  This primary analysis 
will be considered the final analysis for the primary and secondary efficacy endpoints.  Hence 
there will be no need for alpha adjustment due to the primary analysis.  
If a decision is made to perform the primary analysis, in order to maintain study integrity with 
respect to the post-treatment follow-up visits, safety visits and analyses, a dissemination plan will 
be written.  This plan will clearly identify the team (including the statistician) that will perform 
the primary analysis and all related activities, restrict other clinical team members and other 
Sponsor personnel from access to individual patient treatment allocation and site level analysis 
results, and ensure that the dedicated team will not participate in the data review or data decisions 
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for the following post treatment analyses.  However, the dedicated team can participate in the 
analysis following the final database lock. 
11.6. 
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. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted, and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s).  The planned quality assurance and quality 
control procedures for the study are described in this section. 
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical) will be done using 
internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC). 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
• Digital archive system for photographs 
• eCOA instruments/eDiaries/tablet devices for some of the efficacy assessment data 
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12.2. 
Study Monitoring 
12.2.1. 
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.  This study will 
use the principles of risk-based monitoring (ICH).  This means that the number of visits for any 
given site may vary based on site risk indicators.  The investigator must allow study-related 
monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents).  The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and CRF data are timely, accurate and complete. 
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. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel.  All required CRFs must be 
completed for each and every patient enrolled in the study.  The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the sponsor in the CRFs.  After 
review of the clinical data for each patient, the investigator must provide an electronic signature.  
A copy of each patient CRF casebook 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 EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
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 
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• 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. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
12.4.2. 
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 obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period 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 (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination. 
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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 
Adult Patients 
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 drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed 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, or if there 
are significant changes to the study procedures, 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. 
Pediatric Patients 
The principles of informed consent are described in ICH guidelines for Good Clinical Practice. 
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 drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient and his/her parent(s) or legal guardian(s) prior to the 
patient’s participation in the study and after the aims, methods, objectives, and potential hazards 
of the study have been explained to the fullest possible extent in language that the patient and the 
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parent(s) or legal guardian(s) can understand.  The ICF should be signed and dated by the patient’s 
parent(s) or legal guardian(s) and the same investigator or designee who explained the ICF. 
Local law must be observed in deciding whether 1 or both parents/guardians consent is required.  
If only 1 parent or guardian signs the consent form, the investigator must document the reason the 
other parent or guardian did not sign.  The patient may also be required to sign and date the ICF, 
as determined by the IRB/EC and in accordance with the local regulations and requirements. 
• Patients who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
• 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’s parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately.  All study patients and their parent(s) or legal guardian(s) must be informed of the 
new information and provide their written consent if they wish the patient 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’s parent(s) or legal guardian(s). 
13.3. 
Patients 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 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. 
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 patient, 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. 
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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. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigation site 
thereafter. 
14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment.  Where required per local legislation, regulatory authority approval will also 
be sought. 
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), 
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breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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Scalone L, Cortesi PA, Mantovani LG, Belisari A, Ayala F, Fortina AB, et al. Clinical 
epidemiology of hand eczema in patients accessing dermatological reference centres: results 
from Italy. Br J Dermatol 2015; 172(1):187-95. 
Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two Phase 3 
Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med 2016; 375(24):2335-48. 
Simpson EL, Thompson MM, Hanifin JM. Prevalence and morphology of hand eczema in 
patients with atopic dermatitis. Dermatitis 2006; 17(3):123-7. 
Stout M, Silverberg JI. Variable impact of dupilumab on patch testing results and allergic contact 
dermatitis in adults with atopic dermatitis. J Am Acad Dermatol 2019; 81(1):157-62. 
Suresh R, Murase JE. The role of expanded series patch testing in identifying causality of 
residual facial dermatitis following initiation of dupilumab therapy. JAAD Case Rep 2018; 
4(9):899-904. 
Thaci D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al. Efficacy and safety of 
dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical 
treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet 2016; 
387(10013):40-52. 
Zirwas MJ. Dupilumab for hand eczema. J Am Acad Dermatol 2018; 79(1):167-9. 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF DUPILUMAB IN ADULT AND ADOLESCENT PATIENTS WITH 
MODERATE-TO-SEVERE ATOPIC HAND AND FOOT DERMATITIS and agree to abide by 
all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
 
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APPENDIX 1. HANIFIN AND RAJKA DIAGNOSTIC CRITERIA FOR 
ATOPIC DERMATITIS – MAJOR AND MINOR 
CRITERIA 
Hanifin and Rajka criteria (Hanifin, 1980) 
 
Major criteria: 
• pruritus 
• dermatitis affecting flexural surfaces in adults and the face and extensors in infants 
• chronic or relapsing dermatitis 
• personal or family history of cutaneous or respiratory atopy. 
 
Minor criteria: 
• features of the so-called “atopic facies”: facial pallor or erythema, hypopigmented patches, 
infraorbital darkening, infraorbital folds or wrinkles, cheilitis, recurrent conjunctivitis, and 
anterior neck folds 
• triggers of atopic dermatitis: foods, emotional factors, environmental factors, and skin irritants 
such as wool, solvents, and sweat 
• complications of atopic dermatitis: susceptibility to cutaneous viral and bacterial infections, 
impaired cell-mediated immunity, immediate skin-test reactivity, raised serum IgE, 
keratoconus, anterior subcapsular cataracts 
• others: early age of onset, dry skin, ichthyosis, hyperlinear palms, keratosis pilaris (plugged 
hair follicles of proximal extremities), hand and foot dermatitis, nipple eczema, white 
dermatographism, and perifollicular accentuation 
 
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APPENDIX 2. INVESTIGATOR GLOBAL ASSESSMENT FOR HAND 
AND FOOT ATOPIC DERMATITIS 
The assessment of the IGA should be based on overall impression of disease severity in hands and 
feet as per clinical judgment of investigator at time of assessment. 
It is not necessary that all signs be present for a patient to be assigned to an IGA category. 
Score  
Category IGA Morphological Descriptors 
0 
Clear 
Absence of inflammatory signs of hand and foot atopic dermatitis 
(erythema, scaling, lichenification, vesicles, fissures, edema).  
1 
Almost 
clear 
Barely perceptible erythema, barely perceptible scaling, barely 
perceptible lichenification and/or barely perceptible edema. No 
vesicles/erosions or fissures. 
2 
Mild  
Slight but definite erythema (pink), slight but definite scaling (fine 
scales), slight but definite lichenification (slight thickening of the skin 
with skin markings minimally exaggerated), slight but definite edema 
(elevation of skin surface discernible only by palpation), slight but 
definite vesicles/erosions (scattered, small vesicles or erosions) and/or 
slight but definite fissures (only superficial fissures are present). 
3 
Moderate Clearly perceptible erythema (dull red), clearly perceptible scaling 
(moderately coarse scales), clearly perceptible lichenification (definite 
thickening of the skin with skin markings clearly exaggerated), clearly 
perceptible edema (visible elevation of skin surface), clearly perceptible 
vesicles/erosions (larger vesicles or erosions) and/or clearly perceptible 
fissures (predominantly superficial fissures but deep fissures may be 
present)  
4 
Severe 
Prominent erythema (deep dark red), prominent scaling (thick, large 
scales), prominent lichenification (thickened indurated skin with skin 
markings visibly portraying an exaggerated criss-cross pattern or with 
deep furrows), prominent edema (skin surface grossly swollen/elevated), 
prominent vesicles/erosions (bullae, or densely, clustered vesicles or 
erosions, often with oozing and crusting) and/or prominent fissures 
(predominantly deep fissures are present)  
Notes: 
1. In case of indeterminate cases:  
a. Use extent to guide rating of IGA severity for, example, a patient with prominent 
erythema and clearly perceptible scaling, with limited extent of disease which would 
be classified as moderate IGA. 
b. Use severity rating for vesicles and fissures (signs with greater impact on 
patient’s QoL) to step up rating of IGA severity. For example, a patient with clearly 
perceptible vesicles and slight but definite erythema should be assigned moderate 
IGA score. 
2. Non-inflammatory signs of atopic dermatitis such as post-inflammatory hyper- or 
hypo-pigmentation, skin dryness etc. should not be used in assessment of IGA. 
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APPENDIX 3. mTLSS: MODIFIED TOTAL LESION SIGN SCORE FOR 
HAND AND FOOT ATOPIC DERMATITIS 
Instructions:  
Assign a score to each of the 6 features (erythema, scaling/flaking, lichenification, 
vesiculation/erosion, edema, fissures) on a scale of 0 to 3 (0=absent, 1=mild, 2=moderate, 
3=severe) based on the morphological descriptions of severity provided in the tables below.  
A separate score should be assigned for hands and feet. 
mTLSS Table for Hand: 
Feature 
Description of Severity 
Erythema 
0 = Absent 
1 = Barely perceptible (pink) redness (mild) 
2 = Clearly perceptible (dull red) OR prominent (deep/dark red) 
redness in limited areas (moderate) 
3 = Prominent (deep/dark red) redness over widespread areas 
(severe) 
Scaling/Flakinga 
a Hyperkeratosis is not 
explicitly included as a 
separate sign, but 
hyperkeratosis as seen in 
hyperkeratotic eczema 
should be captured by 
scaling, fissures, and skin 
thickening 
0 = Absent 
1 = Barely perceptible (fine) scales/flakes (mild) 
2 = Clearly perceptible (medium sized scales/flakes that are 
identifiable as individual scales/flakes on close inspection) 
scales/flakes OR prominent (thick, large scales/flakes that are easily 
identifiable as individual scales/flakes) scales/flakes over a limited 
area (moderate)  
3 = Prominent (thick, large scales/flakes that are easily identifiable 
as individual scales/flakes) scales/flakes over widespread areas 
(severe) 
Lichenificationb 
b Palmar hyperlinearity as 
seen in ichthyosis vulgaris 
is not to be taken into 
account while assessing 
exaggerated skin markings 
0 = Absent 
1 = Barely perceptible (slight thickening of the skin with skin 
markings minimally exaggerated) thickening/exaggerated skin 
markings 
2 = Clearly perceptible (definite thickening of the skin with skin 
markings clearly exaggerated) thickening/exaggerated skin markings 
OR prominent (thickened indurated skin with skin markings visibly 
portraying an exaggerated criss-cross pattern) 
thickening/exaggerated skin markings over a limited area (moderate) 
3 = Prominent (thickened indurated skin with skin markings visibly 
portraying an exaggerated criss-cross pattern) 
thickening/exaggerated skin markings over widespread areas 
(severe) 
Vesiculation/Erosion 
0 = Absent 
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1 = Vesicles or erosions affecting up to 10% of the hands (mild) 
2 = Vesicles or erosions affecting between 10%-30% of the hands 
(moderate) 
3 = Vesicles or erosions affecting more than 30% of the hands 
(severe) 
Edema 
0 = Absent 
1 = Barely perceptible (slight elevation of skin surface discernible 
only by palpation) dermal swelling (mild) 
2 = Clearly perceptible (visible elevation of skin surface) dermal 
swelling OR prominent (skin surface grossly swollen/elevated) 
dermal swelling over a limited area (moderate) 
3 = Prominent (skin surface grossly swollen/elevated) dermal 
swelling over widespread areas (severe) 
Fissures 
0 = Absent 
1 = Barely perceptible (superficial) fissuring (mild) 
2 = Clearly perceptible (a single deep) fissuring OR prominent 
(multiple deep) fissuring over limited areas (moderate) 
3 = Prominent (multiple deep) fissuring over widespread areas 
(severe) 
 
Total hand mTLSS (0-18) _______ 
 
mTLSS Table for Foot: 
Feature 
Description of Severity 
Erythema 
0 = Absent 
1 = Barely perceptible (pink) redness (mild) 
2 = Clearly perceptible (dull red) OR prominent (deep/dark red) 
redness in limited areas (moderate) 
3 = Prominent (deep/dark red) redness over widespread areas 
(severe) 
Scaling/Flakinga 
a Hyperkeratosis is not 
explicitly included as a 
separate sign, but 
hyperkeratosis as seen in 
hyperkeratotic eczema 
should be captured by 
0 = Absent 
1 = Barely perceptible (fine) scales/flakes (mild) 
2 = Clearly perceptible (medium-sized scales/flakes that are 
identifiable as individual scales/flakes on close inspection) 
scales/flakes OR prominent (thick, large scales/flakes that are easily 
identifiable as individual scales/flakes) scales/flakes over a limited 
area (moderate)  
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scaling, fissures, and skin 
thickening 
3 = Prominent (thick, large scales/flakes that are easily identifiable 
as individual scales/flakes) scales/flakes over widespread areas 
(severe) 
Lichenificationb 
b Plantar hyperlinearity as 
seen in ichthyosis vulgaris 
is not to be taken into 
account while assessing 
exaggerated skin markings 
0 = Absent 
1 = Barely perceptible (slight thickening of the skin with skin 
markings minimally exaggerated) thickening/exaggerated skin 
markings 
2 = Clearly perceptible (definite thickening of the skin with skin 
markings clearly exaggerated) thickening/exaggerated skin markings 
OR prominent (thickened indurated skin with skin markings visibly 
portraying an exaggerated criss-cross pattern) 
thickening/exaggerated skin markings over a limited area (moderate) 
3 = Prominent (thickened indurated skin with skin markings visibly 
portraying an exaggerated criss-cross pattern) 
thickening/exaggerated skin markings over widespread areas 
(severe) 
Vesiculation/ Erosion 
0 = Absent 
1 = Vesicles or erosions affecting up to 10% of the feet (mild) 
2 = Vesicles or erosions affecting between 10%-30% of the feet 
(moderate) 
3 = Vesicles or erosions affecting more than 30% of the feet (severe) 
Edema 
0 = Absent 
1 = Barely perceptible (slight elevation of skin surface discernible 
only by palpation) dermal swelling (mild) 
2 = Clearly perceptible (visible elevation of skin surface) dermal 
swelling OR prominent (skin surface grossly swollen/elevated) 
dermal swelling over a limited area (moderate) 
3 = Prominent (skin surface grossly swollen/elevated) dermal 
swelling over widespread areas (severe) 
Fissures 
0 = Absent 
1 = Barely perceptible (superficial) fissuring (mild) 
2 = Clearly perceptible (a single deep) fissuring OR prominent 
(multiple deep) fissuring over limited areas (moderate) 
3 = Prominent (multiple deep) fissuring over widespread areas 
(severe) 
 
Total foot mTLSS (0-18) _______ 
A total mTLSS score will be calculated as the sum of hand score and foot score: 
Total hand and foot mTLSS (0-36) _______ 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
 A 
MULTICENTER, 
RANDOMIZED, 
DOUBLE-BLIND, 
PLACEBO-
CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF DUPILUMAB IN ADULT AND ADOLESCENT PATIENTS WITH 
MODERATE-TO-SEVERE ATOPIC HAND AND FOOT DERMATITIS 
 
Protocol Number: 
R668-AD-1924 
Protocol Version: 
R668-AD-1924 Amendment 2 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
                                        VV-RIM-00138022-1.0 Approved - 13 Jan 2021 GMT-5:00

Signature Page for VV-RIM-00138022 v1.0
Signature Page for VV-RIM-00138022 v1.0 Approved
ESig Approval
13-Jan-2021 14:38:51 GMT+0000
ESig Approval
13-Jan-2021 14:50:10 GMT+0000
ESig Approval
13-Jan-2021 19:55:20 GMT+0000
ESig Approval
14-Jan-2021 00:14:26 GMT+0000
                                        VV-RIM-00138022-1.0 Approved - 13 Jan 2021 GMT-5:00