Clinical trial NCT04417894
Conditions: Moderate to Severe Atopic Hand and Foot Dermatitis
Sponsor: Regeneron Pharmaceuticals
Start date: 2021-04-14; Completion date: 2022-11-23
Enrollment: 133 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 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

Detailed description:

Arms: arm 1: Administered subcutaneously (SC) once every 2 weeks (Q2W), following a loading dose on Day 1 arm 2: Administered SC Q2W, following a loading dose on Day 1
Interventions: intervention 1: dupilumab intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for subcutaneous (SC) injection administration intervention 2: Solution for SC injection administration

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
R668-AD-1924 Amendment 2 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 108 
CONFIDENTIAL
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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CONFIDENTIAL 
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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association between atopic dermatitis and hand eczema: a systematic review and meta-analysis. 
Br J Dermatol 2018; 178(4):879-88. 
Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth-Jones J, Coenraads PJ, et al. Efficacy and 
safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema 
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refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, 
multicentre trial. Br J Dermatol 2008; 158(4):808-17. 
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
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 74 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: 1.0 
Clinical Study Protocol 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 
Compound: 
Dupilumab (REGN668) 
Protocol Number: 
R668-AD-1924.02 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
Original Statistical Analysis Plan / June 14, 2022 
 
 
 
 
 
 
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NCT04417894


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 2 of 74 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
   
 
 
 
See appended electronic signature page 
 
 
 
See appended electronic signature page 
 
 
 
See appended electronic signature page 
 
 
 
 
See appended electronic signature page 
  
 
 
 
See appended electronic signature page 
 
 
 
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Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 3 of 74 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background and Rationale ............................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Exploratory Objectives ...............................................................................................10 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.5. 
Revision History for SAP Amendments .....................................................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design and Randomization ..............................................................................11 
2.2. 
Statistical Hypothesis ..................................................................................................13 
2.3. 
Sample Size and Power Considerations .....................................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................14 
3.1. 
Efficacy Analysis Sets (FAS) .....................................................................................14 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................14 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................14 
3.4. 
The Immunogenicity Analysis Set..............................................................................15 
3.5. 
Subgroups ...................................................................................................................15 
4. 
ANALYSIS ENDPOINTS .........................................................................................17 
4.1. 
Demographic and Baseline Characteristics ................................................................17 
4.2. 
Medical History and Atopic Disease Medical History ...............................................17 
4.3. 
Prior / Concomitant Medications and Procedures ......................................................17 
4.4. 
Efficacy Variables ......................................................................................................19 
4.4.1. 
Primary Efficacy Variable ..........................................................................................19 
4.4.2. 
Secondary Efficacy Variables .....................................................................................20 
4.4.3. 
Exploratory Efficacy Variable(s) ................................................................................23 
4.5. 
Safety Variables ..........................................................................................................24 
4.5.1. 
Adverse Events and Serious Adverse Events Variables .............................................24 
4.5.2. 
Laboratory Safety Variables .......................................................................................25 
4.5.3. 
Vital Sign Variables ....................................................................................................27 
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Statistical Analysis Plan 
 
Date: June 14, 2022 
 
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4.5.4. 
Body Weight and Height ............................................................................................27 
4.5.5. 
Physical Examination Variables .................................................................................27 
4.6. 
Pharmacokinetic (PK) Variables ................................................................................27 
4.7. 
Immunogenicity Variables ..........................................................................................27 
4.8. 
Biomarkers Variables .................................................................................................27 
5. 
STATISTICAL METHODS .......................................................................................28 
5.1. 
Demographics and Baseline Characteristics ...............................................................28 
5.2. 
General Medical History and AD History ..................................................................28 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................28 
5.4. 
Subject Disposition .....................................................................................................29 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................29 
5.5.1. 
Measurement of Compliance ......................................................................................29 
5.5.2. 
Exposure to Study Drug and Observation Period .......................................................29 
5.6. 
Analyses of Efficacy Variables ..................................................................................30 
5.6.1. 
Analysis of Primary Efficacy Variable .......................................................................30 
5.6.2. 
Analysis of Secondary Efficacy Variable ...................................................................31 
5.6.3. 
Adjustment for Multiple Comparison .........................................................................32 
5.6.4. 
Subgroup Analysis ......................................................................................................33 
5.6.5. 
Analyses of Other Efficacy Variables ........................................................................33 
5.7. 
Analysis of Safety Data ..............................................................................................33 
5.7.1. 
Adverse Events ...........................................................................................................34 
5.7.2. 
Clinical Laboratory Measurements.............................................................................35 
5.7.3. 
Analysis of Vital Signs ...............................................................................................35 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................35 
5.9. 
Analysis of Immunogenicity Data ..............................................................................36 
5.9.1. 
Analysis of ADA Data ................................................................................................36 
5.9.2. 
Analysis of Neutralizing Antibodies (NAb) Data ......................................................37 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................37 
5.10.1. 
Association of immunogenicity with exposure ..........................................................37 
5.10.2. 
Immunogenicity and Safety/ Efficacy ........................................................................37 
5.11. 
Analysis of Biomarker Data .......................................................................................38 
6. 
DATA CONVENTIONS ............................................................................................39 
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Statistical Analysis Plan 
 
Date: June 14, 2022 
 
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6.1. 
Definition of Study Baseline for Efficacy/Safety Variables .......................................39 
6.2. 
General Data Handling Conventions ..........................................................................39 
6.3. 
Data Handling Convention Missing Data ...................................................................39 
6.4. 
Analysis Visit Window ...............................................................................................41 
7. 
INTERIM ANALYSIS ...............................................................................................44 
8. 
TIMING OF STATISTICAL ANALYSIS .................................................................45 
9. 
SOFTWARE ...............................................................................................................46 
10. 
REFERENCES ...........................................................................................................47 
11. 
APPENDIX.................................................................................................................49 
11.1. 
Summary of Statistical Analyses ................................................................................49 
11.1.1. 
Summary of Primary Estimand for Primary Endpoint and Secondary 
Endpoints ....................................................................................................................49 
11.1.2. 
Summary of Efficacy Analyses ..................................................................................50 
11.2. 
Schedule of Events .....................................................................................................52 
11.3. 
Criteria for Treatment-Emergent Potentially Clinical Significant Value ...................60 
11.4. 
Search Criteria for TEAE of Special Interest .............................................................70 
11.5. 
Algorithm for RESCUE TREATMENTS ..................................................................72 
 
LIST OF TABLES 
Table 1: 
The Hierarchical Testing Order ..................................................................................32 
Table 2: 
Analysis Visit Window for Efficacy Endpoints: IGA(hand and foot), 
mTLSS, Hand and Foot Area Involvement, HECSI, and QOLHEQ .........................42 
Table 3: 
Analysis Visit Window for Efficacy Endpoints: WPAI+CIQ, IGA(global) 
and EASI .....................................................................................................................42 
Table 4: 
Analysis Visit Window for Safety labs, Vitals, and PK .........................................43 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................12 
 
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Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 6 of 74 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACD 
Allergic Contact Dermatitis 
AD 
Atopic dermatitis 
ADA 
Anti-Drug Antibodies 
AE 
Adverse event 
ALT (SGOT) 
Alanine aminotransferase 
AST (SGPT) 
Aspartate aminotransferase 
AAS 
Anti-Drug Antibody Analysis Set 
BUN 
Blood urea nitrogen 
CRF 
Case report form 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema area and severity index 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
GB 
Great Britain 
HLT 
High Level Term 
ICD 
Irritant Contact Dermatitis 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IGA 
Investigator global assessment 
IL 
Interleukin 
IgE 
Immunoglobulin E 
LDH 
Lactate dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing Antibodies 
NRS 
Numerical rating scale 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
POEM 
Patient Oriented Eczema Measure 
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Statistical Analysis Plan 
 
Date: June 14, 2022 
 
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PT 
Preferred term 
q2w 
Once every 2 weeks 
q4w 
Once every 4 weeks 
QOL 
Quality of life 
qw 
Once every week 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SCORAD 
SCORing atopic dermatitis 
SD 
Standard deviation 
SOC 
System organ class 
SOE 
Schedule of events 
TEAE 
Treatment emergent adverse event 
WHODD 
World health organization drug dictionary 
 
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Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 8 of 74 
1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying statistical approaches for the analysis of the study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data for R668-AD-1924 study. This plan will be finalized 
prior to the database lock for the primary analysis planned when all patients have completed the 
16-week treatment period.  
1.1. 
Background and Rationale 
Atopic hand and foot dermatitis refers to dermatitis in corresponding anatomical locations in 
patients with a history of, or presence of concurrent atopic dermatitis (AD) (Agner, 2015).   
Patients with AD are at a 3 to 4-fold increased risk of hand dermatitis of any etiology as 
compared to the general population (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 hand and foot dermatitis1 presents with redness, infiltration, scaling, vesicles, areas of 
hyperkeratosis, and cracks (fissures) (Coenraads 2012). Lesions are associated with significant 
itching and pain. 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 health 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).  
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. Type 2 helper T cell (Th2) 
mediated immune response is believed to play a central role in the pathogenesis of AD, including 
that of hand and foot. 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).  
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 
                                                 
1 For the purpose of this protocol, atopic hand and foot dermatitis refers to involvement of either hands only, feet 
only, or both hands and feet.   
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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 hand and foot explains the limited 
efficacy of topical anti-inflammatory agents.   
There is no Food and Drug Administration (FDA) approved systemic therapy specifically 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. 
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 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.  
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.  
Additional detailed background information can be found in the study protocol. 
1.2. 
Study Objectives  
1.2.1. 
Primary 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.  
1.2.2. 
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 
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• To evaluate systemic exposure and immunogenicity of dupilumab in patients with 
atopic hand and foot dermatitis 
1.2.3. 
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 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
  
The per protocol set (PPS) will be removed from the analysis since it is not applied in this study. 
The secondary endpoints of change from baseline to week 16 in weekly average of daily hand 
and foot peak Pain NRS and change from baseline to week 16 in weekly average of daily Sleep 
NRS will be used instead of percent change from baseline to week 16 in weekly average of daily 
hand and foot peak Pain NRS and percent change from baseline to week 16 in weekly average of 
daily Sleep NRS since the majority of patients have small baseline values for weekly average of 
daily hand and foot peak Pain NRS and weekly average of daily Sleep NRS which will result in 
large percent change and standard deviation values.  
 
1.2.5. 
Revision History for SAP Amendments 
None. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 3, 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 are planned to be 
enrolled in this study.  
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) 
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 hand and foot 
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. 
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 on hands/feet. Patients will 
need to follow these measures throughout the screening period in order to remain eligible for the 
study. 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 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 EU).  Randomization will 
be capped for adults at approximately 100 to ensure that, at a minimum, approximately 30 
adolescents will be enrolled. 
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Information on the anatomical area of involvement (hands only vs. hand and foot 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 week 2 and week 4, and then in- 
clinic visits every 4 weeks through week 16 with bi-weekly phone visits in between the in-clinic 
visits. Safety laboratory tests, collection of samples for study drug concentrations, 
immunogenicity, and clinical assessments will be performed at specified clinic visits. 
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. 
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). 
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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2.2. 
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. 
 
2.3. 
Sample Size and Power Considerations 
It is reasonable to assume that the effect size of dupilumab on AD of hand and foot would be 
similar to that seen in global AD lesions in previously conducted phase 3 trials as the underlying 
pathophysiology is the 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). 
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.  
The sample size calculations were done using nQuery (7.0). 
 
 
 
 
 
 
 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis: 
3.1. 
Efficacy Analysis Sets (FAS) 
The full analysis set (FAS) includes all randomized patients.  Efficacy analyses will be based on 
the treatment allocated at randomization (as randomized).  
All efficacy variables will be evaluated on the FAS.  Analysis on the FAS will be considered as 
primary. 
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who receive at least one dose of 
study drug and will be analyzed as treated. Treatment compliance/administration and all clinical 
safety variables will be summarized based on the SAF. 
The actual treatment group as treated is defined to be the real received treatment: 
• For a patient who received at least one dupilumab injections, the actual treatment will 
be assigned as dupliumab Q2W. 
• For a patient who received all placebo injections, the actual treatment will be assigned 
as placebo.  
For safety summaries, the following analysis periods are defined: 
• week 16 treatment period is defined as  
− Time after the first dose of study drug to the date of week 16 visit if patients 
completed week 16 with known visit date. 
− Time after the first dose of study drug to study day 113 (16 weeks times 7 
days/week), or to patient’s last study participation date, whichever comes earlier, if 
patients did not complete week 16 visit or had missing week 16 visit date. 
• Follow-up period is defined as the day after the end of treatment period to the patient 
last study participation date. 
SAF will be the basis for the analyses for the treatment period; however, for the analyses for the 
follow-up period, only a subset of the corresponding SAF will be included, which is defined as the 
patients who entered the follow-up period and had at least one visit after week 16 visit. 
 
3.3. 
The Pharmacokinetic Analysis Set (PKAS)  
The PK analysis set includes all randomized patients who received any study drug and who had at 
least one non-missing drug concentration result following the first dose of study drug. 
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3.4. 
The Immunogenicity Analysis Set  
The ADA analysis set (AAS) includes all treated patients who received any amount of study drug 
(active or placebo [safety analysis set]) and had at least one non-missing ADA result following the 
first dose of study drug or placebo. The ADA analysis set is based on the actual treatment received 
(as treated) rather than as randomized. 
The NAb analysis set (NAbAS) includes all treated patients (active or placebo) that are included 
in the ADA analysis set and that tested negative at all ADA sampling times or tested positive at 
one or more post-dose ADA sampling times and had at least one non-missing post-dose NAb result 
(either imputed or analysis result). Samples that tested negative for ADA are not assayed in the 
NAb assay and the corresponding NAb results are imputed as negative and included as such in the 
NAb analysis set. Patients in the NAbAS with multiple post-dose ADA results which consist of 
both imputed NAb-negative result(s) for ADA negative samples and only missing NAb results for 
all ADA-positive result(s), are set to NAb negative. Patients in the NAbAS that have at least one 
post-dose positive NAb analysis result are set to NAb positive even if other NAb results are 
missing. 
3.5. 
Subgroups 
Subgroups are defined by key baseline factors recorded on the eCRF and listed as follows. The 
analysis for the subgroups defined may not be performed if the number of patients within the 
subgroup is small, e.g. <10 patients per treatment arm. No subgroup analysis will be performed if 
the study fails to meet its primary objective, i.e. fails to test significant difference in primary and 
key secondary endpoints. 
Subgroups are listed as follows: 
Subgroups to be considered for primary efficacy analyses:  
• Age group (12-<18 yrs., ≥18yrs.)  
• Sex (Male, Female) 
• Race (White, Black, Asian, Other) 
• Age of onset of hand and foot dermatitis (<18 yrs., ≥18 yrs.) 
• Baseline weight group (<60 kg,  ≥60-<90 kg,  ≥90 kg) 
• BMI (overweight or obese as defined by BMI ≥ 25 in adults and ≥ 85th percentile for 
age and gender in adolescents, BMI<25 in adults and <85th percentile for age and 
gender in adolescents) 
• Region for global submission (United States, Japan, EU) 
• Baseline disease severity [moderate (hand and foot IGA=3) and severe (hand and foot 
IGA=4)] 
• Baseline hand and foot peak Pruritus NRS (<7, ≥7) 
• Hand and foot Surface area of involvement (<50%, ≥50%) 
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• AD outside hand and foot (no (IGA=0), mild (IGA=1,2), moderate to severe AD 
(IGA=3 or 4)) 
• Morphology of hand and foot AD (Chronic dry fissured, hyperkeratotic, dyshidrotic, 
others) 
• Patients with positive patch test to one or more allergens (yes, no) 
• Hand and foot involvement (hands only, hand and foot or feet only) 
• Previous use of systemic immunosuppressants for hand and foot AD (Yes, No) 
• Previous use of systemic cyclosporine for hand and foot AD (Yes, No) 
• Previous usage of Alitretinoin (Yes, No)  
• History of irritant contact dermatitis of hand and foot (yes/no) 
• High risk occupation for hand eczema (yes/no) 
• Smoking status (non smoker and past smoker, occasional current smoker (> 0 
day/month and ≤ 25days/month), regular current smoker (> 25days/month)) 
Additional subgroups based on patient’s baseline characteristics may be performed.   
The following subgroups will be considered for safety analyses: 
• Age group (12-<18 yrs., ≥18 yrs.)  
• Sex (Male, Female) 
• Race (White, Black, Asian, Other) 
• Baseline weight group (<60 kg,  ≥60-<90 kg,  ≥90 kg) 
• Region for global submission (United States, Japan, EU) 
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4. 
ANALYSIS ENDPOINTS 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized: 
• Demographic variables: Age at screening (year), Age group (≥12 - <18, ≥18-<65, , ≥65), Sex 
(Male, Female), Ethnicity (Hispanic or Latino, Not-Hispanic or Latino), Race (White, Black 
or African American, Asian, Other), Region (United States, Japan, EU), Baseline weight (kg), 
Baseline weight  with grouping (≥60kg,  <60kg for adolescents, <60 kg,  ≥60-<90 kg,  ≥90 kg 
for adults), height (m), BMI, BMI with grouping (overweight, not overweight for adolescents, 
<25, ≥25-<30, ≥30 for adults), Smoking status (current smoker, past smoker, non smoker) 
• Baseline characteristics: Duration of hand and foot AD), Age of onset of hand and foot AD 
(mean (sd), median q1, q3, min, max, <18 yrs, ≥18yrs.), Morphology of hand and foot AD 
( chronic dry fissured, hyperkeratotic, dyshidrotic, others), Number of patients with hand and 
foot involvement (hands only, hand and foot, feet only), Number of patients with positive patch 
test (yes, no), Number of patients with history of irritant contact dermatitis (yes, no), 
Investigator’s Global Assessment (IGA) of hand and foot score [IGA = 3, 4], Modified Total 
Lesion Sign Score (mTLSS) for hand and foot, hand and foot peak Pruritus Numerical Rating 
Scale (NRS), hand and foot skin peak pain Numerical Rating Scale (NRS), sleep Numerical 
Rating Scale (NRS), hand and foot Area Involvement of Atopic Dermatitis, Hand Eczema 
Severity Index (HECSI), Quality of Life in Hand Eczema Questionnaire (QoLHEQ), Duration 
of hand and foot AD, Eczema Area and Severity Index (EASI), Investigator’s Global 
Assessment (IGA), Work Productivity and Activity Impairment Questionnaire Plus Classroom 
Impairment Questions (WPAI+CIQ) 
 
4.2. 
Medical History and Atopic Disease Medical History 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). Information on conditions related to AD including diagnosis of hand and foot AD and 
AD treatment history, history of ACD, personal and/or family history of asthma, allergic 
conjunctivitis, allergic rhinitis, chronic rhinosinusitis, nasal polyps, eosinophilic esophagitis, food 
allergy, hives and other allergies due to medications, animals, plants, mold, dust mites, etc. are 
collected.   
 
4.3. 
Prior / Concomitant Medications and Procedures 
Medications/Procedures will be recorded from the day of informed consent until the end of study 
(EOS) visit. Medications will be coded using WHO Drug Dictionary (WHODD). Procedures will 
be coded using MedDRA. 
Prior medications/procedures: medications taken, or procedures performed prior to 
administration of the first dose of study drug. Recent hand and foot AD topical treatments history 
within 6 months before the screening visit is collected. History of treatment with systemic 
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immunosuppressants for hand and foot AD (cyclosporine, systemic corticosteroids, 
methotrexate, azathioprine, alitretinoin and other treatments) will also be collected. 
Concomitant medications/procedures (CMs/CPs): medications taken, or procedures performed 
following the first dose of study drug through the EOS visit.  
• Concomitant medications/procedures during the 16-week treatment period are 
medications/procedures taken after the first dose up to the week 16 visit date or date 
of study day 113 if the week 16 visit date is missing. Medications/procedures taken 
during the 16-week treatment period and continued afterwards into the follow-up 
period will be counted only once as concomitant medications/procedures during the 
16-week treatment period. 
• Concomitant medications/procedures during the follow-up period are 
medications/procedures taken after the week 16 visit date to end of study. 
Prohibited concomitant medications/procedures: Treatment with the following concomitant 
medications is prohibited during the study period: 
• 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 
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) 
  
The following concomitant procedures are prohibited during study period: 
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• 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 
Blinded adjudication of prohibited concomitant medications and procedures will be performed by 
the medical monitor before database locks with documented procedures. 
 
Rescue treatments (i.e. both medications and procedures):  
Rescue treatment for worsening of AD of hand and foot 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 hand and foot 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 hand and foot.  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.   Blinded adjudication of rescue treatments will be implemented before database locks by 
considering the type of medication or procedure, indication, timing, frequency and the potential 
impact of the use of the medication or procedure. The rescue treatments will be adjudicated by the 
medical director (or medical monitor) with documented procedures. 
4.4. 
Efficacy Variables 
4.4.1. 
Primary Efficacy Variable 
The primary endpoint in the study is: 
• Proportion of patients achieving an IGA (hand and foot) score of 0 or 1 at week 16 
Investigator Global Assessment (IGA) of Hand and Foot  
The IGA for hand and foot 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). 
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Investigators will be asked to assess the severity of signs of disease on hand and foot on this scale. 
It is important that this assessment be limited to only the hand and foot and not be influenced by 
severity of AD lesions on other parts of the body. IGA score will be assessed at the scheduled and 
unscheduled clinic visits according to Appendix 11.2. 
4.4.2. 
Secondary Efficacy Variables 
The key secondary endpoints: 
• Proportion of patients with improvement (reduction) of weekly average of daily hand 
and foot peak Pruritus NRS ≥4 from baseline to week 16 
Hand and Foot Pruritus Numerical Rating Scale (NRS) 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.  
Itch will be measured using a worst scratch/itch NRS that was developed and tested for the 
study-relevant age group.  This is an 11-point scale (0 to 10) in which 0 indicates no 
scratching/itching while 10 indicates worst scratching/itching possible.  
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. Clinical sites will 
check and remind patient to complete the diary at each visit. The baseline worst scratch/itch scale 
score is defined as the prorated average of the worst scratch/itch scale scores reported continuously 
for 7 days right before the baseline visit (i.e. study day -7 to day -1) with a minimun of 4 daily 
scores. For post-baseline worst itch scale score, the weekly mean of daily worst scratch/itch score 
is calculated as the average of the available reported daily worst scratch/itch score within the week 
with a minimun of 4 daily scores.  
 
Other secondary efficacy endpoints (not necessarily in order of testing in statistical 
hierarchy): 
• 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  
• Change from baseline to week 16 in weekly average of daily hand and foot peak Pain NRS 
• 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 
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• 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) 
 
Hand and Foot Skin Pain Numerical Rating Scale (NRS) 
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. Patients will be instructed 
on using the scale to record their hand and/or foot 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. 
Sleep Numerical Rating Scale (NRS) 
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.  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.  
Modified Total Lesion Sign Score for Hand and foot 
The Modified Total Lesional Sign Score is adapted for hand and foot; 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). 
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It is important that this assessment be limited to only the hand and foot and not be influenced by 
severity of AD lesions on other parts of the body.  The mTLSS for hand and foot will be assessed 
at time points according to the schedule of events table in Appendix 11.2. 
Surface Area of Hand and Foot Involvement of Atopic Dermatitis 
This assessment will be performed at time points according to Appendix 11.2.  The hand and foot 
area assessment tool is provided in the study reference manual. 
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, 
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 Appendix 11.2, The HECSI is provided in 
the study reference manual. 
Quality of Life in Hand Eczema Questionnaire 
The QoLHEQ will be assessed at time points according to Appendix 11.2. 
The QoLHEQ is provided in the study reference manual. 
Work Productivity and Activity Impairment Questionnaire (WPAI) Plus Classroom 
Impairment Questions (CIQ) 
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.  
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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 Appendix 11.2. 
4.4.3. 
Exploratory Efficacy Variable(s) 
• In patients with AD lesions on other parts of the body in addition to hand and foot; 
− Percent change in EASI score from baseline to week 16 (in patients who have EASI≥16 
at baseline) 
− Percent change in HECSI score from baseline to week 16 (in patients who have 
EASI≥16 at baseline) 
− Proportion of patients with IGA score of 0/1 on hand and foot at week 16 (in patients 
with IGA=3 or 4 on hand and foot at baseline) 
− Proportion of patients with IGA score of 0/1 at week 16 (in patients with global IGA=3 
or 4 at baseline) 
− Proportion of patients with EASI-75 at week 16 (in patients who have EASI≥16 at 
baseline) 
− Proportion of patients with HECSI-75 at week 16 (in patients who have EASI ≥ 16 at 
baseline) 
− Proportion of patients with EASI-50 at week 16 (in patients who have EASI ≥ 16 at 
baseline) 
− Proportion of patients with HECSI-50 at week 16 (in patients who have EASI ≥ 16 at 
baseline) 
− Proportion of patients with EASI-90 at week 16 (in patients who have EASI ≥ 16 at 
baseline) 
− Proportion of patients with HECSI-90 at week 16 (in patients who have EASI ≥ 16 at 
baseline) 
Eczema Area and Severity Index (EASI) 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin, 2001).  The EASI is a composite index with scores ranging from 0 to 
72.  Four AD disease characteristics (erythema, thickness [induration, papulation, edema], 
scratching [excoriation], and lichenification) will each be assessed for severity by the investigator 
or designee on a scale of “0” (absent) through “3” (severe).  In addition, the area of AD 
involvement will be assessed as a percentage by body area of head, trunk, upper limbs, and lower 
limbs, and converted to a score of 0 to 6.  In each body region, the area is expressed as 0, 1 (1% to 
9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). 
The EASI will be collected at the scheduled and unscheduled clinic visits according to 
Appendix 11.2. The EASI assessment tool is provided in the study reference manual. 
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4.5. 
Safety Variables  
4.5.1. 
Adverse Events and Serious Adverse Events Variables 
Adverse events (AE) and serious adverse events (SAE) will be collected starting from the time of 
informed consent signature and at each visit until the end of the study. All adverse events are to be 
coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The definition of AE and SAE are referred to protocol section 10.2.1 and section 10.2.2. 
Pre-treatment AEs and treatment emergent AEs (TEAEs) are defined as follows:  
• Pre-treatment AEs are AEs that developed or worsened in severity during the pre-treatment 
period, which is defined as the period from the patient providing informed consent up to the 
first dose of study drug. 
• Treatment-emergent AEs (TEAEs) are AEs that developed or worsened in severity compared 
to the baseline during the treatment and follow-up period. As only worsening pre-existing AEs 
and new AEs reported during the treatment and follow-up period will be collected in the study, 
all AEs collected during the treatment and follow-up period are considered TEAEs. 
AEs of Special Interest (AESI):   
The following AESIs will be analyzed:  
• Anaphylactic reactions 
• Systemic hypersensitivity reactions 
• Helminthic infections  
• Any severe type of conjunctivitis or blepharitis 
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms) 
Other AEs: 
Skin Infections on hand and foot (with adjudication by clinical), Herpes Infections on hand and 
foot and Injection Site Reactions will be analyzed.  
Additionally other AEs such as Narrow and Broad Conjunctivitis CMQ will be analyzed. 
• Narrow conjunctivitis CMQ is defined as the following PT terms 
− Conjunctivitis 
− Conjunctivitis allergic 
− Conjunctivitis bacterial 
− Conjunctivitis viral 
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− Atopic Keratoconjunctivitis 
• Broad conjunctivitis CMQ is defined as the following PT terms 
− Conjunctivitis 
− Conjunctivitis allergic 
− Conjunctivitis bacterial 
− Conjunctivitis viral 
− Atopic Keratoconjunctivitis 
− Blepharitis 
− Dry eye 
− Eye irritation 
− Eye pruritus 
− Lacrimation increased 
− Eye discharge 
− Foreign body sensation in eyes 
− Photophobia  
− Ocular hyperaemia 
− Conjunctival hyperaemia 
− Xerophthalmia 
Note that, Appendix 11.4 provides a list of AESIs search criteria. 
4.5.2. 
Laboratory Safety Variables 
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 Appendix 11.2.  Tests will 
include: 
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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  
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 Appendix 11.2 . 
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 
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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. 
4.5.3. 
Vital Sign Variables 
Vital signs (including pulse rate, sitting blood pressure, body temperature, and respiratory rate) 
will be collected pre-dose at time points according to Appendix 11.2. At the first  administration 
of study drug, sitting blood pressure, respiratory rate and pulse rate will also be assessed at 30 
minutes (+/- 10 minutes) post-injection.  
4.5.4. 
Body Weight and Height 
Body weight and height will be measured at time points according to Appendix 11.2. 
4.5.5. 
Physical Examination Variables 
The physical examination variable values are dichotomized to normal and abnormal. A thorough 
and complete physical examination will be performed at time points according to the schedule 
described in Appendix 11.2. 
 
4.6. 
Pharmacokinetic (PK) Variables  
The concentrations of functional dupilumab over time will be summarized by descriptive statistics.  
No formal statistical hypothesis testing will be performed. 
 
4.7. 
Immunogenicity Variables   
The immunogenicity variables include ADA status, NAb status and titer at nominal sampling 
time/visit. Serum samples for ADA will be collected at the clinic visits specified in Appendix 
10.2. Samples positive in the dupilumab ADA assay will be further characterized for ADA titers 
and for the presence of NAb against dupilumab.  
 
4.8. 
Biomarkers Variables   
Not applicable. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, first quartile (Q1), third quartile 
(Q3), minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
All data will be summarized by 2 treatment groups: 
• Dupilumab Q2W  
• Placebo 
5.1. 
Demographics and Baseline Characteristics  
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined on FAS population.  
 
5.2. 
General Medical History and AD History  
Medical history will be summarized by primary SOC and PT for each treatment group. The table 
will be sorted by decreasing frequency of SOC, followed by PT, based on the overall incidence 
across treatment groups.  
Information on conditions related to AD will be summarized and includes diagnosis of hand and 
foot AD and AD treatment history, history of ACD, asthma, allergic conjunctivitis, allergic 
rhinitis, chronic rhinosinusitis, nasal polyps, eosinophilic esophagitis, food allergy hives and other 
allergies due to medications, animals, plants, mold, dust mites, etc.. 
All analyses will be based on the FAS population. 
5.3. 
Prior/Concomitant Medications/Procedures  
The number and proportion of patients taking prior/concomitant medications, prohibited 
medications and rescue medications will be summarized, sorted by decreasing frequency of ATC 
Level 2 and ATC level 4, based on the overall incidence for the combined dupilumab treatment 
group. Patients will be counted only once for each medication class (ATC level 2 and 4) linked to 
the medication. 
The number and proportion of patients taking prior/concomitant procedures, prohibited procedures 
and rescue procedures will be summarized, sorted by decreasing frequency of SOC and PT based 
on the overall incidence for the dupilumab treatment group. Patients will be counted only once for 
each SOC and PT linked to the procedure.  
The number and proportion of patients taking adjudicated rescue treatment (concomitant topical 
treatments (medium to high potency TCS/TCI), systemic immunosuppressants) and/or other 
treatments (emollients/ antihistamines) will also be summarized separately. 
The compliance with protocol requirements for application of moisturizers (emollients) used from 
7 days before the baseline visit to end of study, which is defined as the (number of days 
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moisturizers used during the period) / (number of days within the period) x 100%, will be 
summarized by treatment group. 
Kaplan-Meier curves for time to first rescue use will be generated. 
 
5.4. 
Subject Disposition 
The following summaries will be provided for each treatment group and study total (unless 
otherwise specified): 
• 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 (including COVID-19 related reasons) 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation (including COVID-19 related reasons) 
• The total number of patients in each analysis set 
• The total number of patients who entered the 12-week follow-up period 
• Summary table of important protocol deviations (PDs) including PDs due to COVID-
19 will be provided. 
 
5.5. 
Extent of Study Treatment Exposure and Compliance  
5.5.1. 
Measurement of Compliance  
The compliance with protocol-defined study drug administration will be calculated as follows: 
Treatment Compliance= (Number of study drug injections during exposure period) / (Number of 
planned study drug injections during exposure period) x 100% 
The summary of study drug administration will include the number of study drug doses 
administered and treatment compliance. The treatment compliance will be presented by the 
following specific ranges for each treatment group: <80%, and ≥80%. 
5.5.2. 
Exposure to Study Drug and Observation Period 
The duration of treatment (Q2W dosing) exposure during the study in day is calculated as: 
(Date of last study drug injection – date of first study drug injection) + 14 days 
The calculations do not take into account temporary dosing interruption including due to COVID-
19. The summary of exposure to study drug will include the number of study drug doses 
administered and the duration of exposure. Duration of exposure will be summarized for each 
treatment group using the number of patients, mean, SD, minimum, median, Q1, Q3, and 
maximum. 
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In addition, the duration of exposure will be summarized categorically by counts and percentages 
for each of the following categories cumulatively by these categories: ≥ 14 days, ≥ 28 days, ≥ 42 
days, ≥ 56 days, ≥ 70 days, ≥ 84 days, ≥ 98 days and ≥ 112 days with an increment of 2 weeks for 
each subsequent category. 
The duration of observation period during the study in days is calculated as: 
(Date of the last visit – date of the first study drug injection) +1. 
The duration of observation period will be summarized descriptively using number of 
patients, mean, SD, median, Q1, Q3, minimum and maximum. In addition, the number (%) of 
subjects with observation periods will be presented by specific time periods. The time periods of 
interest are specified as: 
≥ 15 days, ≥ 29 days, ≥ 57 days, ≥ 85 days, ≥113 days, and ≥197 days. 
 
5.6. 
Analyses of Efficacy Variables 
The analyses of efficacy variables are described in the subsections below and summarized in 
Appendix 11.1.2. The intercurrent events, strategies, and the corresponding missing data handling 
approaches for the estimands of interest for the primary endpoint and selected secondary endpoints 
are provided in Appendix 11.1.1. 
5.6.1. 
Analysis of Primary Efficacy Variable  
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 EU]).  
Sensitivity analyses: 
Sensitivity analysis using the last observation carried forward (LOCF) approach  to determine 
patient’s status at week 16 will be conducted to assess the robustness of the primary efficacy 
analysis with regards to handling of missing data.  The efficacy data will be set to missing after 
early termination due to AE and other reasons excluding rescue treatment , then the LOCF method 
will be used to determine patients’ status at week 16.  
To assess the robustness of primary analysis results, a delta-adjusting pattern-mixture approach 
for tipping point analysis (2013, Ratitch) under MNAR (missing not at random) assumption, will 
be conducted for the primary endpoint. The impact from missing data on the comparisons in 
proportion of patients achieving IGA 0/1 (co-primary endpoint: EASI-75, only in European 
Union [EU] and EU Reference Market Countries) at week 16 between dupilumab and placebo 
control group will be examined as follows. 
− A sequence of analyses will be performed with the adjustment to artificially decrease the 
response rate in dupilumab group and increase the response rate in placebo group with a 
fixed and definite set of values for data imputation. 
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− For each combination of increasing response rate in placebo and decreasing response rate 
in dupilumab, multiple imputed datasets will be generated and analyzed using CMH test. 
The results obtained from multiple imputed datasets will be combined to generate 
statistical inference, i.e. p-value and treatment difference between 2 treatment groups. 
− A “tipping point” will be identified while the result is no longer statistically significant 
(i.e. p-value >0.05). 
5.6.2. 
Analysis of Secondary Efficacy Variable 
All secondary endpoints will be evaluated based on the FAS population. 
The binary secondary efficacy endpoints (e.g., improvement of weekly average of daily peak 
Pruritus NRS ≥4 from baseline to week 16) will be analyzed using the same approaches used for 
the analysis of the primary endpoints as described in Section 5.6.1.  
The continuous endpoints (e.g., percent change mTLSS for hand/foot lesions from baseline to 
week 16) will be analyzed using analysis of covariance (ANCOVA) model 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 EU]), and relevant baseline 
value included in the model. 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. To be specific, the missing data will be imputed by 
postbaseline worst-observation-carried-forward (WOCF) if there is at least one non-missing 
postbaseline value or by baseline value if there is no postbaseline value.  The multiple imputation 
(MI) approach will be used for the missing due to other reasons, including reasons due to COVID-
19. The MI will be performed based on all observed data before the imputation by WOCF 
approach. To account for the uncertainty in the imputation, missing data from the FAS will be 
imputed 40 times to generate 40 complete data sets by using the SAS procedure MI following the 
2 steps below: 
Step 1: The monotone missing pattern is induced by Markov Chain Monte Carlo (MCMC) method 
in MI procedure using seed number 12345. The monotone missing pattern means that if a patient 
has missing value for a variable at a visit, then the values at all subsequent visits for the same 
variable are all missing for the patient. 
Step 2: The missing data at subsequent visits will be imputed using the regression method for the 
monotone pattern with seed number 54321 and adjustment for covariates including treatment 
groups, randomization strata (baseline weight group, baseline IGA and region), and relevant 
baseline. 
Once imputations are made, the week 16 data of each of the 40 complete datasets will be analyzed 
using ANCOVA model with treatment, randomization strata (baseline weight group, baseline IGA 
and region), and relevant baseline included in the model, and the SAS MIANALYZE procedure 
will be used to generate valid statistical inferences by combining results from the 40 analyses using 
Rubin’s formula. 
Onset of action analysis 
Onset of action in percent change from baseline weekly average of daily hand and foot peak 
Pruritus NRS score can be assessed by providing a nominal p-value at each assessment visits. The 
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analysis will be carried out on the FAS population only. Using this analysis, the first assessment 
visit at which p <0.05 for the difference from placebo in the weekly average of daily worst 
scratch/itch NRS score that remains p < 0.05 at subsequent weekly measurements through week 
16 can be identified. The similar analysis will be carried out on the following binary responses:- 
Hand and foot IGA 0/1 
- Improvement (reduction) of weekly average of daily hand and foot peak Pruritus NRS score ≥4 
from baseline 
Percent change in mTLSS for hand/foot lesions from baseline 
To aid the interpretation of the percent change in mTLSS on hand and foot endpoint, measurement 
properties of the mTLSS on hand and foot were evaluated in blinded data on 65% of the target 
sample size (85 patients out of target sample size of 130).  Using IGA on hand and foot as the 
anchor-measure, it was estimated that a median reduction of 50% to 75% in mTLSS score on hand 
and foot from BL to Week 16 can be considered clinically meaningful since it corresponds to a 1- 
to 2-point improvement in IGA on hand and foot. Therefore, a responder analysis will be 
conducted for dupilumab versus placebo at Week 2, 4, 8, 12, and 16 using the thresholds of at least 
50% and at least 75% reduction in mTLSS on hand and foot from BL. Additionally, a empricical 
cumulative distribution function (CDF)  curve will be generated by plotting the cumulative 
proportion of patients (Y axis) in dupilumab and placebo arm by the percent change in mTLSS on 
hand and foot from BL to Week 16 (x-axis) achieved.  
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 CMH method 
adjusted by randomization strata based on LOCF imputation method will be performed as the 
sensitivity analyses of key secondary endpoint.     
 
5.6.3. 
Adjustment for Multiple Comparison  
Multiplicity Considerations  
A hierarchical procedure, will be used to control the overall Type-1 error rate at 0.05 for the 
primary endpoint and the secondary endpoints of dupilumab versus placebo. Each hypothesis will 
be formally tested only if the preceding one is significant at the 2-sided 0.05 significance level. 
The hierarchical testing order is shown in below table (all comparisons are with the placebo).  
Table 1: 
The Hierarchical Testing Order 
Level 
Efficacy Endpoints (EPs) at Week 16 
 
Testing 
Order  
Primary endpoint 
Proportion of patients with IGA (hand and foot) 0 to 1 
(on a 5-point scale) 
 
1 
Key Secondary endpoints 
Proportion of patients with improvement (reduction) of 
weekly average of daily hand and foot peak Pruritus 
NRS ≥4  
2 
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Level 
Efficacy Endpoints (EPs) at Week 16 
 
Testing 
Order  
Secondary endpoints 
Percent change in mTLSS for hand/foot lesions from 
baseline 
 
3 
Percent change from baseline in weekly average of daily 
hand and foot peak pruritus NRS 
4 
Change from baseline in weekly average of daily hand 
and foot peak Pain NRS 
5 
Percent change from baseline in Hand Eczema Severity 
Index (HECSI) score 
6 
Proportion of patients with HECSI-75 
7 
Change from baseline in percent surface area of hand and 
foot involvement with AD 
8 
Change from baseline in QOLHEQ 
9 
Change from baseline in weekly average of daily Sleep 
NRS 
10 
5.6.4. 
Subgroup Analysis 
Subgroups for the primary endpoint and key secondary endpoint will be analyzed based on the 
FAS. 
The analysis method for the subgroups will be the same as the primary analysis described in 
Section 5.6.1 as appropriate. If for any reason such as due to small number of patients in a 
subgroup, the model-based inferential statistics cannot be computed, or deemed inappropriate, 
only descriptive statistics will be provided.  
Forest plots of the primary and key secondary efficacy endpoint across subgroups will be provided.  
Interactions between the subgroups and treatment groups will also be tested using the logistic 
regression model. The model will include randomization strata,treatment group, subgroup, and 
treatment by subgroup interaction as factors. P-values for the interaction term will be reported. 
5.6.5. 
Analyses of Other Efficacy Variables 
The analyses of other efficacy variables (binary and continuous endpoints) will be conducted in a 
similar fashion as the primary analysis described in  Sections 5.6.1 and 5.6.2. unless otherwise 
noted in the individual descriptions of other efficacy variables or deemed inappropriate.  
 
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed based on the SAF.  
The safety analysis will be based on the reported AEs, clinical laboratory evaluations, physical 
examination and vital signs. 
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Thresholds for treatment-emergent Potentially Clinically Significant Values (PCSVs) in 
laboratory variables and vital signs are defined in Appendix 11.3. A treatment-emergent PCSV is 
any PCSV which developed or worsened in severity compared to baseline during the treatment 
and/or follow-up period.  The time interval to detect any event or abnormality is between the first 
injection of study medication and EOS. 
In addition, the summary of safety results (including TEAEs, clinical laboratory, vital signs and 
ECG) will be performed for subjects who were impacted by COVID-19 pandemic and not 
impacted by COVID-19 pandemic in each study part, respectively if deemed appropriate. The 
summary will be performed for pre-, during, and post-COVID-19 periods for patients impacted by 
COVID-19, if deemed appropriate.  
5.7.1. 
Adverse Events 
The number and proportion of patients reporting TEAEs will be summarized overall during the 
study, during the week 16 treatment period, and during the follow-up period separately, sorted by 
decreasing frequency of SOC and PT in the dupilumab group. 
AE incidence tables will be presented by treatment group for the SAF as well as for selected 
subgroups. TEAE summaries will present the number (n) and percentage (%) of subjects 
experiencing a TEAE by SOC and PT, sorted by decreasing frequency of SOC and PT for the 
dupilumab treatment group. Multiple occurrences of AEs of the same PT (or SOC) in the same 
subject will be counted only once for that PT (or SOC). For tables presenting severity of events, 
the worst severity will be chosen for subjects with multiple instances of the same event. The 
denominator for computation of percentage is the number of patients in each treatment group for 
the corresponding analysis period as specified in Section 3.2. 
An overall summary of TEAEs will be provided with number and proportions of patients with 
any: 
• TEAE 
• Serious TEAE 
• TEAE of special interest (AESI) 
• TEAE leading to death 
• TEAE leading to permanent treatment discontinuation 
Detailed summaries of TEAEs will include: 
• TEAEs 
− TEAEs by SOC/PT 
− TEAEs (for HLTs: Injection site reactions, Herpes viral infections) by 
SOC/HLT/PT  
− TEAEs by PT 
− Common TEAEs by SOC/PT (incidence with PT ≥5%) 
− TEAEs by severity by SOC/PT 
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− TEAEs related to study medication as assessed by the investigator by SOC/PT 
• Serious TEAEs by SOC/PT 
− Serious TEAEs by SOC/PT 
− Serious TEAEs related to study medication as assessed by the investigator by 
SOC/PT  
• TEAEs leading to permanent discontinuation of study treatment by SOC/PT 
• Fatal TEAE by SOC/PT 
• AESI by AESI category (Appendix 11.4) and SOC/PT 
5.7.2. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to standard international units and US conventional units. Summaries of laboratory 
variables will include: 
• Descriptive statistics of laboratory result and change from baseline by visit 
• The number (n) and percentage (%) of subjects with treatment emergent PCSVs. This 
summary will be provided based on the subgroup of SAF patients who did not meet the 
PCSV criterion at baseline. 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest.  
5.7.3. 
Analysis of Vital Signs 
Summaries of vital sign variables will include: 
• Descriptive statistics of vital sign variable and change from baseline by visit 
• The number (n) and percentage (%) of patients with treatment-emergent PCSV  
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
5.8. 
Analysis of Pharmacokinetic Data 
The following analyses will be conducted: 
• Descriptive statistics of functional dupilumab concentrations in serum at each sampling 
time by dose 
• Graphical presentations of median and mean (+/- SD) functional dupilumab 
concentration in serum vs nominal time profiles 
• Graphical presentations of individual functional dupilumab concentration in serum vs 
actual sampling time profiles  
• Assessment of the impact of anti-drug antibodies on functional dupilumab 
concentrations in serum. 
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No formal statistical analysis will be performed. 
5.9. 
Analysis of Immunogenicity Data 
5.9.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.7 will be summarized using descriptive 
statistics in the ADA analysis set.  
Immunogenicity will be characterized by ADA status, ADA category and maximum titer 
observed in patients in the ADA analysis sets.  
The ADA status of each patient may be classified as one of the following:  
• Positive. 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 4-fold the baseline titer value. 
• Negative - If all samples are found to be negative in the ADA assay. 
The ADA category of each positive patient is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one post 
baseline titer result ≥4-fold the baseline titer value  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Patients that are treatment-emergent will 
be further categorized as follows: 
− Persistent - A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 12-week post baseline period [based 
on nominal sampling time], with no ADA-negative results in-between, regardless 
of any missing samples 
− Transient - Not persistent or indeterminate, regardless of any missing samples 
− Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
The maximum titer category of each patient is classified as: 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
 
The following will be summarized by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative patients 
- 
Number (n) and percent (%) of pre-existing patients 
• Number (n) and percent (%) of treatment-emergent ADA-positive patients 
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- 
Number (n) and percent (%) of persistent treatment-emergent ADA positive patients 
- 
Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
- 
Number (n) and percent (%) of transient treatment-emergent ADA positive patients 
• Number (n) and percent (%) of treatment-boosted ADA-positive patients 
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
 
5.9.2. 
Analysis of Neutralizing Antibodies (NAb) Data 
The absolute occurrence (n) and percent of patients (%) with NAb status in the NAb analysis set 
will be provided by treatment groups.  The NAb status is categorized as follows: 
• Negative: Samples tested negative in the ADA assay, or samples positive in the ADA 
assay but tested negative in the NAb assay. 
• Positive: Samples tested positive in the NAb assay.   
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.10.1. 
Association of immunogenicity with exposure 
Potential association between immunogenicity and systemic exposure to dupilumab will be 
explored by treatment groups. Plots of dupilumab concentration may be provided for analyzing 
the potential impact of ADA category, maximum titer category and NAb status on these profiles. 
5.10.2. 
Immunogenicity and Safety/ Efficacy 
The analyses in this section will only be performed if incidence of treatment emergent ADA 
positive response is sufficient to make meaningful conclusions (i.e. more than 5% in any treatment 
group). 
Potential association between immunogenicity variables and safety events will focus on the 
following events: 
• TEAEs 
• Serious TEAEs 
• TEAEs leading to permanent treatment discontinuation 
• Injection site reaction  
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• Anaphylactic Reaction (SMQ: Anaphylactic Reaction [Narrow]) 
Potential association between immunogenicity variables and the primary efficacy endpoints may 
be explored (e.g. scatter plot or spaghetti plot).  
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The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
• ADA Positive 
− Treatment-emergent 
− Treatment-boosted 
• Maximum post-baseline titer category in ADA positive patients 
• NAb positive 
 
5.11. 
Analysis of Biomarker Data 
Not applicable. 
 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
6.1. 
Definition of Study Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment of the study for all measurements will be the 
latest available valid measurement taken prior to the first administration of study drug. If any 
randomized patients are not treated, the baseline will be the last value on or prior to the 
randomization. The baseline of worst scratch/itch scale is defined in Section 4.4.2. 
The following rules specify the determination of baseline by both date/time information: 
1. For the AE, lab, PK and ADA data, both date and time of the measurement will be used to 
determine baseline by comparing with the first injection date and time. 
2. For other data except AE, lab, PK or ADA, only date of the measurement will be used to 
determine baseline by comparing with the first injection date. 
For the rescreened patients, all data from the same patient will be used to derive baseline 
regardless if the data is from the screen- failure subject ID or enrolled subject ID. 
6.2. 
General Data Handling Conventions 
For the laboratory safety variables data, if the data fall below the lower limit of quantification 
(LLOQ) / limit of linearity, half of the lower limit value (i.e., LLOQ/2) will be used for quantitative 
analyses. For data above the upper limit of quantification (ULOQ) / limit of linearity, the upper 
limit value (i.e., ULOQ) will be used for quantitative analyses. 
6.3. 
Data Handling Convention Missing Data 
Missing data will not be imputed in the listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAE. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
Adverse event start date  
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed, and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use the AE end 
date instead. Otherwise impute the AE start day using the first day of the month. If this leads to a 
date before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
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If AE start month is missing, and AE start year is not missing: If AE start year is less than the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month. If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE starting date imputation, in order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use end of follow 
up date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 
31 December as the day and month. If this leads to a date after end of study follow up date, use 
the end of follow up date instead. 
If AE end year is missing: Impute AE end date using the end of follow up date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment medication or concomitant medication or 
both, the missing medication start date is estimated as early as possible, and the missing medication 
end date is estimated as late as possible. If the medication start date is missing, the onset day will 
not be calculated in medication listings. 
Prior medication start date  
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’; 
If start month is missing, and start year is not missing: Impute the day and month using 01 January. 
Imputation flag is ‘M’. 
If start year is missing: Impute start date using 2 years before inform consent date. Imputation flag 
is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, in 
order to simplify the programming flow, the imputation is proposed in line with the protocol which 
specifies to collect up to 2 years of prior medication. Since the start date of prior medication will 
not be used in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
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If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date -
1 instead. Imputation flag is ‘M’ 
If end year is missing: Impute end date using the first dose intake date –1. Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use end of follow up date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the end of follow up 
date instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of follow up date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study DM and study MD. 
PCSV 
Patients who had a post-baseline PCSV but a missing baseline value will be regarded as having a 
treatment emergent PCSV. 
6.4. 
Analysis Visit Window 
Data analyzed by-visit-analysis (including efficacy, laboratory data, visit sign, ADA) will be 
summarized by the study scheduled visits described in the study protocol and SAP “Schedule of 
Events”. The analysis visit windows will be exhaustive so that all available values obtained from 
unscheduled visits, early termination (ET) visit have the potential to be summarized. No analysis 
visit windows will be applied for the study scheduled visits.  
The analysis visit windows are created per study Schedule of Events (SOE) table for each 
parameter and will be applied if the data from study scheduled visits are unavailable. The following 
general rules will be applied to unscheduled visit and/or early termination (ET) visit mapping for 
each parameter.  
1. If ET visit falls in an analysis window which already has no missing observed value of 
this parameter from the scheduled visit, ET will be mapped to the next scheduled visit.  
2. If both ET visit and unscheduled visit of the same parameter are available in the same 
analysis visit window, only ET visit will be mapped.  
3. If multiple unscheduled visits of the same parameter are available in the same analysis 
visit window, the unscheduled visits will be mapped using the following rules: 
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a. The closest unscheduled visit from the target day will be selected. 
b. If multiple unscheduled visits exist on the same day, the first unscheduled visit will 
be used.  
4. If mapping distance is greater than 2 weeks, the unscheduled visit will not be mapped.  
Unscheduled visits and early termination (ET) visit will be mapped per the following analysis visit 
windows based on the visit schedule of each parameter as per Appendix 11.2   
Table 2: 
Analysis Visit Window for Efficacy Endpoints: IGA(hand and foot), mTLSS, 
Hand and Foot Area Involvement, HECSI, and QOLHEQ 
Visit from SOE 
Target Day 
Analysis Visit Window Based on Study 
day* 
Screening 
<1 
<1 
Baseline 
1 
1 
Week 2 
15 
 [2, 22] 
Week 4 
29 
 [23, 43] 
Week 8 
57 
[44, 71] 
Week 12 
85 
[72, 99] 
Week 16 
113 
[100, 155] 
Week 28 
197 
≥ 156 
* Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date +1) 
when date of assessment ≥ 1st injection date; otherwise study day = (date of assessment – 1st injection date). If 
patient never received any dose of study drug, randomization date will be used in place of 1st injection date. 
 
Table 3: 
Analysis Visit Window for Efficacy Endpoints: WPAI+CIQ, IGA(global) and 
EASI 
Visit from SOE 
Target Day 
Analysis Visit Window Based on Study 
day* 
Screening 
<1 
<1 
Baseline 
1 
1 
Week 4 
29 
 [2, 71] 
Week 16 
113 
[72, 155] 
Week 28 
197 
≥ 156 
* Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date +1) 
when date of assessment ≥ 1st injection date; otherwise study day = (date of assessment – 1st injection date). If 
patient never received any dose of study drug, randomization date will be used in place of 1st injection date. 
 
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Table 4: 
Analysis Visit Window for Safety labs, Vitals, and PK  
Visit from SOE 
Target 
Study Day 
in Part Ba 
Vital signs, 
Weight 
Physical 
examination, 
Height 
Pregnancy 
Test 
Lab* 
PK, ADA 
Screening 
<1 
<1 
<1 
<1 
<1 
<1 
Baseline 
1 
1 
 
1 
1 
1 
Week 8 
57 
 
 
[2, 71] 
 
 
Week 12 
85 
 
 
[72, 99] 
 
 
Week 16 
113 
[2, 155] 
[2, 155] 
[100, 155] 
[2, 155]  
[2, 155] 
Week 28  
197 
 ≥  156 
≥  156 
≥ 156 
≥ 156 
≥  156 
*Hematology, Blood Chemistry and Urinalysis. 
Note that both scheduled and unscheduled measurements will be considered for determining abnormal/PCSV values 
for laboratory, vital signs or ECGs as well as the baseline values.  
 
Rules for visit windows of ePRO data collected daily using eDiary: 
For the daily collected ePRO data (e.g. Pruritus worst scratch/itch NRS, skin pain NRS, sleep 
quality NRS), the analysis visit windows will be implemented following the procedure below: 
Step 1: Derive the study day,  
If diary date ≥ 1st injection date, then diary study day=diary date – 1st injection date +1;  
Otherwise diary study day=diary date – 1st injection date 
Step 2: Windows are defined as diary study day -7 to -1 = BL, 1 to 7 = week 1, 8 to 14 = week 2, 
etc, with 7 days interval between visit windows. 
 
 
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7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
 
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8. 
TIMING OF STATISTICAL ANALYSIS 
The primary analysis may be performed when the last patient completes 16 weeks of treatment 
duration in order to expedite the submission to regulatory agencies. No changes in the conduct of 
the study will be made based on this primary analysis. The assessment of co-primary and secondary 
endpoints performed during the analysis will be the final analysis of the co-primary endpoint and 
secondary endpoints. Hence, there will be no need for alpha adjustment due to the primary analysis. 
In order to maintain study integrity (with respect to the post-treatment follow-up visits, safety 
visits, and analyses) in the event a decision is made to perform the primary analysis, 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 for the following post treatment analyses. However, the dedicated team 
can participate in the analysis following the final database lock. 
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9. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
 
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10. 
REFERENCES 
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Classification of hand eczema. J Eur Acad Dermatol Venereol 2015; 29(12):2417-22. 
Agner T, Andersen KE, Brandao FM, Bruynzeel DP, Bruze M, Frosch P, et al. Hand eczema 
severity and quality of life: a cross-sectional, multicentre study of hand eczema patients. Contact 
Dermatitis 2008; 59(1):43-7. 
Coenraads PJ. Hand eczema. N Engl J Med 2012; 367(19):1829-37. 
Diepgen TL, Agner T, Aberer W, Berth-Jones J, Cambazard F, Elsner P, et al. Management of 
chronic hand eczema. Contact Dermatitis 2007; 57(4):203-10. 
Fowler JF, Ghosh A, Sung J, Emani S, Chang J, Den E, et al. Impact of chronic hand dermatitis 
on quality of life, work productivity, activity impairment, and medical costs. J Am Acad 
Dermatol 2006; 54(3):448-57. 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and 
severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp 
Dermatol 2001; 10(1):11-8. 
Held E, Skoet R, Johansen JD, Agner T. The hand eczema severity index (HECSI): a scoring 
system for clinical assessment of hand eczema. A study of inter- and intraobserver reliability. Br 
J Dermatol 2005; 152(2):302-7. 
Holm JG, Agner T, Clausen ML, Thomsen SF. Quality of life and disease severity in patients 
with atopic dermatitis. J Eur Acad Dermatol Venereol 2016; 30(10):1760-7. 
ICH Harmonized tripartite guideline: Statistical principles for clinical trials (E9). February 5, 
1998. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. 
Leung DY. Pathogenesis of atopic dermatitis. J Allergy Clin Immunol 1999; 104(3 Pt 2):S99-
108. 
Oosterhaven JAF, Romeijn GLE, Schuttelaar MLA. Dupilumab Treatment of Very Severe 
Refractory Atopic Hand Eczema. JAMA Dermatol 2018; 154(8):969-70. 
Politiek K, Oosterhaven JA, Vermeulen KM, Schuttelaar ML. Systematic review of cost-of-
illness studies in hand eczema. Contact Dermatitis 2016; 75(2):67-76. 
Ruff SMD, Engebretsen KA, Zachariae C, Johansen JD, Silverberg JI, Egeberg A, et al. The 
association between atopic dermatitis and hand eczema: a systematic review and meta-analysis. 
Br J Dermatol 2018; 178(4):879-88. 
Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth-Jones J, Coenraads PJ, et al. Efficacy and 
safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema 
refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, 
multicentre trial. Br J Dermatol 2008; 158(4):808-17. 
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. 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 48 of 74 
Simpson EL, Thompson MM, Hanifin JM. Prevalence and morphology of hand eczema in 
patients with atopic dermatitis. Dermatitis 2006; 17(3):123-7. 
Zirwas MJ. Dupilumab for hand eczema. J Am Acad Dermatol 2018; 79(1):167-9.
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 49 of 74 
11. 
APPENDIX 
11.1. 
Summary of Statistical Analyses 
11.1.1. 
Summary of Primary Estimand for Primary Endpoint and Secondary Endpoints 
Primary and Key Secondary 
Endpoints 
Population Intercurrent Event(s) and Handling 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) 
 
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) 
FAS 
The intercurrent events will be handled in the 
following order: 
1. Rescue treatment: if rescue treatment is received 
no matter treatment discontinuation occurs, patients 
will be considered as non-responders after such 
events (composite strategy).  
2. Treatment discontinuation: data collected after 
treatment discontinuation without rescue treatment 
will be included in the analysis (treatment policy 
strategy).  
Note: if both treatment and rescue treatment occur, 
refer to rescue treatment handling strategy. 
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. 
Other Secondary endpoints 
Continuous Endpoints (e.g. 
Percent change in mTLSS for 
hand/foot lesions from baseline 
to week 16) 
FAS 
The intercurrent events will be handled in the 
following order: 
1. Rescue treatment: data after rescue treatment 
will be assigned by the worst possible value 
(composite strategy).  
2. Treatment discontinuation: data collected after 
treatment discontinuation without rescue treatment 
will be included in the analysis (treatment policy 
strategy).  
Note: if both treatment and rescue treatment occur, 
refer to rescue treatment handling strategy.  
Missing data due to 
rescue treatment, AE, 
and lack of efficacy will 
be imputed by WOCF. 
 
Missing data due to 
other reasons will be 
imputed by MI. 
 
Binary Endpoints (e.g. 
Proportion of patients with 
improvement (reduction) of 
weekly average of daily hand 
and foot peak Pruritus NRS ≥3 
from baseline to week 16 ) 
FAS 
Will be analyzed with the same fashion as the primary endpoint of proportion of 
patients achieving an IGA score of 0 or 1 on hand and foot at week 16 . 
 
 
 
 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 50 of 74 
 
11.1.2. 
Summary of Efficacy Analyses 
Parameter
(s) 
 
Analysis 
Populati
ons 
Endpoints  
Primary Statistical 
Method 
Supportive
/Sensitivity 
Statistical 
Method 
Subgr
oup 
Analys
is 
Investigator’s 
Global 
Assessment 
(IGA) on 
hand and foot 
(Primary) 
 
FAS, PPS 
 
• 
IGA 0 to 1 
(Categorical) 
 
• CMH test adjusted by 
randomization strata (Age, 
IGA Severity and Region) 
LOCF, 
Tipping point 
analysis, Use 
all observed 
data  
Yes 
hand and foot 
peak Pruritus 
NRS 
 
(NRS ≥4, key 
secondary) 
 
FAS 
Categorical: 
• 
NRS ≥3 
• 
NRS ≥4 
Continuous: 
• 
% change from 
baseline 
•Categorical: CMH test 
adjusted by randomization 
strata for categorical 
variables 
• Continuous: Multiple 
imputation (MI) using 
pattern mixture ((MI-
WOCF) ) with ANCOVA 
for continuous variables  
 
LOCF, 
Use all 
observed data 
for key 
secondary 
endpoint 
Yes for 
NRS ≥4 
 
No for 
other 
NRS 
endpoint
s  
hand and foot 
Modified 
Total Lesion 
Sign Score 
(mTLSS) 
 
FAS 
 
• 
% change from 
baseline 
 
Multiple imputation (MI) 
using pattern mixture (MI-
WOCF) with ANCOVA 
for continuous variables  
No 
No 
hand and foot 
peak Pain 
NRS 
 
FAS 
• 
% change from 
baseline 
 
Multiple imputation (MI) 
using pattern mixture (MI-
WOCF) with ANCOVA 
for continuous variables 
No  
No 
Sleep NRS 
FAS 
• 
% change from 
baseline 
 
Multiple imputation (MI) 
using pattern mixture (MI-
WOCF) with ANCOVA 
for continuous variables 
 
No 
No 
hand and foot 
involvement 
with AD 
FAS 
• 
Change from 
baseline 
Multiple imputation (MI) 
using pattern mixture (MI-
WOCF) with ANCOVA 
No 
No 
 
 
hand 
dermatitis, 
HECSI 
 
FAS 
 
Continuous: 
• 
% change from 
baseline 
 
Categorical: 
• 
HECSI75 
• 
HECSI50 
• 
HECSI90 
• Multiple imputation 
(MI) using pattern mixture 
(MI-WOCF) with 
ANCOVA for continuous 
variables 
• CMH test adjusted by 
randomization strata for 
categorical variables 
 
No 
No 
IGA 
 
FAS 
• 
Proportion of 
patients with IGA 
score of 0/1 at week 
16 
CMH test adjusted 
randomization strata 
 
No 
No 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 51 of 74 
Parameter
(s) 
 
Analysis 
Populati
ons 
Endpoints  
Primary Statistical 
Method 
Supportive
/Sensitivity 
Statistical 
Method 
Subgr
oup 
Analys
is 
EASI 
 
FAS 
• 
Percent change in 
EASI score from 
baseline to week 16 
• 
Proportion of 
patients with EASI-
75 at week 16 
CMH test adjusted 
randomization strata 
 
No 
No 
 
Safety Analyses: 
 
Analysis 
Statistical 
Supportive 
Subgrou
p 
Other 
Endpoint 
Populati
ons 
Method 
Analysis 
Analysis 
Analyses 
 
 
 
 
 
 
Adverse Events 
SAF 
Descriptive statistics 
No 
Yes for 
selected 
AE 
summary 
No 
Skin 
infection 
TEAE 
 
SAF 
Incidence of skin 
infection TEAE 
(excluding herpetic 
infections) through 
week 16 
Descriptive 
summary 
(incidence) 
 
No 
No 
TE-SAE 
 
SAF 
Incidence of 
treatment-emergent 
serious adverse events 
(SAE) through week 
16 
 
Descriptive 
summary 
(incidence) 
No 
No 
Laboratory 
Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 52 of 74 
11.2. 
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 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 53 of 74 
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 
 
 
Assign anatomical area 
of involvement10 
 
 
X 
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 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 54 of 74 
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 
 
 
Patient assessment of 
hand and foot skin pain 
and sleep NRS16 
X 
X 
X 
X 
X 
  
 
   
  
   
X 
X  
  
  
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 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 55 of 74 
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 
 
 
Urinalysis 
X 
 
X  
  
  
   
   
   
  
  
X 
X 
X 
X 
Pregnancy test, WOCBP 
only 
Serum 
 
Urine  
  
  
  
Urine  
  
Urine  
  
Urine 
Urine 
Urine 
Urine 
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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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 56 of 74 
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 hand and foot. 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
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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.  
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.   
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 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 58 of 74 
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 
• Hand and foot 
• 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. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 59 of 74 
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 hand and foot. 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 hand and foot. 
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. 
** 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. 
 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 60 of 74 
11.3. 
Criteria for Treatment-Emergent Potentially Clinical Significant Value 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
Clinical Chemistry 
 
 
ALT* 
 >3 and ≤ 5 ULN and baseline ≤ 3 
ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 
ULN 
>10 and ≤ 20 ULN and baseline ≤ 
10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzyme activity must be expressed 
in ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Each category is calculated 
independently. 
>3 and ≤ 5 ULN and baseline ≤ 
3 ULN* 
>5 and ≤ 10 ULN and baseline 
≤ 5 ULN 
>10 and ≤ 20 ULN and baseline 
≤ 10 ULN 
>20 ULN and baseline ≤ 20 
ULN 
Enzyme activity must be 
expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
Each category is calculated 
independently. 
* At least one level is required, 
multiple levels are optional for 
phase 2/3 studies. If it is 
desirable to get the distribution 
across the different  PCSV 
levels, additional shift table on 
≤3, >3 to ≤5,  > 5 to  ≤10, >10 
to ≤20, and > 20 category for 
baseline vs. post baseline may 
be provided  
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 
ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 
ULN 
>10 and ≤ 20 ULN and baseline ≤ 
10 ULN 
>20 ULN and baseline ≤ 20 ULN  
Enzyme activity must be expressed 
in ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Each category is calculated 
independently. 
>3 and ≤ 5 ULN and baseline ≤ 
3 ULN* 
>5 and ≤ 10 ULN and baseline 
≤ 5 ULN 
>10 and ≤ 20 ULN and baseline 
≤ 10 ULN 
>20 ULN and baseline ≤ 20 
ULN 
Enzyme activity must be 
expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
Each category is calculated 
independently. 
* At least one level is required, 
multiple levels are optional for 
phase 2/3 studies. If it is 
desirable to get the distribution 
across the different  PCSV 
levels, additional shift table on 
≤3, >3 to ≤5,  > 5 to ≤10, >10 
to ≤20, and > 20 category for 
baseline vs. post baseline may 
be provided 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 61 of 74 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
Alkaline Phosphatase 
>1.5 ULN and baseline ≤ 1.5 ULN Enzyme activity must be expressed 
in ULN, not in IU/L. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
>1.5 ULN and baseline ≤ 1.5 
ULN 
Enzyme activity must be 
expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
 
Total Bilirubin* 
≥1.3 ULN and baseline < 1.3 ULN Must be expressed in ULN, not in 
µmol/L or mg/L. 
Based on normal range: <1 mg/dL, 
CF = mg x 1.7 = μmol 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
>1.5 and ≤ 2 ULN and baseline 
≤ 1.5 ULN* 
>2 ULN and baseline ≤ 2.0 
ULN 
Must be expressed in ULN, not 
in µmol/L or mg/L. Categories 
are cumulative. 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
* At least one level is required, 
multiple levels are optional for 
phase 2/3 studies. If it is 
desirable to get the distribution 
of  significant level, additional 
shift table on  ≤1.5, >1.5 to 
≤2.0 and > 2.0 category for 
baseline vs. post baseline may 
be provided 
Conjugated Bilirubin 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin ≥1.3 
ULN)  
Conjugated bilirubin will be 
measured when the total bilirubin is 
above the ULN 
Based on normal range: 0 to 0.4 
mg/dL 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin 
>1.5 ULN) and (Direct 
Bilirubin <=35%  Total 
Bilirubin or  Total Bilirubin 
<=1.5 ULN) at baseline 
Conjugated bilirubin dosed on 
a case-by-case basis. 
ALT and Total Bilirubin 
(ALT≥3 ULN and TBILI≥2 ULN) 
and baseline (ALT <3 ULN or 
TBILI <2 ULN) 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
(ALT>3 ULN and TBILI>2 
ULN) and baseline (ALT <=3 
ULN or TBILI <=2 ULN) 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 62 of 74 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
CPK* 
≥3 ULN and baseline < 3ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
>3 and ≤ 10 ULN and baseline 
≤ 3ULN* 
>10 ULN and baseline ≤ 
10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required, 
multiple levels are optional for 
phase 2/3 studies. If it is 
desirable to get the distribution 
of  significant level, additional 
shift table on ≤3, >3 to ≤10, 
and > 10 category for baseline 
vs. post baseline may be 
provided 
Creatinine 
≥132µmol/L and baseline < 
132µmol/L 
(or ≥1.5 mg/dL and baseline <1.5 
mg/dL) 
>=30% change from baseline 
Benichou C., 1994 
Two independent criteria 
≥150 μmol/L (Adults) and 
baseline < 150 μmol/L 
>=30%  change from baseline 
and <100% change from 
baseline 
≥100% change from baseline 
Benichou C., 1994. 
3 independent criteria  
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>8.0 mg/dL and <8.0 mg/dl at 
baseline (or >476 µmol/L and 
<476 µmol/L at baseline 
≤2 mg/dL and >2 mg/dL at 
baseline (or ≤119 µmol/L and 
baseline > 119 µmol/L) 
 
 
>408 μmol/L and <=408 
μmol/L at baseline 
<120 μmol/L and >= 120 
μmol/L at baseline 
Harrison- Principles of internal 
Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea Nitrogen 
≥20 mg/dL and <20 mg/dL at 
baseline (or >=7.14 mmol/L and 
<7.14 mmol/L at baseline) 
 
≥17 mmol/L and <17 mmol/L at 
baseline 
Two independent criteria 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 63 of 74 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
Chloride 
Hypochloremia 
Hyperchloremia 
<80 mmol/L and baseline ≥ 80 
mmol/L  
≥115 mmol/L and baseline < 115 
mmol/L  
Two independent criteria  
Reference ranges are same in 
adolescents (12-17 yrs. old) and 
adults 
 
<80 mmol/L and baseline ≥ 80 
mmol/L  
>115 mmol/L and baseline ≤ 
115 mmol/L  
Two independent criteria  
Sodium 
Hyponatremia 
Hypernatremia 
<129 mmol/L and baseline ≥ 129 
mmol/L  
≥150 mmol/L and baseline <150 
mmol/L  
Two independent criteria 
Reference ranges are similar in 
adolescents (12-17 yrs. old) and 
adults 
 
≤129 mmol/L  and baseline > 
129 mmol/L  
≥160 mmol/L  and baseline 
<160 mmol/L  
Two independent criteria 
Potassium 
Hypokalemia 
Hyperkalemia 
 
≤3.5 mmol/L and baseline >3.5 
mmol/L  
≥5.5 mmol/L and baseline <5.5 
mmol/L  
FDA Feb 2005. 
Two independent criteria 
Reference ranges are similar in 
adolescents (12-17 yrs. old) and 
adults 
 
<3 mmol/L and baseline ≥ 3 
mmol/L  
≥5.5 mmol/L and baseline <5.5 
mmol/L  
FDA Feb 2005. 
Two independent criteria 
Calcium total 
<2 mmol/L and baseline ≥2 
mmol/L 
(or ≤ 8 mg/dL and baseline >8 
mg/dL) 
≥2.9 mmol/L and baseline <2.9 
mmol/L  
(or ≥11.6 mg/dL and baseline 
<11.6 mg/dL) 
 
 
 
LDL Cholesterol 
≥4.91 mmol/Land <4.91 mmol/L 
at baseline 
(≥ 190 mg/dl and <190 mg/dl at 
baseline) 
Threshold for therapeutic 
intervention with pharmacotherapy 
in children 
(Expert Panel on Integrated 
Guidelines for Cardiovascular 
Health and Risk Reduction in 
Children and Adolescents; 2011). 
 
 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 64 of 74 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
Total Cholesterol 
≥6.20 mmol/Land < 6.20 mmol/L 
at baseline  
(or ≥ 240 mg/dL and < 240 mg/dL 
at baseline) 
 
≥7.74 mmol/L and < 7.74 
mmol/L at baseline 
Threshold for therapeutic 
intervention. 
Triglycerides 
Fasting level ≥ 5.64 mmol/Land < 
5.64 mmol/L at baseline 
(or ≥ 500 mg/dL and < 500 mg/dL 
at baseline) 
Threshold for therapeutic 
intervention with pharmacotherapy 
in children. (Expert Panel on 
Integrated Guidelines for 
Cardiovascular Health and Risk 
Reduction in Children and 
Adolescents; 2011). 
CF = g x 1.14 = mmol 
≥4.6 mmol/L and < 4.6 mmol/L 
at baseline 
Threshold for therapeutic 
intervention. 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
<2.7 mmol/L and ≥2.7 mmol/L at 
baseline (or < 50 mg/dL and ≥ 50 
mg/dL at baseline) 
≥10 mmol/L (unfasted) and < 10 
mmol/L (unfasted) at baseline (or 
≥180 mg/dl and <180 mg/dl at 
baseline); ≥7 mmol/L (fasted) and 
<7 mmol/L (fasted) at baseline (or 
≥120 mg/dL and <120 mg/dL at 
baseline) 
 
 
(≤3.9 mmol/L and <LLN) and 
(>3.9 mmol/L or >=LLN) at 
baseline 
≥11.1 mmol/L (unfasted); ≥7 
mmol/L (fasted) and < 11.1 
mmol/L (unfasted); <7 mmol/L 
(fasted) at baseline 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>6.5% and <= 6.5% at baseline 
WHO 2006/2011 
ADA 2003 and 2012 
>8% and <= 8% at baseline 
 
Albumin 
≤25 g/L and >25 g/L at baseline 
Reference ranges are same in 
children (6-17 yrs. old) and adults 
≤25 g/L and >25 g/L at baseline   
CRP 
 
 
>2 ULN or >10 mg/L (if ULN 
not provided) and 
<=2 ULN or <=10 mg/L (if 
ULN not provided) at baseline 
 FDA Sept 2005. 
Hematology 
 
 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 65 of 74 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
WBC 
<4.0 Giga/L and ≥4.0 Giga/L at 
baseline  
>13.5 Giga/L and ≤13.5 Giga/L at 
baseline  
 
<3.0 Giga/L and >=3.0 Giga/L 
at baseline (Non-Black);  
<2.0 Giga/L and >=2.0 Giga/L 
at baseline (Black) 
≥16.0 Giga/L and < 16 Giga/L 
at baseline 
Increase in WBC: not relevant. 
 
 
To be interpreted only if no 
differential count available. 
Lymphocytes 
<0.6 Giga/L and ≥0.6 Giga/L at 
baseline  
>6.0 Giga/L and ≤6.0 Giga/L at 
baseline 
 
>4.0 Giga/L and <= 4.0 Giga/L 
at baseline 
 
Neutrophils 
<1.2 Giga/L and ≥1.2 Giga/L at 
baseline  
>ULN and baseline ≤ ULN 
International Consensus meeting on 
drug-induced blood cytopenias, 
1991. 
FDA criteria. 
<1.5 Giga/L and >=1.5 Giga/L 
at baseline (Non-Black);  
<1.0 Giga/L and >=1.0 Giga/L 
at baseline (Black) 
International Consensus 
meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>1.2 Giga/L and <= 1.2 Giga/L at 
baseline 
 
>0.7 Giga/L <= 0.7 Giga/L at 
baseline 
 
Basophils 
 
 
>0.1 Giga/L <= 0.1 Giga/L at 
baseline 
 
Eosinophils 
(>0.5 Giga/L and >ULN) and 
(<=0.5 Giga/L or <= ULN at 
baseline) 
Harrison- Principles of internal 
Medicine 17th Ed., 2008. 
(>0.5 Giga/L and >ULN) and 
(<=0.5 Giga/L or <= ULN at 
baseline) 
Harrison- Principles of internal 
Medicine 17th Ed., 2008. 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 66 of 74 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
Hemoglobin 
<10 g/dL and >10 g/dL at baseline 
(or <100 g/L and >=100 g/L at 
baseline) 
≥20 g/dL and <20 g/dL at baseline 
(or >=200 g/L and <200 g/L at 
baseline) 
Two criteria are independent 
≤115 g/L and > 115 g/L at 
baseline for male; 
 ≤95 g/L and> 95 g/L at 
baseline for Female. 
 
≥185 g/L and <185 g/L at 
baseline for Male; 
 ≥165 g/L and < 165 g/L at 
baseline for Female 
 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
 
Criteria based upon decrease 
from baseline are more 
relevant than based on absolute 
value. Other categories for 
decrease from baseline can be 
used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
Hematocrit 
For males: 
<0.37 v/v and ≥0.37 v/v at 
baseline;  
>0.52 v/v and ≤0.52 v/v at 
baseline  
For females: 
<0.33 v/v and ≥0.33 v/v at 
baseline 
<0.47 v/v and ≥0.47 v/v at 
baseline 
Two Criteria are independent 
≤0.37 v/v and > 0.37 v/v at 
baseline for Male ;  
≤0.32 v/v and > 0.32 v/v at 
baseline forFemale 
≥0.55 v/v and < 0.55 v/v at 
baseline for Male ;  
≥0.5 v/v and < 0.5 v/v at 
baseline for Female 
Two Criteria are independent 
RBC 
 
 
Female 
<3 Tera/L and baseline ≥3 
Tera/L 
≥6 Tera/L and baseline < 6 
Tera/L  
Male 
<4 Tera/L and baseline ≥4 
Tera/L 
≥7 Tera/L and baseline < 7 
Tera/L 
Unless specifically required 
for particular drug 
development, the analysis is 
redundant with that of Hb. 
Otherwise, consider FDA 
criteria. 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 67 of 74 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
Platelets 
<100 Giga/L and ≥100 Giga/L at 
baseline 
>700 Giga/L and ≤ 700 Giga/L at 
baseline 
International Consensus meeting on 
drug-induced blood cytopenias, 
1991. 
Two independent criteria 
<100 Giga/L and >=100 Giga/L 
at baseline 
≥700 Giga/L and < 700 Giga/L 
at baseline 
International Consensus 
meeting on drug-induced 
blood cytopenias, 1991. 
Two independent criteria 
Urinalysis 
 
 
Ketonuria 
Presence and absence at baseline 
Semi-quantitative methods 
 
 
Glycosuria 
Presence and absense at baseline 
Semi-quantitative methods 
 
 
Microscopic Hematuria 
> 5 RBCs/ HPF and ≤5 RBCs/ 
HPF at baseline 
Semi-quantitative methods 
 
 
Proteinuria 
≥ 1+ and <1 at baseline 
Semi-quantitative methods, ≥ 1+ 
means concentration >=30 mg/dL 
 
 
pH 
 
 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
Two independent criteria 
Vital signs 
 
 
HR 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
To be applied for all positions 
(including missing) except 
STANDING. 
SBP 
Hypotension: SBP<5th percentile 
for gender, age and height; 
baseline >=5th percentile and 
decrease from baseline ≥20 mmHg 
Hypertension: At or above the 
95th percentile for age, sex and 
height postbaseline; baseline < 
95% percentile; and increase from 
baseline ≥20 mmHg 
Based on definition of hypotension 
as SBP<5th percentile for gender, age 
and height 
Based on definition of Hypertension 
as average SBP ≥ 95th percentile for 
gender, age, and height on ≥ 3 
occasions 
≤95 mmHg and decrease from 
baseline ≥20mmHg 
≥160 mmHg and increase from 
baseline ≥20 mmHg 
To be applied for all positions 
(including missing) except 
STANDING. 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 68 of 74 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
DBP 
Hypotension: DBP<5th percentile 
for gender, age and height; 
baseline >=5th percentile and 
decrease from baseline ≥10 mmHg 
Hypertension: At or above the 
95th percentile for age, sex and 
height postbaseline; baseline 
< 95% percentile and increase 
from baseline ≥10 mmHg 
Based on definition of Hypertension 
as average DBP ≥ 95th percentile for 
gender, age, and height on ≥ 3 
occasions 
≤45 mmHg and decrease from 
baseline ≥10 mmHg 
≥110 mmHg and increase from 
baseline ≥10 mmHg 
To be applied for all positions 
(including missing) except 
STANDING. 
Temperature 
Rectal, ear: >100.4 °F/38.0 °C 
Oral: >99.5 °F/37.5 °C  
Axillary: >99 °F/37.2 °C 
 
 
 
Respiratory rate 
<12 per minute and ≥12 per 
minute at baseline 
>20 per minute and ≤20 per 
minute at baseline 
 
 
 
Weight 
≥5% decrease from baseline 
Based on identification of trends in 
the child’s growth with a series of 
visits WHO Multicentre Reference 
Study Group, 2006; Center for 
Disease Control.  Growth chart 
2007. 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
 
 
 
HR 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
 
PR 
≥200 ms and < 200 ms at baseline  
≥220 ms and increase from 
baseline ≥20 ms 
 
QRS 
≥110 ms & < 110 ms at baseline 
 
≥120 ms & < 120 ms at baseline  
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 69 of 74 
Parameter 
Adolescents (≥12 to <18) 
Comments for Adolescents (≥12 to <18) 
Adults (≥18) 
Comments for Adults (≥18) 
QTc 
Borderline 
Prolonged* 
Additional 
 
Absolute values (ms) 
Borderline: 
431-450 ms and < 431ms at 
baseline for Male; 451-470 ms and 
< 451 ms at baseline for Female 
Prolonged:  
>450 to <500 ms and <= 450 ms 
at baseline for Male;  
>470 to <500 ms and <= 470 ms 
at baseline for Female 
Additional: 
≥500 ms and < 500 ms at baseline 
Increase from baseline 
Borderline: Increase from baseline 
30-60 ms 
Prolonged: Increase from baseline 
>60 ms 
Bazett’s formula (measured QT 
interval divided by the square root of 
the R-R) to be applied to arrive at 
corrected QT value interval) 
QTc prolonged and QTc>60 ms are 
the PCSA to be identified in 
individual subjects/patients listings. 
independent criteria 
Absolute values (ms) 
 
Borderline: 
 431-450 ms and < 431ms at 
baseline for Male; 451-470 ms 
and < 451 ms at baseline for 
Female 
Prolonged:  
>450 to  <500 ms and <= 450 
ms at baseline for Male;  
 >470 to <500 ms and <= 470 
ms at baseline for Female 
 ≥500 ms and < 500 ms at 
baseline 
 
Increase from baseline 
Borderline: Increase from 
baseline 30-60 ms 
Prolonged: Increase from 
baseline >60 ms 
To be applied to any kind of 
QT correction formula.  
 
 
 
*QTc prolonged and QTc>60 
ms are the PCSA to be 
identified in individual 
subjects/patients listings. 
 
5 independent criteria 
 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 70 of 74 
11.4. 
Search Criteria for TEAE of Special Interest  
Below table is the search criteria for AESI under protocol amendment 2. 
AESI 
Search Criteria 
Anaphylactic reactions  
  
Narrow SMQ for anaphylactic reaction 
Systemic hypersensitivity reactions  
  
Narrow SMQ for “hypersensitivity” minus SMQ (Narrow) Anaphylactic reaction 
Note:  manual adjudication of relevant PTs will be required by the study medical monitor, 
before database lock 
Helminthic infections 
-HLT = Cestode infections 
-HLT = Helminthic infections NEC 
-HLT = Nematode infections 
-HLT = Trematode infection 
Any severe type of conjunctivitis or 
blepharitis 
Broad CMQ conjunctivitis (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, 
Conjunctivitis viral, Atopic keratoconjunctivitis, Blepharitis, Dry eye, Eye irritation, Eye 
pruritus, Lacrimation increased, Eye discharge, Foreign body sensation in eyes, 
Photophobia, Ocular hyperaemia, Conjunctival hyperaemia, Xerophthalmia); 
AND 
Blepharitis PTs (Blepharitis, blepharitis allergic);  
AND  
Serious AE= “Yes” OR Severity= “severe” 
Keratitis 
Narrow SMQ for “corneal disorders” 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 71 of 74 
Clinically symptomatic eosinophilia (or 
eosinophilia associated with clinical 
symptoms) 
 
HLT = Eosinophilic disorders  
PT = Eosinophil count increased 
Note: manual adjudication of relevant PTs will be required by the study medical monitor, 
before database lock. 
 
 
 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 72 of 74 
11.5. 
Algorithm for RESCUE TREATMENTS 
1. Not required to adjudicate rescue treatment: 
Post-baseline medications (WHODD-coded) given for indications consistent with AD of hands and feet. 
a. Always considered rescue: 
• ATC2 = CORTICOSTEROIDS FOR SYSTEMIC USE 
• ATC2 = IMMUNOSUPPRESSANTS 
• Preferred Drug Name = Ciclosporin 
• Preferred Drug Name = Methotrexate 
• Preferred Drug Name = Mycophenolate sodium 
• Preferred Drug Name = Mycophenolic acid 
• Preferred Drug Name = Mycophenolate mofetil 
• Preferred Drug Name = Azathioprine 
• Preferred Drug Name = Alitretinoin 
b. Never considered rescue: 
• ATC2 = EMOLLIENTS AND PROTECTIVES 
• ATC2 = VASOPROTECTIVES 
• ATC2 = ANALGESICS 
• ATC2 = ANTI-ACNE PREPARATIONS 
• ATC2 = TOPICAL PRODUCTS FOR JOINT AND MUSCULAR PAIN 
• ATC2 = ANTIBIOTICS AND CHEMOTHERAPEUTICS FOR 
DERMATOLOGICAL USE 
• ATC2 = ANTIVIRALS FOR SYSTEMIC USE 
• ATC2 = ANTIFUNGALS FOR DERMATOLOGICAL USE 
• ATC2 = ANTISEPTICS AND DISINFECTANTS 
• ATC2 = ANTIHISTAMINES FOR SYSTEMIC USE 
• ATC2 = ANTIPRURITICS, INCL. ANTIHISTAMINES, ANESTHETICS, ETC. 
• ATC2 = GENERAL NUTRIENTS 
• ATC2 = VITAMINS 
• ATC2 = DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES 
• ATC2 = OPHTHALMOLOGICALS 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 73 of 74 
• ATC2 = ANTIINFLAMMATORY AND ANTIRHERUMATIC PRODUCTS 
• ATC2 = PSYCHOLEPTICS 
• ATC1 = ANTIINFECTIVES FOR SYSTEMIC USE 
• ATC1 = BLOOD AND BLOOD FORMING ORGANS 
• ATC1 = ALIMENTARY TRACT AND METABOLISM 
• ATC1 = MUSCULO-SKELETAL SYSTEM 
• ATC2 = COUGH AND COLD PREPARATIONS 
• ATC2 = CORTICOSTEROIDS, DERMATOLOGICAL PREPARATIONS, if used before day 15 
• Preferred Drug Name = Tacrolimus, if used before day 15 
• Preferred Drug Name = Pimecrolimus, if used before day 15 
• Preferred Drug Name = Crisaborole, if used before day 15 
 
A blinded review of all post-baseline medications to adjudicate rescue treatment, based on medical judgement, may be performed in 
addition. A listing of treatments classified as rescue/non-rescue in a manner inconsistent with the classification under #1 will be 
provided, along with supporting rationale. 
 
2. Required to adjudicate rescue treatment: 
• All other medications (not noted in 1 above) given for indications consistent with hand and foot AD 
Medications noted in 1a above, when given for indications not consistent with hand and foot AD. Medications in 1a above when given 
for generalized AD will be considered rescue. 
 Below is a list of indications consistent with AD based on PT level from concomitant medication/procedure data using MedDRA 
dictionary 
 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-AD-1924 
Statistical Analysis Plan 
 
Date: June 14, 2022 
 
CONFIDENTIAL 
Page 74 of 74 
 
                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


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                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00


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                                        VV-RIM-00201342-1.0 Approved - 27 Jun 2022 GMT-5:00