Master Protocol of Three Randomized, Double-blind, Placebo Controlled, Multi-center, Parallel-group Studies of Dupilumab in Patients With Chronic Spontaneous Urticaria (CSU) Who Remain Symptomatic Despite the Use of H1 Antihistamine Treatment in Patients naïve to Omalizumab and in Patients Who Are Intolerant or Incomplete Responders to Omalizumab
Phase: PHASE3
Conditions: Chronic Spontaneous Urticaria
Sponsor: Sanofi

 
 
 
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affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
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direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: RDSD-002540 VERSION N° 3.0 (19-FEB-2019) based on TransCelerate CPT version 5 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 05  
Protocol title: 
Master protocol of three randomized, double-blind, 
placebo-controlled, multi-center, parallel-group 
studies of dupilumab in patients with chronic 
spontaneous urticaria (CSU) who remain 
symptomatic despite the use of H1 antihistamine 
treatment in patients naïve to omalizumab and in 
patients who are intolerant or incomplete 
responders to omalizumab 
Protocol number: 
EFC16461 
Amendment number: 
05 
Compound number 
(INN/Trademark): 
SAR231893/REGN668 
dupilumab/Dupixent 
Study phase: 
Phase 3 
Short title: 
Dupilumab for the treatment of chronic 
spontaneous urticaria in patients who remain 
symptomatic despite the use of H1 antihistamine 
and who are naïve to, intolerant of, or incomplete 
responders to omalizumab 
LIBERTY-CSU CUPID (Chronic Urticarial Pruritus Itch 
Dupilumab Trial) 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered address: 
1 avenue Pierre Brossolette 
91380 Chilly-Mazarin France 
Monitoring Team’s 
Representative Name and 
Contact Information 
  
Regulatory agency identifier number(s): 
IND: 
105379 
EudraCT: 
2019-003775-19 
NCT: 
NCT04180488 
WHO: 
U1111-1241-8208 
Other: 
Not applicable 
Approval Date: 
17-Mar-2022 
Total number of pages: 137 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 05 
All 
17 March 2022, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 
All 
29 April 2021, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
France only 
09 October 2020, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
30 April 2020, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01  
Japan only 
10 February 2020, version 1 (electronic 1.0) 
Original Protocol 
 
24 October 2019, version 1 (electronic 4.0) 
Amended protocol 05 (17 March 2022) 
This amended protocol 05 (Amendment 05) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
EFC16461 is a double-blind placebo-controlled phase 3 study in patients with chronic 
spontaneous urticaria (CSU) who remain symptomatic despite the use of H1 antihistamine  
(H1-AH) treatment, composed of Study A conducted in patients naïve to omalizumab and Study 
B in patients who are intolerant or incomplete responders to omalizumab.  
The primary purpose of this amendment is to conduct a Study C with a study population and 
design similar to the completed Study A, to meet Health Authority requirements to provide data 
from two adequate and well-controlled clinical trials to support filing of a marketing application. 
In addition, key Study A results and information on the Study B prespecified interim analysis 
outcome have been added to this amended protocol. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page; 1.1 Synopsis; 
1.2 Schema; 1.3 Schedule of 
Activities (SoA); 2.1 Study rationale; 
2.2 Background; 2.3 Benefit/risk 
assessment; 3 Objectives and 
Endpoints; 4.1 Overall design; 
4.2 Scientific rationale for study 
design; 5.1 Inclusion criteria; 
5.2 Exclusion criteria; 6 Study 
intervention; 6.3 Measures to 
minimize bias: randomization and 
blinding; 8 Study assessments and 
procedures; 8.8 Biomarkers; 
9.1 Statistical hypotheses; 
9.2 Sample Size Determination; 
9.3 Populations for Analyses; 
9.4.1 Efficacy Analyses; 
9.5 Interim Analyses; 
Study C was added, with a design similar to 
Study A. 
Study C will be conducted in the same 
study population with a similar design 
as Study A, to meet Health Authority 
requirements to provide data from two 
adequate and well-controlled clinical 
trials to support filing of a marketing 
application. 
1.1 Synopsis; 4.1 Overall design; 
4.2 Scientific rationale for study 
design; 6.3 Measures to minimize 
bias: randomization and blinding 
Study C will include not more than 
approximately 50% of participants having their 
H1-AH therapy at recommended doses, and not 
less than approximately 30% but not more than 
approximately 45% of participants presenting 
with angioedema at baseline. 
For Study C, in adults, in addition to 
randomization stratification by country, 
randomization will be stratified by presence of 
angioedema at baseline. 
To maintain consistency between the 
study population in studies A and C, 
and reflect the real-life distribution of 
patients with angioedema and 
uncontrolled by both standard dose or 
maximal H1-AH therapy. 
To ensure equal distribution of patients 
with angioedema at baseline in both 
treatment groups.  
1.1 Synopsis; 2.1 Study rationale; 
2.3 Benefit/risk assessment; 
4.2 Scientific rationale for study 
design; 4.3 Justification for Dose 
Study A results are presented. 
Study A has been completed and 
results are available, demonstrating 
dupilumab efficacy and acceptable 
safety in the studied population. 
1.1 Synopsis; 2.1 Study rationale; 
2.3 Benefit/risk assessment 
Study B prespecified interim analysis outcome 
is presented. 
The outcome of the Study B pre-
specified interim analysis met the 
protocol efficacy statistical criteria for 
futility (stop for futility outcome), with no 
new safety concerns identified. 
2.3 Benefit/Risk Assessment 
Information on dupilumab marketing 
authorization status has been updated. 
Updated to include additional marketing 
authorizations.  
6.3 Measures to minimize bias: 
randomization and blinding 
Change in wording regarding participant 
unblinding process: the Investigator may 
contact the Sponsor at his/her discretion prior to 
unblinding. 
Change in template standard wording. 
Whole document 
Minor editorial changes were made throughout 
the document 
 
 
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TABLE OF CONTENTS  
 
AMENDED CLINICAL TRIAL PROTOCOL 05 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 21 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 22 
2 
INTRODUCTION ............................................................................................................................ 27 
2.1 
STUDY RATIONALE...................................................................................................................... 27 
2.2 
BACKGROUND ............................................................................................................................. 30 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 30 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 33 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 34 
4 
STUDY DESIGN ............................................................................................................................ 36 
4.1 
OVERALL DESIGN ........................................................................................................................ 36 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 37 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 39 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 39 
5 
STUDY POPULATION .................................................................................................................. 40 
5.1 
INCLUSION CRITERIA .................................................................................................................. 40 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 42 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 45 
5.4 
SCREEN FAILURES...................................................................................................................... 45 
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6 
STUDY INTERVENTION ............................................................................................................... 46 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 46 
6.1.1 
Investigational medicinal product(s) ............................................................................................... 46 
6.1.2 
Noninvestigational medicinal product(s) ........................................................................................ 48 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 48 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 49 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 50 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 51 
6.5.1 
Rescue medicine ............................................................................................................................ 52 
6.6 
DOSE MODIFICATION .................................................................................................................. 52 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 52 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 53 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 53 
7.1.1 
Definitive discontinuation ............................................................................................................... 53 
7.1.2 
Temporary discontinuation ............................................................................................................. 54 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 55 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 56 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 57 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 58 
8.1.1 
Urticaria activity score .................................................................................................................... 58 
8.1.2 
Angioedema activity score ............................................................................................................. 59 
8.1.3 
Urticaria control test ....................................................................................................................... 59 
8.1.4 
Dermatology life quality index and children’s dermatology quality life quality index ..................... 59 
8.1.5 
Chronic urticaria quality of life questionnaire ................................................................................. 60 
8.1.6 
Patient Global Impression of Change of CSU disease and Patient Global Impression of 
Severity of CSU disease ................................................................................................................ 60 
8.1.7 
EuroQOL 5 dimensions questionnaire ........................................................................................... 61 
8.1.8 
Missed school/work days ............................................................................................................... 61 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 61 
8.2.1 
Physical examinations ................................................................................................................... 62 
8.2.2 
Vital signs ....................................................................................................................................... 62 
8.2.3 
Electrocardiograms ........................................................................................................................ 62 
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8.2.4 
Clinical safety laboratory assessments .......................................................................................... 62 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 63 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 64 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 64 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 65 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 65 
8.3.5 
Pregnancy ...................................................................................................................................... 65 
8.3.6 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 66 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 66 
8.3.8 
Patients with angioedema .............................................................................................................. 66 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 66 
8.5 
PHARMACOKINETICS .................................................................................................................. 67 
8.5.1 
Systemic drug concentration and anti-drug antibodies .................................................................. 67 
8.5.1.1 
Sampling time ................................................................................................................................ 67 
8.5.1.2 
Handling procedures ...................................................................................................................... 67 
8.5.1.3 
Bioanalytic method ......................................................................................................................... 67 
8.6 
PHARMACODYNAMICS ............................................................................................................... 68 
8.7 
GENETICS ..................................................................................................................................... 68 
8.8 
BIOMARKERS ............................................................................................................................... 68 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................... 69 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 70 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 70 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 70 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 71 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 72 
9.4.1 
Efficacy analyses ........................................................................................................................... 72 
9.4.2 
Safety analyses .............................................................................................................................. 74 
9.4.3 
Other analyses ............................................................................................................................... 75 
9.5 
INTERIM ANALYSES .................................................................................................................... 76 
9.5.1 
Data Monitoring Committee ........................................................................................................... 77 
9.5.2 
Unblinding plan .............................................................................................................................. 77 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 78 
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10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 78 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 78 
10.1.2 
Financial disclosure........................................................................................................................ 78 
10.1.3 
Informed consent process .............................................................................................................. 79 
10.1.4 
Data protection ............................................................................................................................... 80 
10.1.5 
Committees structure ..................................................................................................................... 80 
10.1.6 
Dissemination of clinical study data ............................................................................................... 80 
10.1.7 
Data quality assurance .................................................................................................................. 81 
10.1.8 
Source documents ......................................................................................................................... 82 
10.1.9 
Study and site closure .................................................................................................................... 82 
10.1.10 Publication policy ........................................................................................................................... 82 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 83 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 85 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 89 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 91 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW UP 
ASSESSMENTS ............................................................................................................................ 92 
10.7 
APPENDIX 7: CLINICIAN-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES .................................................................................................................................. 94 
10.7.1 
Urticaria activity score (UAS) ......................................................................................................... 94 
10.7.2 
Angioedema activity score (AAS) .................................................................................................. 95 
10.7.3 
Urticaria control test (UCT) .......................................................................................................... 101 
10.7.4 
Dermatology life quality index (DLQI) .......................................................................................... 102 
10.7.5 
Children’s dermatology life quality index (CDLQI) ....................................................................... 103 
10.7.6 
Chronic urticaria quality of life questionnaire (CU-Q2OL)............................................................ 105 
10.7.7 
Patient Global Impression of Change (PGIC) .............................................................................. 108 
10.7.8 
Patient Global Impression of Severity (PGIS) .............................................................................. 108 
10.7.9 
EuroQol 5-dimensional questionnaire Youth (EQ-5D-Y) ............................................................. 109 
10.7.10 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L) .......................................................... 112 
10.7.11 Missed school/work days ............................................................................................................. 114 
10.8 
APPENDIX 8: DEFINITION OF ANAPHYLAXIS ......................................................................... 116 
10.9 
APPENDIX 9: LIST OF OPPORTUNISTIC INFECTIONS........................................................... 116 
10.10 
APPENDIX 10: LIST OF PROHIBITED LIVE ATTENUATED VACCINES .................................. 117 
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10.11 
APPENDIX 11: COUNTRY-SPECIFIC REQUIREMENTS .......................................................... 117 
10.11.1 Amendment for Japan .................................................................................................................. 117 
10.11.2 Amendment for France ................................................................................................................ 118 
10.12 
APPENDIX 12: ABBREVIATIONS ............................................................................................... 118 
10.13 
APPENDIX 10: PROTOCOL AMENDMENT HISTORY .............................................................. 120 
10.13.1 Amended protocol 01 (10 February 2020) ................................................................................... 120 
10.13.2 Amended protocol 02 (30 April 2020) .......................................................................................... 121 
10.13.3 Amended protocol 03 (09 October 2020) .................................................................................... 130 
10.13.4 Amended protocol 04 (29 April 2021) .......................................................................................... 130 
OVERALL RATIONALE FOR THE AMENDMENT .................................................................................... 130 
11 
REFERENCES ............................................................................................................................. 135 
 
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LIST OF TABLES  
Table 1 - Summary of the primary endpoints in Study A - ITT population .................................................... 29 
Table 2 - Objectives and endpoints ............................................................................................................... 33 
Table 3 - Overview of study interventions administered ............................................................................... 46 
Table 4 - Summary of handling procedures .................................................................................................. 67 
Table 5 - Summary of bioanalytical methods for functional dupilumab and anti-dupilumab antibodies ....... 67 
Table 6 - Populations for analyses ................................................................................................................ 71 
Table 7 - Efficacy analyses ........................................................................................................................... 72 
Table 8 - Safety analyses .............................................................................................................................. 74 
Table 9 - Possible outcomes from the Study B interim analysis ................................................................... 77 
Table 10 - Protocol-required laboratory assessments .................................................................................. 83 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 21 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
Master protocol of three randomized, double-blind, placebo-controlled, multi-center, parallel-
group studies of dupilumab in patients with chronic spontaneous urticaria (CSU) who remain 
symptomatic despite the use of H1 antihistamine treatment in patients naïve to omalizumab and in 
patients who are intolerant or incomplete responders to omalizumab 
Short title: 
Dupilumab for the treatment of chronic spontaneous urticaria in patients who remain symptomatic 
despite the use of H1 antihistamine and who are naïve to, intolerant of, or incomplete responders 
to omalizumab. 
LIBERTY-CSU CUPID (Chronic Urticarial Pruritus Itch Dupilumab Trial) 
Rationale: 
Chronic spontaneous urticaria (CSU), also referred to as chronic idiopathic urticaria (CIU), is 
a common condition characterized by the spontaneous appearance of itchy wheals (hives) with or 
without angioedema persisting for more than 6 weeks without a specific known cause. Chronic 
spontaneous urticaria patients with and without angioedema experience debilitating hives and 
pruritus secondary to mast cell and basophil dysregulation. Degranulation of these cell types by 
Fc gamma receptor (FcεRI) activation, through agonistic autoantibodies or cell surface-bound 
immunoglobulin E (IgE) cross-linked by antigen, release histamine and other pro-inflammatory 
mediators leading to local tissue edema and pruritus. Many symptoms of urticaria are mediated 
primarily by the actions of histamine (a mast cell mediator) on the H1-receptors, and treatment 
with H1-antihistamines (H1-AH) is a mainstay of therapy (1). Approximately 50% of patients 
achieve symptomatic control with conventional H1-AH therapy (2). Even with uptitration of 
antihistamines, approximately 40% to 50% of patients remain symptomatic. The mechanism by 
which omalizumab exerts its therapeutic effects is likely constrained to reduction in serum IgE 
and consequent down-regulation of IgE receptors. Targeting IgE by omalizumab has been 
successful in treating CSU patients but not all patients are equally responsive to this therapy (3). 
Therefore, there remains an unmet need. One possible way to meet this need is through novel 
therapies that target signaling pathways important for mast cell and basophil survival and 
function. Interleukin-4 (IL-4)/interleukin-13 (IL-13) signaling is required for antibody isotype 
switching to IgE production in B cells and contribute to mast cell and basophil survival and 
function (4, 5). Therefore, blockade of IL-4/IL-13 by dupilumab represents a novel therapeutic 
approach for CSU patients. In a small case series of patients who had concurrent atopic dermatitis 
(AD) and CSU and were resistant to omalizumab, treatment with dupilumab improved their 
urticaria. This further supports the rationale to target aberrant IL-4/IL-13 signaling with 
dupilumab in patients with CSU. As this is a novel therapy that acts further upstream than 
IgE-targeted therapies, the clinical trials proposed here will test the efficacy of dupilumab in 
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patients who have failed anti-histamines alone or who have failed both anti-histamines and 
omalizumab or who were intolerant to omalizumab.  
Dupilumab is a fully human monoclonal antibody (mAb) directed against the interleukin-4 
receptor alpha subunit (IL-4Rα), which is a component of interleukin (IL)-4 receptors Type I and 
Type II, the latter being also a receptor for IL-13. The binding of dupilumab to IL-4Rα results in 
blockade of both IL-4 and IL-13 signaling. As a targeted immunomodulatory agent, dupilumab 
selectively inhibits the Type 2 immune response, including T helper 2 (Th2) cells, which can 
potentially achieve the desired therapeutic effect without the side effects typically associated with 
the use of broad immunosuppressants. The Type 2/Th2 pathway is responsible for several 
pathophysiological mechanisms including inhibition of mast cell and basophil degranulation, and 
reduction of IgE serum levels and down-regulation of the Type 2 pathway may prevent or reverse 
the development of atopic diseases. Dupilumab has shown efficacy in multiple diseases with 
underlying Type 2 inflammation such as AD, asthma, chronic rhinosinusitis with nasal polyposis 
(CRSwNP), and eosinophilic esophagitis (EoE). In these clinical studies, treatment with 
dupilumab resulted in continuous decreases in blood total IgE. Moreover in CRSwNP, decrease in 
urinary leukotriene E4 (LTE4) and prostaglandin D2 metabolite (PGDM) suggest inhibition of 
mast cells activation and release of preformed mediators. 
LIBERTY-CSU CUPID Study A was completed, demonstrating the efficacy of dupilumab and an 
acceptable safety profile in participants with chronic spontaneous urticaria (CSU) who remain 
symptomatic despite the use of H1-AH treatment (6). LIBERTY-CSU CUPID Study B evaluating 
dupilumab in participants with CSU who are intolerant or incomplete responders to omalizumab, 
has completed recruitment. As prespecified in the study protocol, the Sponsor performed an 
interim analysis of study B. The outcome of this pre-specified interim analysis met the protocol 
efficacy statistical criteria for futility, with no new safety concerns identified (7). LIBERTY-CSU 
CUPID Study C will be conducted in the same study population as Study A and with a similar 
study design, to meet Health Authority requirements to provide data from two adequate and well-
controlled clinical trials to support filing of a marketing application.   
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To demonstrate the efficacy of 
dupilumab in study participants with 
CSU who remain symptomatic despite 
the use of H1-AH (Study A and 
Study C: omalizumab naïve; Study B: 
omalizumab intolerant or incomplete 
responders)  
• 
Change from baseline in weekly itch severity score (ISS7) at 
Week 24 (except EU and EU reference countries) 
• 
For EU and EU reference countries only: Change from baseline 
in weekly urticaria activity score (UAS7, composite patient 
reported itch and hive score) at Week 24 
Secondary 
• 
To demonstrate the efficacy of 
dupilumab on urticaria activity 
composite endpoint and itch or hives, 
separately, at various time points 
• 
Change from baseline in weekly urticaria activity score (UAS7) 
at Week 12a and Week 24b (except EU and EU reference 
countries) 
• 
Change from baseline in ISS7 at Week 12a and at Week 24b 
(in EU and EU reference countries) 
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Objectives 
Endpoints 
• 
Change from baseline in weekly hives severity score (HSS7) at 
Week 12 and Week 24 
• 
Time to ISS7 minimally important (MID) (ISS7 ≥5) response 
• 
Proportion of ISS7 MID (≥5 points) responders at Week 12a and 
Week 24a 
• 
Change from baseline in ISS7 at all time points (onset of action 
is assessed by the first p <0.05 that remains significant at 
subsequent measures until Week 24)  
• 
Proportion of patients with UAS7 ≤6 at Week 12a and Week 24a 
• 
Proportion of patients with UAS7 = 0 at Week 12a and Week 24a 
• 
To demonstrate the efficacy of 
dupilumab on angioedema 
• 
Change from baseline in angioedema activity score over 7 days 
(AAS7) at Week 12 and Week 24 
• 
To demonstrate the efficacy of 
dupilumab on urticaria control 
• 
Change from baseline in urticaria control test (UCT) at Week 12 
and Week 24 
• 
Proportion of well-controlled patients (UCT ≥12) at Week 12 and 
Week 24 
• 
To demonstrate improvement in health-
related quality-of-life and overall 
disease status and severity 
• 
Change from baseline in health-related quality-of-life (HRQoL) 
as measured by Dermatology Life Quality Index (DLQI) in 
patients ≥16 years old, and in Children’s Dermatology Life 
Quality Index (CDLQI) in patients ≥6 to <16 years old at 
Week 12 and Week 24 
• 
Patient Global Impression of Change (PGIC) of CSU at Week 12 
and Week 24 
• 
Change from baseline in Patient Global Impression of Severity 
(PGIS) of CSU at Week 12 and Week 24 
• 
To evaluate the ability of dupilumab in 
reducing the proportion of patients who 
require treatment with oral 
corticosteroids (OCS)  
• 
Time-to-event and proportion of patients receiving OCS for CSU 
during the planned treatment period 
• 
To evaluate safety outcome measures 
• 
Percentages of participants experiencing treatment-emergent 
adverse events (TEAEs) or serious adverse events (SAEs) 
• 
To evaluate immunogenicity of 
dupilumab 
• 
Incidence of treatment-emergent anti-drug antibodies (ADA) 
against dupilumab over time 
a Key secondary endpoint for Study A and Study B 
b Key secondary endpoint for Study C: UAS7 at Week 24 (except EU and EU reference countries, where ISS7 at Week 24 is 
key secondary endpoint) 
Overall design: 
The master protocol EFC16461 will be comprised of 3 studies of similar design, 2 studies in 
participants who are omalizumab naïve (Study A and Study C) and 1 study in participants who are 
intolerant or incomplete responders to omalizumab (Study B). Study A and Study C will include 
adults, adolescents (≥12 to <18 years) and children (≥6 to <12 years in some selected countries). 
Study B will include adults and adolescents. The three studies are 24-week, double-blind, 
randomized, placebo-controlled studies to evaluate the use of dupilumab in participants with CSU 
who remain symptomatic despite the use of H1-AH. The studies will assess the effect of 
dupilumab on the itch and hives scored separately once daily and averaged over 7 days and on the 
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itch and hives frequency/severity through the urticaria activity score (composite) averaged over 
7 days, on angioedema activity, urticaria control, and on patients’ health-related quality-of-life 
(HRQoL), and health status.  
Disclosure statement: Each Study A, B, and C is a Treatment study with 2 Parallel arms  that is 
blinded/masked for participants and Investigators. While these are double blind trials with regard 
to the treatment with either dupilumab or placebo, they are not blinded to weight-based dose 
levels, due to the different volume size (2 mL versus 1.14 mL) of the dose level of dupilumab 
(300 mg/matching placebo or 200 mg/matching placebo) that will be used for the different weight 
categories for adolescents and children ≥6 to <12 years of age. In addition, in children, the study 
is not blinded to dose regimen due to the different frequency of IMP administration (q4w versus 
q2w).  
Number of participants: 
The total anticipated number of participants across the 3 studies is approximately 384 randomized 
participants. 
For Study A, conducted in the omalizumab naïve population, approximately 130 participants will 
be randomized. This corresponds to approximately 65 participants who will be randomly assigned 
to each intervention arm. It is planned that approximately 5% of participants enrolled will be 
adolescents and up to approximately 5% of participants enrolled will be children ≥6 to <12 years 
of age (both children and adolescents recruited in some selected countries). The actual number of 
participants randomized in Study A was 138. 
For Study B, conducted in the omalizumab intolerant or incomplete responder population, 
approximately 104 participants were to be randomized. It was planned that approximately 5% of 
participants enrolled would be adolescents (recruited in some selected countries). The study 
recruitment ended, and the final number of participants randomized in Study B was 108. An 
interim analysis was performed when the first 83 randomized participants had completed their 
24-week treatment period, by the interim analysis cut-off date, and met futility criteria. The study 
treatment is being stopped for the participants still on study treatment and all participants should 
complete their follow up period.   
Omalizumab incomplete responders are defined as participants treated with at least 300 mg 
omalizumab every 4 weeks (q4w) for at least 3 months (minimum of 3 injections) and who have 
had an inadequate response resulting in omalizumab discontinuation, as confirmed by Investigator 
assessment. 
For Study C, to be conducted in the omalizumab naïve population, approximately 150 participants 
will be randomized. This corresponds to approximately 75 participants who will be randomly 
assigned to each intervention arm. It is planned that approximately 5% of participants enrolled 
will be adolescents and up to approximately 5% of participants enrolled will be children ≥6 to 
<12 years of age (both children and adolescents recruited in some selected countries).  In Study A, 
overall 52% of participants received H1-AH at recommended doses as background therapy, and 
45% of participants presented with angioedema at baseline. To maintain consistency between the 
study population in studies A and C, and reflect the real-life distribution of patients with 
angioedema and uncontrolled by both standard dose or maximal H1-AH therapy, it is planned that 
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Study C would include not more than approximately 50% of participants (n=75) having their  
H1-AH therapy at recommended doses (for more details please see Section 6.1.2), and not less 
than approximately 30% (n=45) but not more than approximately 45% (n=68) of participants 
presenting with angioedema at baseline. 
It is anticipated that approximately 30%-40% of enrolled participants will have angioedema.  
Intervention groups and duration: 
Patients who satisfy the inclusion and exclusion criteria will be randomized (1:1) to 1 of the 
following investigational medicinal product (IMP) treatment groups:  
• Dupilumab:  
- 
Adults: 300 mg every 2 weeks (q2w)  
- 
Adolescents: 200 mg q2w for adolescents <60 kg at screening or 300 mg q2w for 
adolescents ≥60 kg at screening  
- 
Study A and Study C (only): Children ≥6 to <12 years of age: 200 mg q2w for children 
≥30 kg at screening and 300 mg q4w for children <30 kg and ≥15 kg at screening  
• Matched placebo  
Duration of study period (per participant) 
• Screening period (2 to 4 weeks) 
• Randomized IMP treatment period (24 weeks) 
• Post IMP treatment period (12 weeks) 
Study interventions 
Investigational medicinal product:  
• Dupilumab 300 mg and placebo matching dupilumab 300 mg supplied in prefilled 
syringes that are visually indistinguishable 
• Dupilumab 200 mg and placebo matching dupilumab 200 mg supplied in prefilled 
syringes that are visually indistinguishable 
Dupilumab 
Formulation:  
• Dupilumab 300 mg: a 150 mg/mL dupilumab solution in a pre-filled syringe to deliver 
300 mg in a 2 mL injection or 
• Dupilumab 200 mg: a 175 mg/mL dupilumab solution in a pre-filled syringe to deliver 
200 mg in a 1.14 mL injection 
Route of administration: Subcutaneous (SC) injection 
Dose regimen:  
• 1 injection q2w/q4w after an initial loading dose (2 injections) on Day 1  
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Placebo:  
Formulation:  
• Placebo matching dupilumab 300 mg: identical formulation to the active 300 mg 
formulation without dupilumab, in a pre-filled syringe to deliver placebo in a 2 mL 
injection or 
• Placebo matching dupilumab 200 mg: identical formulation to the active 200 mg 
formulation without dupilumab, in a pre-filled syringe to deliver placebo in a 1.14 mL 
injection  
Route of administration: SC injection 
Dose regimen:  
• 1 injection q2w/q4w after an initial loading dose (2 injections) on Day 1  
Participants should continue their established standard of care background therapy with a 
long-acting non-sedating H1-AH, at up to 4-fold the recommended dose. If participants are 
on a dose higher than 4-fold the recommended dose at the screening visit (Visit 1), the 
Investigator can adjust the participant dose within the stipulated range at the screening 
visit (Visit 1). Participants should continue to take the same daily dose throughout the 
study unless they experience a flare for which rescue therapy may be initiated. Please refer 
to Section 6.5.1 for rescue therapy. The following list of H1-AH is allowed and noted with 
their recommended dose:  
• Cetirizine 10 mg once per day (qd). 
• Levocetirizine dihydrochloride 5 mg qd 
• Fexofenadine 60 mg twice per day or 180 mg qd 
• Loratadine 10 mg qd 
• Desloratadine 5 mg qd 
• Bilastine 20 mg qd 
• Rupatadine 10 mg qd 
• Other H1-AH after discussion with the Sponsor 
For other information related to H1-AH including safety precautions, please refer to the National 
Product labeling. 
Background therapy will be supplied by Sponsor’s local affiliate as locally required or by sites. 
Reimbursement will be provided when deemed necessary and as per country regulation. 
Post-trial access to study medication 
The Sponsor does not plan to provide post-trial access to the study medication. 
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Statistical considerations: 
Study A and Study C (omalizumab naïve); and Study B (omalizumab intolerant or incomplete 
responders) will all be analyzed separately and each tested at alpha level at 0.05. Integrated 
analyses may also be performed. 
• Sample size calculations 
For Study A (omalizumab naïve): An effect size of 0.7 or higher is assumed. An absolute 
change of 5 in ISS7 score is considered the minimal clinically important difference 
(MCID) and an absolute change of 10 in UAS7 score is considered the MCID. Based upon 
an SD of 7, a change of 5 in the ISS7 would correspond to an effect size of approximately 
0.7. Based upon an SD of 14, a change of 10 in the UAS7 would correspond to an effect 
size of approximately 0.7. Based on this assumption, plus the assumption of a 15% 
dropout rate and inclusion of children, it is estimated that 65 participants per group will 
provide 96% power to detect an effect size of 0.7 or higher between the dupilumab arm 
and placebo using a 2-sided t-test with alpha = 0.05. This sample size estimate applies to 
both ISS7 (primary endpoint for all countries except EU and EU reference countries) and 
UAS7 (primary endpoint for EU and EU reference countries). 
For Study B (omalizumab intolerant or incomplete responders): An effect size of 0.7 or 
higher is assumed. An absolute change of 5 in ISS7 score is considered the minimal 
clinically important difference (MCID) and an absolute change of 10 in UAS7 score is 
considered the MCID. Based upon an SD of 7, a change of 5 in the ISS7 would correspond 
to an effect size of approximately 0.7. Based upon an SD of 14, a change of 10 in the 
UAS7 would correspond to an effect size of approximately 0.7. Based on this assumption, 
plus the assumption of a 15% dropout rate, it is estimated that 52 participants per group 
will provide 90% power to detect an effect size of 0.7 or higher between the dupilumab 
arm and placebo using a 2-sided t-test with alpha = 0.05. This sample size estimate applies 
to both ISS7 (primary endpoint for all countries except EU and EU reference countries) 
and UAS7 (primary endpoint for EU and EU reference countries).  
Considering the reduced drop-out rate of 10% observed during the Study A, an interim 
analysis will be performed when the first 80 randomized participants would have 
completed their Week 24 visit by the interim analysis cut-off date. Using the  
O’Brien-Fleming approach with information fraction 0.77 and overall type-I error 
controlled at 0.05, the alpha spending at this interim analysis will be 0.021, and the alpha 
spending at the final analysis when all 104 participants complete the study will be 0.043. 
At the Study B interim analysis, it is estimated that 40 participants per group will provide 
74% power to detect a treatment effect of 5 or higher with SD 7 and minimal detectable 
difference (MDD) of approximately 3.8 for ISS7 and a treatment effect of 10 or higher 
with SD 14 and MDD of approximately 7.6 for UAS7 between the dupilumab arm and 
placebo using a 2-sided t-test with alpha = 0.021. 
With the decision process outlined in Section 9.5, the overall power for the study will be 
approximately 88%. 
For Study C (omalizumab naïve): An effect size of 0.564 or higher is assumed. Based 
upon an SD of 7.5 (pooled SD from the observed data in Study A), a treatment difference 
of 4.23 in the ISS7 would correspond to an effect size of approximately 0.564. Based upon 
an SD of 14.3 (pooled SD from the observed data in Study A), a treatment difference of 
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8.53 in the UAS7 would correspond to an effect size of approximately 0.597. Based on 
this assumption, plus the assumption of a 10% dropout rate, it is estimated that 
75 participants per group will provide 90% power to detect an effect size of 0.564 or 
higher between the dupilumab arm and placebo using a 2-sided t-test with alpha = 0.05. 
This sample size estimate applies to both ISS7 (primary endpoint for all countries except 
EU and EU reference countries) and UAS7 (primary endpoint for EU and EU reference 
countries). 
The sample size calculations and the alpha spending by O’Brien-Fleming approach were 
calculated by nQuery Advisor and nTerim 4.0. 
• Randomization 
Participants will be randomized into Study A (omalizumab naïve), Study B (omalizumab 
intolerant or incomplete responders), and Study C (omalizumab naïve) separately. For 
each study, patients will be randomized 1:1 to dupilumab or placebo. The randomization 
will be first stratified by age (adults versus adolescents versus children in Study A and 
Study C, adults versus adolescents in Study B; up to approximately 5% of total sample 
size for children and approximately 5% of total sample size for adolescents in Study A and 
Study C; up to approximately 5% of total sample size for adolescents in Study B). In 
adults, randomization will be stratified further by country (Study A, B and C) and presence 
of angioedema at baseline (Study C only). In adolescents/children ≥6 to <12 years of age, 
randomization will not be stratified further. In Study A, overall 52% of participants 
received H1-AH at recommended doses as background therapy, and 45% of participants 
presented with angioedema at baseline. To maintain consistency between the study 
population in studies A and C, and reflect the real-life distribution of patients with 
angioedema and uncontrolled by both standard dose or maximal H1-AH therapy, it is 
planned that Study C would include not more than approximately 50% (n=75) of 
participants having their H1-AH therapy at recommended doses (for more details please 
see Section 6.1.2), and not less than approximately 30% (n=45) but not more than 
approximately 45% (n=68) of participants presenting with angioedema at baseline.  
• Analysis population 
Within each study, the primary analysis population for the efficacy endpoints will be the 
randomized intent-to-treat population which includes all participants who have been 
allocated to a randomized treatment regardless of whether the treatment kit was used or 
not. The efficacy analyses will be conducted according to the treatment to which they were 
randomized. For Study B interim analysis, the primary analysis population will be the 
intent-to-treat24 (ITT24) population, defined as all participants who were randomized at 
least 24 weeks before the interim analysis cut-off date and would have completed the 
Week 24 visit by the cut-off date of interim analysis. 
Within each study, the analysis population for safety endpoints is defined as all 
randomized participants exposed to study medication, regardless of the amount of 
treatment administered. The safety analyses will be conducted according to the treatment 
participants actually received. 
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• Primary analysis 
The primary efficacy variable is change from baseline in ISS7 at Week 24 (except EU and 
EU reference countries).  
For EU and EU reference countries, the primary efficacy variable is change from baseline 
in UAS7 at Week 24. 
The following null hypothesis and alternative will be tested for dupilumab against placebo: 
- 
Null hypothesis H0: No treatment difference between dupilumab and placebo. 
- 
Alternative hypothesis H1: There is a treatment difference between dupilumab and 
placebo. 
The primary efficacy endpoint will be analyzed using a hybrid method of the 
worst-observation carried forward (WOCF) and multiple imputation. For participants 
taking selected prohibited medications and/or rescue medications (details of selection will 
be specified in the statistical analysis plan [SAP]), their data after the medication usage 
will be set to missing, and the worst postbaseline value on or before the time of the 
medication usage will be used to impute missing Week 24 value (for participants whose 
postbaseline values are all missing, the baseline will be used to impute). Participants who 
discontinue the treatment prematurely are encouraged to follow the planned clinical visits 
and in these participants, who did not take the selected prohibited medications and/or 
rescue medications, all data collected after treatment discontinuation will be used in the 
analysis. For these participants, missing data may still happen despite all efforts have been 
tried to collect the data after treatment discontinuation. For participants who discontinue 
due to lack of efficacy, all data collected after discontinuation will be used in the analysis, 
and a WOCF approach will be used to impute missing Week 24 value if needed. For 
participants who discontinue not due to lack of efficacy, a multiple imputation approach 
will be used to impute missing Week 24 value, and this multiple imputation will use all 
participants excluding participants who have taken the selected prohibited medications 
and/or rescue medications on or before Week 24 and excluding patients who discontinue 
due to lack of efficacy on or before Week 24. Each of the imputed complete data will be 
analyzed by fitting an analysis of covariance model with the baseline value of the primary 
endpoint, treatment group, presence of angioedema at baseline, and region (combined 
countries) as covariates. Statistical inference obtained from all imputed data will be 
combined using Rubin’s rule. 
• Analysis of secondary endpoints 
Continuous endpoints will be analyzed using the same approach as the primary efficacy 
variable. 
Responder endpoints will be analyzed using the Cochran-Mantel-Haenszel (CMH) test 
adjusted by baseline disease severity, presence of angioedema at baseline, and regions. 
The baseline disease severity will be defined according to UAS7 <28 or ≥28. Comparisons 
of the response rates between dupilumab dose and placebo will be derived. 
Participants who receive selected prohibited medications and/or rescue medications will be 
considered as non-responders for time points after medication usage. For other patients, all 
available data including those collected during the off-treatment period will be used to 
determine the responder/non-responder status. Missing data will be considered as 
non-responders. 
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Time-to-event endpoints will be analyzed using the Cox proportional hazards model, 
including treatment, the corresponding baseline value, presence of angioedema at baseline, 
and region as covariates. The estimates of the hazard ratio between dupilumab dose and 
placebo will be derived. 
The safety variables, including adverse events (AEs), laboratory parameters, vital signs, 
electrocardiogram (ECG), and physical examinations will be summarized using 
descriptive statistics. 
• Missing data handling 
The ISS7 score is the sum of the daily ISS scores over 7 days each week. When 1 or more 
of the daily ISS scores are missing, the following principles will be applied to handle the 
missing data:  
- 
Baseline ISS7 should not have missing daily ISS score which is guaranteed by the 
inclusion criteria (I 05).  
- 
For postbaseline ISS7, if a patient has at least 4 non-missing daily ISS scores within 
the 7 days of the calculated week, the ISS7 score is calculated as the sum of the 
available electronic diary (e-diary) ISS scores in the 7 days, divided by the number of 
days that have a non-missing diary ISS score, multiplied by 7.  
- 
For postbaseline ISS7, if there are less than 4 non-missing daily ISS scores within the 
7 days of the calculated week, then the ISS7 score is missing for the week.  
The same principle will be applied to handle the missing data for all of the weekly 
outcomes including UAS7 and HSS7. 
For participants discontinuing the treatment before Week 24, off study-treatment values 
measured up to Week 24 will be included in the analysis. For participants taking selected 
prohibited medications and/or rescue medications, their data after the medication usage 
will be set to missing. For continuous endpoints, missing data will be imputed by the 
hybrid method of WOCF and multiple imputation as described above. For binary 
endpoints, missing data will be considered as non-responder. 
In addition to the missing data handling approaches specified above, the reason and pattern 
of missing data will be carefully examined and tipping point analyses and additional 
sensitivity analyses will be performed. 
• Multiplicity considerations 
Within each study, Study A and Study C (omalizumab naïve), and Study B (omalizumab 
intolerant or incomplete responders), the multiplicity procedure is proposed to control the 
overall Type-I error rate for testing the primary endpoint and the key secondary endpoints. 
Detailed hierarchical testing procedure will be defined in the study SAP.  
Study A and Study C are each considered positive when the primary endpoint achieves 
statistical significance with 2-sided significance level 0.05. 
At the interim analysis, the study B is considered positive when the primary endpoint 
achieves statistical significance using 2-sided significance level 0.021. If Study B meets 
the criteria to continue at the interim analysis, at the final analysis of Study B, it will be 
considered positive when the primary endpoint achieves statistical significance using  
2-sided significance level 0.043. 
Multiplicity adjustment for the other efficacy endpoints will be described in the study 
SAP. 
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• Planned database lock date/interim analysis 
The database locks will be implemented separately for Study A (omalizumab naïve), 
Study B (omalizumab intolerant or incomplete responders), and Study C (omalizumab 
naïve). 
Study A and Study C:  
A primary database lock for each study will be performed when all randomized 
participants have completed their 24-week treatment phase. 
The database for each study will be updated at the end of the study for all participants to 
include the post-treatment follow-up information and updates for the events previously 
ongoing at the time of the primary lock. 
Study B 
An interim analysis was performed for Study B when the defined ITT24 population data 
were available. The final database lock for study B will occur at the end of the study for all 
participants.  
• Unblinding plan 
The detailed unblinding plan for the 3 studies, Study A and Study C (omalizumab naïve) 
and Study B (omalizumab intolerant or incomplete responders), will be included in the 
SAP or in a separate document. 
Data Monitoring Committee: No 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
Abbreviations: EOS = End of study; EOT = End of treatment; R = randomization; SC = subcutaneous; Q2W = every 2 weeks; Q4W = every 4 weeks 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
 
Procedures 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period 
(Weeks) 
Follow-up 
(12 weeks) 
Notes 
 
0 (Day 1) 
12 
24 
36 
Visit window: ±3 days for Visits 3, 4, and 5 
Visit 
1 
2a 
3 
4 (EOT)b 
5 (EOS) 
 
Screening/baseline: 
Informed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Prior and concomitant medication 
X 
X 
X 
X 
X 
Concomitant medication including rescue OCS taken since last visit 
will be collected throughout the study  
Demographics 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Patient e-diary training 
X 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Study intervention 
Call IVRS/IWRS 
X 
X 
X 
X 
X 
 
IMP administration 
 
Xc 
 
IMP will be administered every other week except (for study A and 
study C) for children <30 kg and ≥15 kg where it will be administered 
every 4 weeks. The planned last dose is at Week 22 except (for 
study A and study C) for children <30 kg and ≥15 kg where it will be 
administered at Week 20. Participants (or their care givers) are 
allowed to perform IMP injections at home. 
Dispense/Upload electronic diaryd 
X 
X 
Device is dispensed at Screening (including instructions for use). At 
the EOS, the e-diary is returned to the site. 
Safetye 
Physical examinationf 
X 
X 
 
X 
X 
 
Vital signsg 
X 
X 
X 
X 
X 
 
Electrocardiogram (12 lead)  
X 
 
 
X 
 
ECG to be locally collected and read 
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Procedures 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period 
(Weeks) 
Follow-up 
(12 weeks) 
Notes 
 
0 (Day 1) 
12 
24 
36 
Visit window: ±3 days for Visits 3, 4, and 5 
Visit 
1 
2a 
3 
4 (EOT)b 
5 (EOS) 
 
Hematology, biochemistry, urine analysish 
X 
X 
X 
X 
X 
 
Hepatitis, HIV Serology, TB testi 
X 
 
 
 
 
 
Pregnancy testj 
Serum 
Ur 
Ur 
Ur 
Ur 
In between visit urine pregnancy tests must be performed at home 
(Weeks 4, 8, 16, 20, 28, and 32) 
AE reporting, including SAEs 
X 
X 
X 
X 
X 
 
Pharmacokinetics and ADAe 
Serum PK samples for dupilumab 
concentrationk 
 
X 
X 
X 
X 
 
Anti-dupilumab antibodyk 
 
X 
X 
X 
X 
 
Biomarkerse 
Serum total IgE 
 
X 
X 
X 
X 
 
Basophil activation test  
(optional sub-study)  
 
X 
X 
X 
 
For participants (except pediatric participants in Studies A and B and 
all Study C participants) who decide to participate and provide 
consent for the optional basophil activation test. 
Skin biopsy (optional sub-study)  
 
X 
 
X 
 
For participants (except pediatric participants) who decide to 
participate and provide consent for the optional skin biopsy. Two 
biopsies will be taken from each participant, 1 from lesion and 1 from 
non-lesion. 
Archive serum and plasma samples 
(optional)  
 
X 
X 
X 
X 
For participants (except pediatric participants) who decide to 
participate and consent for the optional archive serum and plasma 
sample. Archive serum and plasma samples (optional) are collected 
for future analysis of potential biomarkers of drug response, disease 
activity, safety and the Type 2 inflammation pathway. 
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Procedures 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period 
(Weeks) 
Follow-up 
(12 weeks) 
Notes 
 
0 (Day 1) 
12 
24 
36 
Visit window: ±3 days for Visits 3, 4, and 5 
Visit 
1 
2a 
3 
4 (EOT)b 
5 (EOS) 
 
DNA  
(whole blood) samples - Optional  
 
X 
 
 
 
For participants (except pediatric participants) who decide to 
participate and provide consent for the optional genomics sub-study 
(DNA sample collection). The DNA sample should be collected at the 
Day 1 visit, but can be collected at any visit during the study. 
RNA  
(whole blood) samples - Optional 
 
X 
 
X 
 
For participants (except pediatric participants) who decide to 
participate and provide consent for the optional genomics sub-study 
(RNA sample collection). The RNA sample must be collected before 
the administration of the first dose of study drug and at Week 24 
before the administration of study drug 
Efficacyd, e 
UAS7 
UAS7 (includes ISS7 and HSS7 as components), once daily from 
screening to EOS 
To be recorded in e-diary on the same time of the day 
AAS7 
AAS7, once daily from screening to EOS 
To be recorded in e-diary on the same time of the day 
UCT  
 
X 
X 
X 
X 
 
DLQI/CDLQI  
 
X 
X 
X 
X 
 
CU-Q2oL  
 
X 
X 
X 
X 
 
PGIC 
 
 
X 
X 
 
 
PGIS 
X 
X 
X 
X 
 
 
EQ-5D-5L/EQ-5D-Y 
 
X 
X 
X 
X 
 
Missed school/work daysl 
 
X 
X 
X 
X 
 
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Procedures 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period 
(Weeks) 
Follow-up 
(12 weeks) 
Notes 
 
0 (Day 1) 
12 
24 
36 
Visit window: ±3 days for Visits 3, 4, and 5 
Visit 
1 
2a 
3 
4 (EOT)b 
5 (EOS) 
 
Photographs CSU representative area for 
commercial activities (at selected sites in 
selected countries)  
 
X 
X 
X 
X 
For participants (except pediatric participants in Studies A and B and 
all Study C participants) who decide to participate and provide 
consent for the photography, photographs will be taken of a 
representative area of CSU involvement for commercial activities. 
Instructions for taking the photographs are provided in the 
photography reference manual. 
Abbreviations: AAS7 = angioedema activity score over 7 days; ADA = anti-drug antibodies; AE = adverse events; CDLQI = children’s dermatology life quality index; CU-Q2oL = chronic urticaria quality of life 
questionnaire; DLQI = dermatology life quality index; DNA = deoxyribonucleic acid; ECG = electrocardiogram; eCRF = electronic Case Report Form; EOS = End of study; EOT = End of treatment; EQ-5D 5L = 5-level 
EuroQol 5-dimensional questionnaire; EQ-5D-Y = EuroQol 5-dimensional questionnaire youth; HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B surface antibody; HCV Ab = hepatitis C virus antibodies; 
HIV = Human Immunodeficiency Virus; HSS7 = hives severity score over 7 days; IgE = immunoglobulin E; IMP = investigational medicinal product; ISS7 = weekly itch severity score; IVRS = interactive voice response 
system; IWRS = interactive web response system; OCS = oral corticosteroids; PGIC = patient global impression of change; PGIS = patient global impression of severity; PK = pharmacokinetic; q2w = every 2 weeks; 
RNA = ribonucleic acid; SAE = serious adverse event; SC = subcutaneous; TB = tuberculosis; UAS7 = urticaria activity score over 7 days; UCT = urticaria control test; Ur = urine.  
a Randomization/baseline Visit is defined as Day 1. All assessments at Visit 2 (Day 1) are to be conducted pre-IMP dose with the exception of the assessment of local tolerability of subcutaneous (SC) injections. 
b Participants who discontinue the study treatment prematurely (prior to completing the 24--week treatment period) will perform the EOT assessments at the time of discontinuation to assure a complete clinical 
assessment in close temporal proximity to the premature termination of study treatment In addition, to allow assessment of participant outcomes over the stipulated study period, participants will be asked and 
encouraged to complete all remaining study visits and participate in all assessments according to the visit schedule. 
c Loading dose on Day 1 of 600 mg (2 SC injections of 300 mg) followed by 300 mg every 2 weeks (q2w) regimen for adults and adolescents ≥60 kg OR 400 mg (2 SC injections of 200 mg) followed by 200 mg q2w 
for adolescents <60 kg and children ≥30 kg (Study A and Study C) OR 600 mg (2 SC injections of 300 mg) followed by 300 mg q4w for children <30 kg and ≥15 kg (Study A and Study C) OR matched placebo. 
d Electronic diary is used for daily recording of patient’s answers to the urticaria activity score over 7 days (UAS7) and angioedema activity score over 7 days (AAS7) questionnaires as well as antihistamines 
medication use for the duration of the study. This device is dispensed at screening visit (Visit 1), including instructions for use. Electronic devices will be returned to the Sponsor after end of study (EOS). For 
urticaria control test (UCT), dermatology life quality index (DLQI [>16 years old]) /children’s dermatology life quality index (CDLQI [≥6 to <16 years old]), chronic urticaria quality of life questionnaire (CU-Q2oL), 
5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L [>16 years old]) /EuroQol 5-dimensional questionnaire youth (EQ-5D-Y [≥6 to <16 years old]), patient global impression of change (PGIC), patient global 
impression of severity (PGIS), and missed school/work days questionnaires, the participant will fill in the questionnaires during their site visit on a tablet that will be provided to the site.  
e Assessments/procedures should be conducted in the following order: participant-reported outcomes (other than participant assessment of injection pain), Investigator assessments, safety and laboratory 
assessments (including sample collection for anti-drug antibodies (ADA), pharmacokinetic (PK), biomarker, and optional DNA and RNA), and administration of study drug.  
f 
Physical examinations will include skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
g Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), axillary or oral temperature (same method of temperature measurement should be used during the course of the 
study) (°C), and respiratory rate will be measured at every visit in a semi-supine or sitting position after 5 minutes rest. Height (cm) will be measured at screening visit (Visit 1) only. Body weight (kg) will be 
measured at screening visit (Visit 1) and at end of treatment (EOT)/EOS Visits. 
h Hematology will include hemoglobin, hematocrit, platelet count, total white blood cell count, differential count, and total red blood cell count. Serum chemistry will include creatinine, blood urea nitrogen, glucose, 
lactate dehydrogenase, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), 
bicarbonate, and creatine phosphokinase. Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen and bilirubin. In case the urine dipstick test result is 
abnormal, a urine sample should be sent into the central laboratory for microscopic and macroscopic examination. 
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i 
Clinical laboratory testing at screening visit ( Visit 1) will include hepatitis screen covering hepatitis B surface antigen (HBs Ag), hepatitis B surface antibody (HBs Ab), hepatitis B core antibody (HBc Ab), hepatitis 
C virus antibodies (HCV Ab), Human Immunodeficiency Virus (HIV) screen (Anti-HIV-1 and HIV-2 antibodies). In case of results showing HBs Ag (negative) and HBc Ab (positive), an HBV DNA testing will be 
performed and should be confirmed negative prior to randomization. In case of results showing HCV Ab (positive), an HCV RNA testing will be performed and should be confirmed negative prior to randomization. 
TB test will be performed locally if required and results noted in the eCRF. 
j 
Only for women of childbearing potential. Pregnancy will lead to definitive treatment discontinuation in all cases. Pregnancy testing should be done monthly, female participants will be supplied with dipsticks for 
months with no site visits planned. In female participants who discontinue the study intervention, the pregnancy testing should continue for a minimum of 12 weeks after the last dose of study intervention. 
k In the event of any SAE, any AE of severe injection site reaction lasting longer than 24 hours, or any AESI of anaphylactic reaction or systemic allergic reaction that is related to IMP and require treatment, PK and 
ADA samples will be collected at or near the onset of the event for any additional analysis if required or for archival purposes.  
l 
Baseline version to be administered at Baseline; post-Baseline version to be administered at the subsequent visits. 
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2 
INTRODUCTION  
Chronic spontaneous urticaria (CSU) is a common condition characterized by the spontaneous 
appearance of itchy wheals (hives) with or without angioedema persisting for more than 6 weeks 
without a specific known cause. Note that, CSU can also be referred to as chronic idiopathic 
urticaria (CIU). The underlying pathologic mechanism, while not well understood, is thought to 
be driven by mast cell activation and degranulation. Many symptoms of urticaria are mediated 
primarily by the actions of histamine (a mast cell mediator) on the H1-receptors, and treatment 
with H1-antihistamines (H1-AH) is a mainstay of therapy (1). Approximately 50% of patients 
achieve symptomatic control with conventional H1-AH therapy, defined as reduction of hives and 
itch to such an extent that UAS7 <6 (2). Some patients may remain symptomatic despite ongoing 
H1-antihistamine treatment. Omalizumab, a monoclonal anti-immunoglobulin E (IgE) antibody, 
has been approved for treatment for this group of patients. However, approximately a third of the 
patients, are not well-controlled by Week 12 following treatment with omalizumab, defined as 
persistent hives and itch, clinically validated as UAS7 >6 (3). 
Dupilumab is a fully human monoclonal antibody (mAb) directed against the interleukin-4 
receptor alpha (IL-4Rαs, which is a component of IL-4 receptors Type I and Type II, the latter 
being also a receptor for IL-13. The binding of dupilumab to IL-4Rα results in blockade of both 
IL-4 and IL-13 signaling. As a targeted immunomodulatory agent, dupilumab selectively inhibits 
the Type 2 immune response, including T helper 2 (Th2) cells, which can potentially achieve the 
desired therapeutic effect without the side effects typically associated with the use of broad 
immunosuppressants. The Type 2/Th2 pathway is responsible for several pathophysiological 
mechanisms including inhibition of mast cell and basophil degranulation, and reduction of IgE 
serum levels and down-regulation of the Type 2 pathway may prevent or reverse the development 
of atopic diseases. Dupilumab has shown efficacy in multiple diseases with underlying Type 2 
inflammation such as AD, asthma, CRSwNP, and EoE. In these clinical studies, treatment with 
dupilumab resulted in continuous decreases in blood total IgE. Moreover in CRSwNP, decrease in 
urinary LTE4 and PGDM suggest inhibition of mast cells activation and release of preformed 
mediators. 
2.1 
STUDY RATIONALE  
Chronic spontaneous urticaria (CSU) patients with and without angioedema experience 
debilitating hives and pruritus secondary to mast cell and basophil dysregulation. Degranulation 
of these cell types by Fc gamma receptor (FcεRI) activation, through agonistic autoantibodies or 
cell surface-bound IgE cross-linked by antigen, release histamine and other pro-inflammatory 
mediators leading to local tissue edema and pruritus. While antihistamines are the mainstay of 
therapy, not all patients are controlled with antihistamines alone. Targeting IgE by omalizumab 
has been successful in treating CSU patients but not all patients are adequately responsive to this 
therapy. Therefore, there remains an unmet need. One possible way to meet this need is through 
novel therapies that target signaling pathways important for mast cell and basophil survival and 
function. Interleukin-4/IL-13 signaling is required for antibody isotype switching to IgE 
production in B cells and contributes to mast cell survival and function (4, 5). Therefore, blockade 
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of IL-4/IL-13 by dupilumab represents a novel therapeutic approach for CSU patients. In a small 
case series of patients who had concurrent AD and CSU and were resistant to omalizumab, 
treatment with dupilumab improved their urticaria. This further supports the rationale to target 
aberrant IL-4/IL-13 signaling with dupilumab in patients with CSU. As this is a novel therapy that 
acts further upstream than IgE-targeted therapies, the clinical trials proposed here will test the 
efficacy of dupilumab in patients who have failed anti-histamines alone or who have failed 
both anti-histamines and omalizumab. Efficacy in patients who were intolerant to omalizumab 
will also be assessed. The master protocol EFC16461 will include 3 studies in CSU patients who 
remain symptomatic despite the use of H1-AH treatment - 2 studies will be in patients who are 
omalizumab naïve (Study A and Study C) and the third study in patients who are intolerant or 
incomplete responders to omalizumab (Study B). The selected dosing regimen is dupilumab 
300 mg every 2 weeks (q2w) with a loading dose of 600 mg for adults; 300 mg q2w with a 
loading dose of 600 mg for adolescents >60 kg at screening OR 200 mg q2w with a loading dose 
of 400 mg for adolescents <60 kg at screening; and 200 mg q2w with a loading dose of 400 mg 
for children ≥6 to<12 years of age with weight ≥30 kg at screening OR 300 mg q4w with a 
loading dose of 600 mg for children ≥6 to <12 years of age with weight <30 kg and ≥15 kg at 
screening. This dose is expected to achieve concentrations in serum that saturate the IL-4/IL-13 
receptor and hence it is expected to provide the maximum benefit and therefore to achieve the 
optimal benefit/risk ratio in this patient population. 
LIBERTY-CSU CUPID Study A was completed and demonstrated that dupilumab at the above-
mentioned dosing regimen is efficacious versus placebo in participants with CSU who remain 
symptomatic despite the use of H1 antihistamine (H1-AH) treatment (6). The trial included a total 
of 138 participants (132 adults, 4 adolescents and 2 children), with 68 participants in the placebo 
group and 70 participants in the dupilumab group.  
At the end of the 24-week treatment period, dupilumab demonstrated clinically meaningful and 
statistically significant improvement versus placebo, across the key components of CSU. These 
components include itch, as measured by the primary endpoint Itch Severity Score over 7 days 
(ISS7, range 0-21) at week 24, and overall urticaria activity, as measured by the key secondary 
composite endpoint of Urticaria Activity Score over 7 days (UAS7, range 0-42) at week 24.  For 
ISS7, which was the primary endpoint, the least squares mean change from baseline was -6 for 
placebo and -10.2 for dupilumab (p <0.001), demonstrating that dupilumab treatment led to a 
statistically significant reduction in itch compared to placebo among participants with CSU. 
Similarly, for UAS7, the least squares mean change from baseline was -12 for placebo and  
-20.5 for dupilumab (p<0.001), demonstrating that dupilumab treatment also led to a statistically 
significant reduction in urticaria activity compared to placebo among patients with CSU. 
Details are provided in Table 1 below. 
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Table 1 - Summary of the primary endpoints in Study A - ITT population  
Parameter 
Placeboa 
(N=68) 
Dupilumaba 
(N=70) 
Difference (95% CI)b 
for Dupilumab vs. 
Placebo 
P-value 
  
Primary endpoint for US and US ref. countries (key 
secondary endpoint for EU and EU ref countries)  
 
 
 
  
Change from baseline in ISS7 at Week 24 
-6.01 (0.94) 
-10.24 (0.91) 
-4.23 (-6.63, -1.84) 
0.0005  
Primary endpoint for EU and EU ref. countries (key 
secondary endpoint for US and US ref countries)  
 
 
 
  
Change from baseline in UAS7 at Week 24 
-12.00 (1.81) 
-20.53 (1.76) 
-8.53 (-13.16, -3.90) 
0.0003  
a Values presented are LS mean change from baseline  
b Difference is LS mean difference  
In regard to the safety endpoints, overall treatment-emergent adverse events reported in at least 
5% of participants in any treatment group were comparable for placebo and dupilumab. A total of 
58.8% of participants in the placebo group experienced any treatment-emergent adverse event, 
whereas 54.3% of participants in the dupilumab group experienced any treatment-emergent 
adverse event. Among the reported treatment-emergent adverse events, skin and subcutaneous 
tissue disorders were reported in 26.5% of participants in the placebo group and 14.3% of 
participants in the dupilumab group. These disorders included CSU in 8.8% of participants in the 
placebo group and 4.3% of participants in the dupilumab group. Additionally, 5 participants 
(7.4%) of the placebo group versus 1 participant (1.4%) of the dupilumab group experienced 
angioedema. The trial demonstrated safety results similar to the known safety profile of 
dupilumab in its approved indications. 
Overall, in Study A dupilumab demonstrated clinically and statistically significant efficacy in 
patients with CSU who remain symptomatic despite the use of H1-AH treatment, as demonstrated 
by significantly reduced itch and hive severity and urticaria activity compared with standard of 
care H1-antihistamines alone. Dupilumab was well tolerated and demonstrated an acceptable 
safety profile in patients with CSU. 
LIBERTY-CSU CUPID Study B evaluating dupilumab in participants with CSU who are 
intolerant or incomplete responders to omalizumab, has completed recruitment. Per protocol, a 
prespecified interim analysis for study B was performed. The outcome of this pre-specified 
interim analysis met the protocol efficacy statistical criteria for futility, with no new safety 
concerns identified. In Study B, the study treatment is being stopped for the participants still on 
study treatment. All participants should complete their follow up period.   
Based on the positive results observed in the Study A in patients with CSU uncontrolled by 
antihistamine treatment, another study, LIBERTY-CSU CUPID Study C, will be conducted in the 
same population as Study A with a similar design to meet the Health Authority requirements to 
provide data from two adequate and well-controlled clinical trials to support filing of a marketing 
application.  
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2.2 
BACKGROUND  
Chronic spontaneous urticaria, formerly also known as chronic idiopathic urticaria and chronic 
urticaria, is 1 of the most frequent skin diseases. At any time, 0.5% to 1% of the population 
suffers from the disease (8). It is characterized by the spontaneous appearance of pruritic wheals 
(hives) and flare-type skin reactions persisting for more than 6 weeks without a specific known 
cause, which may be accompanied by angioedema. Although all age groups can be affected, the 
peak incidence is seen between 20 and 40 years of age. The duration of the disease is generally 
several years but is likely to be longer in more severe cases, cases with concurrent angioedema, in 
combination with physical urticaria or with a positive autologous serum skin test (auto-reactivity). 
Chronic spontaneous urticaria has major detrimental effects on quality-of-life, with sleep 
deprivation and psychiatric comorbidity being frequent. It also has a large impact on society in 
terms of direct and indirect health care costs as well as reduced performance at work and in 
private life (8). 
In many patients, an underlying cause of CSU cannot be identified although release of histamine 
in the skin remains a common end-effector leading tot hives and angioedema. Therefore, the 
current treatment guidelines for the management of CSU recommend the use of non-sedating oral 
H1-AH as first-line therapy (9). In more than 50% of the patients, symptoms persist with standard 
dosing of antihistamines (8). Currently the only licensed treatment in antihistamine-refractory 
patients with CSU is omalizumab, a monoclonal anti-IgE antibody. In 2014, omalizumab was 
licensed for add-on therapy in CSU patients who still have symptoms despite standard-dosed 
antihistamine treatment (9). Omalizumab is highly effective in a large proportion of these patients 
(3, 10) and some patients with inducible urticaria (10). There is, however, still a great medical 
need for additional treatment options as 20% to 40% of patients are still without effective therapy. 
In all 3 studies (A, B, and C), the target population consists of CSU patients who remain 
symptomatic despite treatment with H1-AH alone as these patients have a significant unmet 
medical need. The updated international guideline on the definition, classification, diagnosis and 
management of urticaria (1) provides evidence-based recommendations and a treatment 
algorithm. Steps 1 and 2 of this algorithm is the use of non-sedating H1-AHs at approved, or 
increased doses (up to 4-fold), respectively. Step 3 treatment options are omalizumab, ciclosporin 
A, or montelukast (LTRA). This master protocol allows the use of H1-AH at up to 4-fold the 
approved doses as background medication (Steps 1 and 2). 
2.3 
BENEFIT/RISK ASSESSMENT  
Dupilumab has shown clinically relevant benefit in several Type 2-driven inflammatory disorders 
such as AD, asthma, and CRSwNP. A satisfactory safety profile has been observed so far in 
completed and currently ongoing studies in several other Type 2-mediated indications. 
In asthma and AD indications, studies were also conducted in adolescents and similar efficacy as 
seen in adults has been observed. Data also showed similar efficacy, safety and PK between adult 
and adolescents. For AD and asthma, studies in pediatric participants (≥6 years and <12 years old) 
showed a similar efficacy, safety and PK profile compared with adults. Dupilumab was well 
tolerated in pediatric patients (ie, 6 to <18 years of age) with moderate to severe AD and with 
moderate-to-severe asthma. 
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Dupixent® (dupilumab) is authorized for marketing in over 60 countries worldwide including the 
US, European Union (EU) (Centralized Procedure), Japan, China, Canada, and Australia for the 
adult AD indication. Dupilumab is also authorized in the US, EU, and other jurisdictions for the 
pediatric (6 to <18 years of age) AD indications. Dupilumab is authorized for the asthma 
indication for the adult and pediatric patients (6 to <18 years of age) in the US and for adults and 
adolescents in the EU, Japan, and other jurisdictions. Dupilumab has also been approved for the 
CRSwNP indication in the US, EU, Japan, and other jurisdictions. 
Interleukin-4 is essential for the function/survival of several cell types important in the 
pathogenesis of urticaria, including B-cells, Th2 cells, mast cells, and basophils (4, 5, 11, 12, 13, 
14). Unlike omalizumab, which specifically binds and inhibits IgE only, it is hypothesized that 
dupilumab will be effective in reducing itch and hives frequency/severity individual scores and 
composite, and improve angioedema and urticaria control as well as quality of life, in adults, 
adolescents, and children with CSU. Clinically validated measures, including the UAS7 score 
(which measures hive and itch severity over a 7-day period), its components consisting of the 
ISS7 (which measures itch severity over a 7-day period) and HSS7 (which measures hives 
severity over a 7-day period), the AAS7 (which measures the angioedema severity over a 7-day 
period, as well as health-related quality-of-life assessments will be assessed over a 24-week 
period (see details in Section 3.1). Supporting the mechanistic rationale for dupilumab’s potential 
effectiveness in CSU as described in Section 2.1, dupilumab improved the hives and itch 
severity/frequency in a case series of 6 patients with CSU (4). An Investigator-initiated trial, 
currently ongoing, and this sponsor master protocol are the first 2 protocols studying dupilumab in 
patients with CSU to evaluate this hypothesis. 
No tissue targets or specific hazards to humans were identified in nonclinical general and 
reproductive toxicology studies. 
Dupilumab has an extensive safety database. As of 28 September 2021 (DLP), 13 062 participants 
were enrolled into the development program for dupilumab and were included in the safety 
population: 564 as healthy volunteers, 5011 from AD studies, 4091 from asthma studies, 782 from 
CRSwNP studies, 428 from EoE studies, 103 from the grass allergy study, 173 from peanut 
allergy studies, 1214 from the chronic obstructive pulmonary disease (COPD) studies, 309 from 
prurigo nodularis (PN) studies, and 235 from CSU studies, 30 from the chronic inducible cold 
urticaria (CICU) study, 16 from the chronic rhinosinusitis without nasal polyposis (CRSsNP) 
study, 34 from the bullous pemphigoid (BP) study, 22 from the allergic bronchopulmonary 
aspergillosis (ABPA) study, 42 from atopic hands and foot dermatitis (HFE) study, and eight from 
allergic fungal rhinosinusitis (AFRS) study. The number of participants exposed to dupilumab in 
clinical studies was 10 565 (538 in healthy volunteer studies, 4519 in AD studies, 3530 in asthma 
studies, 470 in CRSwNP studies, 378 in EoE studies, 52 in the grass allergy study, 124 in peanut 
allergy studies, 607 in COPD studies, 155 in PN studies, and 118 in the CSU studies, 15 in the 
CICU study, 8 in the CRSsNP study, 16 in the BP study, 10 in the ABPA study, 20 in the HFE 
study and 4 in the AFRS study. 
Based on the sales figure retrieved from Margin Consolidated (MARCO) application and using 
the World Health Organization’s defined daily dose for dupilumab of 21.4 mg/day, the cumulative 
post marketing exposure to dupilumab is estimated to be 522 786 patient years (01 January 2017 
through 30 September 2021).  
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Dupilumab was generally well tolerated in all populations tested in clinical development 
programs. The adverse drug reactions (ADRs) identified to date for dupilumab include injection 
site reactions, conjunctivitis, oral herpes, conjunctivitis allergic, conjunctivitis bacterial, herpes 
simplex, blepharitis, dry eye, eye pruritus, eosinophilia, and serum sickness. These ADRs were 
generally mild or moderate, transient, and manageable. These ADRs were not consistently 
observed in all indications (see Investigator’s Brochure [IB] for greater details). More significant 
serious allergic reactions were very rare. Importantly, no increased overall infection risk was 
observed in patients treated with dupilumab. 
Systemic hypersensitivity has been established as an important identified risk with dupilumab. As 
protein therapeutics, all monoclonal antibodies 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 program and anaphylaxis related to 
dupilumab in the adult asthma clinical trials. Other potential risks based on the safety profile in 
particular indications are discussed in the IB. It is anticipated that dupilumab in patients with CSU 
will have a favorable safety profile as observed across other type 2-driven immunological 
disorders. 
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 
Type 2 indications (AD, asthma, and CRSwNP) and a case series in CSU so far, support 
a favorable benefit-risk profile for dupilumab. Moreover, as described in Section 2.1 (Study 
Rationale), LIBERTY-CSU CUPID Study A safety results demonstrated that dupilumab was well 
tolerated and demonstrated an acceptable safety profile in patients with CSU who remain 
symptomatic despite the use of H1 antihistamine (H1-AH) treatment. In Study A, a total of 58.8% 
of participants in the placebo group experienced any treatment-emergent adverse event, whereas 
54.3% of participants in the dupilumab group experienced any treatment-emergent adverse event. 
Treatment-emergent adverse events reported in at least 5% of participants in any treatment group 
were comparable for placebo and dupilumab. Among the reported treatment-emergent adverse 
events, skin and subcutaneous tissue disorders were reported in 26.5% of participants in the 
placebo group and 14.3% of participants in the dupilumab group. These disorders included CSU 
in 8.8% of participants in the placebo group and 4.3% of participants in the dupilumab group. 
Additionally, 5 participants (7.4%) of the placebo group versus 1 participant (1.4%) of the 
dupilumab group experienced angioedema. The trial demonstrated safety results similar to the 
known safety profile of dupilumab in its approved indications. 
In addition, no new safety signal was identified in the LIBERTY-CSU CUPID Study B in 
participants with CSU who are intolerant or incomplete responders to omalizumab at the cut-off 
date for the pre-specified interim analysis.  
A risk-benefit statement with respect to the overall development program is provided in the IB.  
The rationale for the study design and justification for doses are detailed in Section 4.2 and 
Section 4.3, respectively. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To demonstrate the efficacy of dupilumab 
in study participants with CSU who 
remain symptomatic despite the use of 
H1-AH (Study A and 
Study C: omalizumab naïve; Study B: 
omalizumab intolerant or incomplete 
responders)  
• 
Change from baseline in weekly itch severity score (ISS7) at 
Week 24 (except EU and EU reference countries) 
• 
For EU and EU reference countries only: Change from baseline 
in weekly urticaria activity score (UAS7, composite patient 
reported itch and hive score) at Week 24 
Secondary 
• 
To demonstrate the efficacy of dupilumab 
on urticaria activity composite endpoint 
and itch or hives, separately, at various 
time points 
• 
Change from baseline in weekly urticaria activity score (UAS7) 
at Week 12a and Week 24b (except EU and EU reference 
countries) 
• 
Change from baseline in ISS7 at Week 12a and at Week 24b 
(in EU and EU reference countries) 
• 
Change from baseline in weekly hives severity score (HSS7) at 
Week 12 and Week 24 
• 
Time to ISS7 minimally important (MID) (ISS7 ≥5) response 
• 
Proportion of ISS7 MID (≥5 points) responders at Week 12a and 
Week 24a 
• 
Change from baseline in ISS7 at all time points (onset of action 
is assessed by the first p <0.05 that remains significant at 
subsequent measures until Week 24)  
• 
Proportion of patients with UAS7 ≤6 at Week 12a and Week 24a 
• 
Proportion of patients with UAS7 = 0 at Week 12a and Week 24a 
• 
To demonstrate the efficacy of dupilumab 
on angioedema 
• 
Change from baseline in angioedema activity score over 7 days 
(AAS7) at Week 12 and Week 24 
• 
To demonstrate the efficacy of dupilumab 
on urticaria control 
• 
Change from baseline in urticaria control test (UCT) at Week 12 
and Week 24 
• 
Proportion of well-controlled patients (UCT ≥12) at Week 12 and 
Week 24 
• 
To demonstrate improvement in health-
related quality-of-life and overall disease 
status and severity 
• 
Change from baseline in health-related quality-of-life (HRQoL) 
as measured by Dermatology Life Quality Index (DLQI) in 
patients ≥16 years old, and in Children’s Dermatology Life 
Quality Index (CDLQI) in patients ≥6 to <16 years old at 
Week 12 and Week 24 
• 
Patient Global Impression of Change (PGIC) of CSU at Week 12 
and Week 24 
• 
Change from baseline in Patient Global Impression of Severity 
(PGIS) of CSU at Week 12 and Week 24 
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Objectives 
Endpoints 
• 
To evaluate the ability of dupilumab in 
reducing the proportion of patients who 
require treatment with oral corticosteroids 
(OCS)  
• 
Time-to-event and proportion of patients receiving OCS for CSU 
during the planned treatment period 
 
• 
To evaluate safety outcome measures 
• 
Percentages of participants experiencing treatment-emergent 
adverse events (TEAEs) or serious adverse events (SAEs) 
• 
To evaluate immunogenicity of 
dupilumab 
• 
Incidence of treatment-emergent anti-drug antibodies (ADA) 
against dupilumab over time 
Tertiary/exploratory 
• 
To demonstrate exploratory outcome 
measures in the urticaria composite 
score and or its components 
• 
Time to UAS7 MID response (9.5 to 10.5 points) by Week 12 
and Week 24 
• 
Change from baseline in the number of itch-free days and/or 
hive-free days at Week 12 and Week 24 
• 
Change in UAS7 in well-controlled patients (UAS ≤6) from 
Weeks 24 to 36 
• 
To demonstrate exploratory health-
related quality-of-life and health status 
measures 
• 
Change from baseline in EQ-5D-5L (or EQ-5D-Y 5L for ≥6 to 
<16 years old) at Week 12 and Week 24 
• 
Change from baseline in CU-Q2oL at Week 12 and Week 24 
• 
Missed school/work days from baseline at Week 12 and 
Week 24 
• 
To demonstrate reduction in use of 
rescue medication 
• 
Use of antihistamine rescue medication 
• 
Total OCS rescue dose prescribed (in mg) during the treatment 
period 
• 
Total OCS rescue intake in days during the treatment period 
 
Pharmacokinetic  
• 
To evaluate PK and pharmacodynamic 
(PD) outcome measures 
• 
Functional dupilumab concentrations in serum and PK profile 
• 
Pharmacodynamic response for selected biomarkers (total IgE) 
a Key secondary endpoint for Study A and B  
b Key secondary endpoint for Study C: UAS7 at Week 24 (except EU and EU reference countries, where ISS7 at Week 24 is 
key secondary endpoint) 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The assessments used in this study are standard for the evaluation of therapy in participants with 
CSU. CSU is characterized by the recurrent formation of itchy hives, angioedema, or both for 
longer than 6 weeks (15, 16). The proposed primary endpoint is the change from baseline in 
weekly itch severity score (ISS7) at Week 24 (except EU and EU reference countries) and change 
from baseline in weekly urticaria activity score (UAS7, composite patient reported itch and hive 
score) at Week 24 for EU and EU reference countries. Itch is one of the most important patient 
relevant symptoms affecting quality of life in CSU and highly linked to how patients perceive 
their disease. ISS7 is one of the 2 components of urticaria activity score UAS7 (a composite score 
assessing both itch and hives) and an established and widely accepted patient-reported outcome 
tool to prospectively measure CSU activity (17) that has been used in most clinical trials in CSU 
in the recent years as a main outcome parameter (3, 18). 
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Angioedema has been described as a highly prevalent clinical feature in CSU. Up to 40% of CSU 
patients can present with a mixed phenotype of urticarial and angioedema and 10% with 
angioedema alone (19). Angioedema Activity Score (AAS) a well-developed and adequately 
validated instrument to measure angioedema activity in CSU patients (20) will thus be assessed to 
explore angioedema activity. 
In addition to the UAS and angioedema, which provides a summary of signs and symptoms, it is 
important to get insights into patient self-assessment of disease control. To get a complete picture 
of the disease and assess its control over the course of treatment, a well-developed and validated 
instrument in CSU patients: the Urticaria Control Test will be used (21). 
Lastly, patients with CSU experience substantial HRQoL impairment. Therefore, the dermatology 
life quality index (DLQI) or the children’s dermatology life quality index (CDLQI), 2 instruments 
developed to measure dermatology-specific quality of life in adult and in pediatric patients, 
respectively (22, 23) will be assessed. 
The proposed primary and secondary endpoints will answer important clinical questions about the 
efficacy on disease symptoms and quality of life (QoL) in patients with CSU. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a master protocol composed of 3 studies of similar design, 2 studies in participants who are 
omalizumab naïve (Study A and Study C) and 1 study in participants who are omalizumab 
intolerant or incomplete responders (Study B). The Study A and Study C will include adults, 
adolescents (≥12 to <18 years) and children (≥6 to <12 years in some selected countries). The 
study B will include adults and adolescents. The three studies are 24-week, double-blind, 
randomized, placebo-controlled studies to evaluate the use of dupilumab in participants with CSU 
who remain symptomatic despite the use of H1-AH.  
Omalizumab incomplete responders are defined as patients treated with at least 300 mg 
omalizumab subcutaneous (SC) every 4 weeks (q4w) for at least 3 months (minimum of 
3 injections) and who have had an inadequate response resulting in omalizumab discontinuation, 
as confirmed by Investigator assessment. Information about intolerance or incomplete response to 
omalizumab should be well documented in the patient´s medical records. 
The total anticipated number of participants across the 3 studies is approximately 384 randomized 
participants. For each study, participants will be randomized 1:1 to dupilumab or placebo. 
The randomization will be stratified first by age (adults versus adolescents versus children in 
Study A and Study C, adults versus adolescents in Study B; up to approximately 5% of total 
sample size for children and approximately 5% of total sample size for adolescents in Study A and 
Study C; up to approximately 5% of total sample size for adolescents in Study B). In adults, 
randomization will be stratified further by country (Study A, B and C) and presence of 
angioedema at baseline (Study C only). In adolescents/children ≥6 to <12 years of age, 
randomization will not be stratified further.  
It is anticipated that approximately 30%-40% of enrolled participants will have angioedema. 
The studies will assess the effect of dupilumab on the itch and hives frequency/severity scored 
individually and through the urticaria activity score (composite), on angioedema activity, urticaria 
control, and on participants’ HRQoL and health status. 
Each of the 3 studies (A, B, and C) consists of 3 periods: 
• Screening period (2 to 4 weeks). 
• IMP treatment period (24 weeks ±3 days): approximately 384 participants 
(130 participants in Study A, 104 participants in Study B, and 150 participants in Study C) 
will be randomized (1:1) to 1 of the following treatments: 
- 
Dupilumab: 300 mg q2w for adults and adolescents ≥60 kg; 200 mg q2w for 
adolescents <60 kg and children ≥6 to <12 years of age ≥30 kg; or 300 mg q4w for 
children ≥6 to <12 years of age <30 kg and ≥15 kg (for Study A and Study C only). 
- 
Matched placebo. 
A loading dose equivalent to treatment group assigned will be administered on Day 1. 
Participants assigned to 300 mg q2w/q4w in dupilumab or matched placebo arm will 
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receive 2 injections of 2 mL on Day 1. Participants assigned to 200 mg q2w in dupilumab 
or matched placebo arm will receive 2 injections of 1.14 mL on Day 1. 
• Post-IMP treatment period (12 weeks ±3 days). 
In each of the 3 studies, participants should continue their established standard of care background 
therapy with a long-acting non-sedating H1-AH, at up to 4-fold the recommended dose. If 
participants are on a dose higher than 4-fold the recommended dose at screening visit (Visit 1), 
the Investigator can adjust the participant dose within the stipulated range at the screening visit 
(Visit 1). Participants should continue to take the same daily dose throughout the study unless 
they experience a flare for which rescue therapy may be initiated. All participants on 1- to 3-fold 
the approved H1-AH dose (maintenance dose used at screening) will be allowed to take additional 
doses of their H1-AH medications as rescue therapy as long as they do not exceed 4-fold the 
recommended dose during the screening, treatment, and follow-up periods. If symptoms are still 
uncontrolled after increase of H1-AH to the maximum allowed dose, participants can take a short 
course of OCS as rescue therapy during the treatment and follow-up periods. The participants who 
already take 4-fold an approved H1-AH dose will be allowed to take a short course of oral 
corticosteroids (OCS) as rescue therapy during the treatment and follow-up periods. For rescue 
therapy in participants in Japan, please see Appendix 11, Section 10.11. However, for the purpose 
of the primary analysis, data collected after OCS use will be set to missing and the worst 
postbaseline value before OCS will be used. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
In each of the Studies A, B, and C, a randomized, placebo-controlled study design where the 
effect of the IMP is assessed in CSU patients with moderate to severe symptoms on top of 
optimized background therapy is considered to be the most appropriate design to explore the 
efficacy and safety of dupilumab in participants with CSU who remain symptomatic despite the 
use of H1-AH and who are omalizumab naïve or intolerant or incomplete responders. 
Study A and Study C will target omalizumab naïve patients; more than 50% of CSU patients do 
not respond to H1 antihistamine treatment (1, 9). In Study A, overall 52% of participants received 
H1-AH at recommended doses as background therapy and 45% of participants presented with 
angioedema at baseline. In order to maintain consistency between the study population in studies 
A and C, and reflect the real-life distribution of patients with angioedema and uncontrolled by 
both standard dose or maximal H1-AH therapy, it is planned that Study C would include not more 
than approximately 50% (n=75) of participants having their H1-AH therapy at recommended 
doses (for more details please see Section 6.1.2), and not less than approximately 30% (n=45) but 
not more than approximately 45% (n=68) of participants presenting with angioedema at baseline.    
As mentioned in Section 2.1, dupilumab at SC doses of 300 mg and 200 mg have been observed 
to suppress both total and antigen specific IgE levels across the indications studied: AD, asthma, 
and CRSwNP. 
Study B will target omalizumab treated CSU patients. Approximately 20% to 40% patients don’t 
respond to omalizumab and remain without an effective third-line treatment; these patients have 
the highest unmet medical need (1). Studies suggests that omalizumab incomplete or 
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non-responder patients had significantly lower baseline serum IgE levels compared to partial and 
complete responders (24, 25). Dupilumab offers a new mechanism of action by inhibiting IL-4 
signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor. 
Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13, key cytokines that drive optimal mast 
cell degranulation and IgE production and other type 2 inflammatory responses, including the 
release of proinflammatory cytokines, chemokines, nitric oxide, and IgE (13). Elevated levels of 
IL-4 and IL-13 in the skin of CSU patients have been reported (26) and IgE levels are suppressed 
by inhibition of the cytokine IL-4. The study will also target omalizumab intolerant patients. 
Similar study designs and endpoints have been employed for recent studies with other biologics 
and are considered “state-of-the-art” for studies in CSU (10).  
Including approximately 5% of adolescent patients in each study is consistent with the 
omalizumab clinical development program and approximates the prevalence of adolescent 
patients with CSU (9). 
The 24-week treatment duration should be sufficient for proving efficacy of dupilumab. 
Dupilumab treatment has shown clinical efficacy prior to Week 24 in all other Phase 3 trials 
examined across all indications. In addition, biomarkers of disease response, including total serum 
IgE levels plateau after Week 16 but before Week 24 in prior atopic dermatitis trials, including the 
52-week atopic dermatitis study (R668-AD-1224; CHRONOS). Given that the clinical efficacy 
and biomarker changes occur prior to Week 24 in prior studies in multiple indications, the 
Sponsor considers that a 24-week study is an appropriate duration to observe dupilumab’s effect 
in chronic spontaneous urticaria. Study A was completed, and results confirm that 24-week 
treatment is an appropriate duration to evaluate dupilumab impact on efficacy in participants with 
CSU. The duration of the 12-week follow-up period is based on the time expected for drug levels 
to reach zero (below the lower limit of quantification) in most participants after the last dose of 
dupilumab. 
Moreover, Study A demonstrated that the proposed dupilumab dosing regimen was efficacious 
versus placebo in omalizumab-naïve patients with CSU who remain symptomatic despite the use 
of H1 antihistamine (H1-AH) treatment (please see Section 2.1 for more details on study results). 
A double-blind, randomized, placebo-controlled design is chosen to minimize bias in data 
collection and interpretation. The presence of a placebo arm is appropriate for the objectives of 
this study since it will provide the most robust assessment of the efficacy and safety of dupilumab, 
Efficacy will be determined using the primary endpoint of the change from baseline in the weekly 
itch severity score (ISS7) at Week 24 (except EU and EU reference countries) and change from 
baseline in weekly urticaria activity score (UAS7, composite patient reported itch and hive score) 
at Week 24 for EU and EU reference countries. Assessment of itch is important as it is the key 
symptom affecting participants´ QoL.  
 
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4.3 
JUSTIFICATION FOR DOSE  
Based on the known pharmacokinetics (PK), safety and efficacy of dupilumab, the selected dosing 
regimen is dupilumab 300 mg q2w with a loading dose of 600 mg for adults; and 300 mg q2w 
with a loading dose of 600 mg for adolescents ≥60 kg OR 200 mg q2w with a loading dose of 
400 mg for adolescents <60 kg. These are the approved dose regimens for AD, another skin 
disease. The doses proposed for children ≥6 to <12 years of age are the dose regimens for the 
same age for AD, which have been submitted to the Health Authorities and are currently in 
review: 200 mg q2w with a loading dose of 400 mg for children ≥6 to <12 years of age with 
weight ≥30 kg or 300 mg q4w with a loading dose of 600 mg for children ≥6 to <12 years of age 
with weight <30 kg and ≥15 kg. The proposed doses are expected to achieve concentrations in 
serum that saturate the IL4/13 receptor in most patients and hence they are expected to provide the 
maximum benefit and therefore to achieve the optimal benefit/risk ratio in this patient population. 
Organ perfusion is anticipated to be similar between AD and CSU and lower than the rate of lung 
perfusion. 
Furthermore, for AD a loading dose was administered to more rapidly achieve effective drug 
concentrations, thereby allowing a rapid pharmacodynamics (PD) response as demonstrated by 
improvement in pruritus, a hallmark of AD. Similarly, as pruritus is a core symptom of CSU, and 
to achieve effective drug concentrations more rapidly, a loading dose is selected for this study. 
EFC16461 Study A (n=138) conducted in adults, adolescents and children ages 6-11 years with 
CSU who remain symptomatic despite the use of H1 antihistamine (H1-AH) treatment 
demonstrated that dupilumab at dose regimens described above provide clinically meaningful and 
statistically significant improvement versus placebo, across the key symptoms of CSU (including 
itch, hives and overall urticaria activity) at Week 24 and is well tolerated in the studies population. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last end of study (EOS) Visit. If a participant discontinues treatment period 
prematurely but completes follow-up to the planned EOS Visit, he/she is considered a completer. 
The overall EOS is defined as the date of the last visit of the last participant in the study.  
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
For each of the 3 Studies A, B, and C, participants are eligible to be included in the study only if 
all of the following criteria apply: 
Age 
I 01. 
Study A and C: Participant must be ≥6 years to 80 years of age at the time of signing the 
informed consent.  
Study B: Participant must be ≥12 years (or the minimum legal age for adolescents in the 
country of the investigational site) to 80 years of age at the time of signing the informed 
consent 
Note: For those countries where local regulations do not permit enrollment of children 
aged ≥6 to <12 years, the recruitment will be restricted to those who are ≥12 years of age 
(or the minimum legal age for adolescents in the country of the investigational site). For 
those countries where local regulations do not permit enrollment of children aged ≥6 to 
<12 years of age and adolescents, the recruitment will be restricted to those who are 
≥18 years of age. See instructions specific to France in Appendix 11 (Section 10.11.2). 
Type of participant and disease characteristics 
Participants who have a diagnosis of CSU refractory to H1-AH at the time of randomization, as 
defined by all of the following: 
I 02. 
Diagnosis of CSU >6 months prior to screening visit (Visit 1). 
I 03. 
The presence of itch and hives for >6 consecutive weeks at any time prior to screening 
visit (Visit 1) despite the use of H1-AH during this time period. 
I 04. 
Participants using a study defined H1-AH for CSU treatment (see Section 6.1.2 for the list 
of antihistamines allowed for the study). Note: Participants should remain on their 
prescreening non-sedating H1-AH dose. Only up to 4-fold the recommended dose is 
allowed. If participants are on dose higher than 4-fold the recommended dose at screening, 
the Investigator can adjust the participant dose to the stipulated range at the screening visit 
(Visit 1). The H1-AH dose should be stable for at least 3 consecutive days prior to the 
screening visit (Visit 1). 
I 05. 
During the 7 days before randomization: 
- 
UAS7 >16 
- 
ISS7 >8 
Note: To be eligible for the study, participants must have no missing electronic diary 
(e-diary) (UAS7 and ISS7) in the 7 days before randomization. 
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I 06. 
Deleted in Amended protocol 02.  
I 07. 
Study A and C (omalizumab naïve): Participants who are omalizumab naïve. 
Study B (omalizumab intolerant or incomplete responders): Omalizumab incomplete 
responders are defined as participants treated with at least 300 mg (q4w) omalizumab for 
at least 3 months (minimum of 3 injections) and who have had an inadequate response 
resulting in omalizumab discontinuation, as confirmed by Investigator assessment. 
Note: Information about intolerance or incomplete response to omalizumab should be well 
documented in the patient´s medical records. 
I 08. 
Participants must be willing and able to complete a daily symptom e-diary for the duration 
of the study.  
  
Sex 
I 09. 
Male or Female 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
- 
  
a) Female participants 
- 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies: 
- 
Is not a woman of childbearing potential (WOCBP)  
OR 
- 
Is a WOCBP and agrees to use an acceptable contraceptive method as described 
in Appendix 4 (Section 10.4) during the study (at a minimum until 12 weeks after 
the last dose of study intervention). 
- 
A WOCBP must have a negative highly sensitive (Section 10.2) pregnancy test 
(urine or serum as required by local regulations) on Day 1 before the first dose of 
study intervention. 
- 
If a urine test on Day 1 cannot be confirmed as negative (eg, an ambiguous 
result), a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. 
- 
Additional details can be found in Appendix 4 (Section 10.4). 
- 
The Investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed consent 
I10. 
Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of 
the protocol which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. Participants ≥6 and <18 years of age 
must provide written informed assent, and their parent(s)/caregiver(s)/legally authorized 
representative(s) must sign the specific ICF. In countries where legal age of majority is 
˃18 years, a specific ICF must also be signed by the participant’s legally authorized 
representative (Section 10.1.3). 
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5.2 
EXCLUSION CRITERIA  
For each of the 3 studies A, B, and C, participants are excluded from the study if any of the 
following criteria apply: 
E 01. Weight is less than 30 kg in adults and adolescents and 15 kg in children aged ≥6 to 
<12 years 
Medical conditions 
E 02. Clearly defined underlying etiology for CUs other than CSU (main manifestation being 
physical urticaria). This includes but not limited to the following urticarias: 
- 
Inducible urticaria: acute urticaria, solar, cholinergic, heat, cold, aquagenic, vibratory 
angioedema, symptomatic dermographism, delayed pressure, or contact. 
- 
Diseases with possible symptoms of urticaria or angioedema: systemic lupus 
erythematosus, urticarial vasculitis, urticaria pigmentosa, erythema multiforme, 
mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, or generalized 
cancer. 
E 03. Presence of skin morbidities other than CSU that may interfere with the assessment of the 
study outcomes. 
E 04. Patients with active AD. 
E 05. 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 
participants with short life expectancy, participants with uncontrolled diabetes 
(hemoglobin A1c ≥9%), participants with cardiovascular conditions (eg, Class III or IV 
cardiac failure according to the New York Heart Association classification), severe renal 
conditions (eg, participants on dialysis), hepato-biliary conditions (eg, Child-Pugh class B 
or C), neurological conditions (eg, demyelinating diseases), active major autoimmune 
diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc), other severe 
endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic diseases. The 
specific justification for participants excluded under this criterion will be noted in study 
documents (chart notes, case report forms [CRF], etc). 
E 06. Patients with active tuberculosis (TB) or non-tuberculous mycobacterial infection, or 
a history of incompletely treated TB will be excluded from the study unless it is well 
documented by a specialist that the participant has been adequately treated and can now 
start treatment with a biologic agent, in the medical judgment of the Investigator and/or 
infectious disease specialist. Tuberculosis testing will be performed on a 
country-by-country basis, according to local guidelines if required by regulatory 
authorities or ethics boards. 
E 07. Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic 
infection, unless clinical and (if necessary) laboratory assessment have ruled out active 
infection before randomization. 
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E 08. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiprotozoals, or antifungals within 2 weeks before the screening visit and during the 
screening period. 
E 09. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections (eg, TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, and 
aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal 
frequency or prolonged duration suggesting an immune-compromised status, as judged by 
the Investigator. 
E 10. Active malignancy or 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. 
E 11. History of systemic hypersensitivity or anaphylaxis to omalizumab or any biologic 
therapy, including any excipients.  
E 12. Patient with any other medical or psychological condition including relevant laboratory or 
electrocardiogram abnormalities at screening that, in the opinion of the Investigator, 
suggest a new and/or insufficiently understood disease, may present an unreasonable risk 
to the study participant 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 participants excluded under this criterion will be noted in study documents 
(chart notes, CRF, etc). 
E 13. Current history of substance and/or alcohol abuse. 
E 14. Planned major surgical procedure during the patient’ participation in this study. 
Prior/concomitant therapy 
E 15. Exposure to another systemic or topical investigative drug (monoclonal antibodies as well 
as small molecules) within a certain time period prior to the screening visit (Visit 1), 
defined as follows: an interval of <6 months or <5 PK half-lives for investigative 
monoclonal antibodies, whichever is longer, and an interval of <30 days or <5 PK 
half-lives, whichever is longer, for investigative small molecules.  
E 16. Having used any of the following treatments within 4 weeks before the screening visit 
(Visit 1). 
- 
Immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids [oral or 
parenteral - intravenous, intramuscular, SC]), cyclosporine, mycophenolate-mofetil, 
interferon gamma, Janus kinase inhibitors, azathioprine, methotrexate, 
hydroxychloroquine, sulfasalazine, dapsone, colchicine, etc). 
- 
Antifibrinolytic tranexamic acid and epsilon-aminocaproic acid. 
- 
Leukotriene receptor antagonists (LTRAs) and H2 receptor antagonists. Note: patients 
taking stable LTRAs and /or H2 receptor antagonists for diseases other than CSU 
(eg, asthma or gastroesophageal reflux disease, respectively) will be permitted to 
continue their use. 
- 
Phototherapy, including tanning beds.  
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E 17. Treatment with biologics as follows: 
- 
Any cell-depleting agents including but not limited to rituximab: within 6 months 
before the screening visit (Visit 1). 
- 
Omalizumab within 4 months before the screening visit (Visit 1). 
- 
Other monoclonal antibodies (which are biological response modifiers): within 
5 half-lives (if known) or 16 weeks before the screening visit (Visit 1), whichever is 
longer. 
E 18. Treatment with a live (attenuated) vaccine (Section 10.10) within 4 weeks before the 
screening visit (Visit 1). 
NOTE: For participants who have vaccination with live, attenuated vaccines planned 
during the course of the study (based on national vaccination schedule/local guidelines), it 
will be determined, after consultation with a physician, whether the administration of 
vaccine can be postponed until after the EOS, or preponed to before the start of the study, 
without compromising the health of the participant: 
- 
Patient for whom administration of live (attenuated) vaccine can be safely postponed 
would be eligible to enroll into the study. 
- 
Patients who have their vaccination preponed can enroll in the study only after a gap of 
4 weeks following administration of the vaccine. 
E 19. Routine (daily or every other day during 5 or more consecutive days) doses of doxepin 
within 14 days prior to screening visit (Visit 1). 
E 20. Either intravenous immunoglobulin (IVIG) therapy and/or plasmapheresis within 30 days 
prior to screening visit (Visit 1).  
E 21. Planned or anticipated use of any prohibited medications (Section 6.5) and procedures 
during screening and study treatment period. 
Prior/concurrent clinical study experience 
E 22. Participation in prior dupilumab clinical study, or have been treated with commercially 
available dupilumab. 
Diagnostic assessments 
E 23. History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at 
the screening visit (Visit 1). 
E 24. Patients with any of the following result at the screening visit (Visit 1): 
- 
Positive (or indeterminate) HBs Ag or,  
- 
Positive total HBc Ab confirmed by positive HBV DNA or, 
- 
Positive HCV Ab confirmed by positive HCV RNA.  
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Other exclusions 
E 25. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or subjects who are legally institutionalized. 
E 26. Any country-related specific regulation that would prevent the subject from entering the 
study - see Section 10.11 (country-specific requirements). 
E 27. Participant not suitable for participation, whatever the reason, including medical or clinical 
conditions, or participants potentially at risk of noncompliance to study procedures. 
E 28. Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 
of the International Council for Harmonisation [ICH]  - Good Clinical Practice [GCP] 
Ordinance E6). 
E 29. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
E 30. Any specific situation during study implementation/course that may rise ethics 
considerations. 
E 31. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study.  
5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure reasons, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Rescreened participants will be assigned a new participant number versus the 
1 received for the initial screening visit (Visit 1). 
There is no requirement for a waiting period between the screen failure date and the rescreening 
date. The Interactive Response Technology (IRT) report will flag rescreened participants. Patients 
that are rescreened must sign a new consent form and all Visit 1 procedures must be repeated. 
If certain dynamic laboratory tests do not meet the eligibility criteria at the screening visit 
(Visit 1), these laboratory assessments may be repeated, at the discretion of the Investigator, if it 
is judged to be likely to return to acceptable range for study inclusion within the screening 
window prior to Day 1. There is no need to screen fail such participants if the test finally meets 
the eligibility criteria. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a participant in Study A, Study B, or Study C 
according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
6.1.1 Investigational medicinal product(s)  
Table 3 - Overview of study interventions administered  
ARM name 
Dupilumab 
Placebo 
Intervention name 
For adults and adolescents ≥60 kg: Dupilumab 
300 mg (q2w) 
 
For adolescents <60 kg and children ≥6 to <12 
years of age ≥30 kg: Dupilumab 200 mg (q2w) 
 
 
For children ≥6 to <12 years of age <30 kg 
and ≥15 kg: Dupilumab 300 mg (q4w) 
For adults and adolescents ≥60 kg: Placebo 
matching dupilumab 300 mg (q2w) 
 
For adolescents <60 kg and children ≥6 to 
<12 years of age ≥30 kg: Placebo matching 
dupilumab 200 mg (q2w) 
 
For children ≥6 to <12 years of age <30 kg and 
≥15 kg: Placebo matching dupilumab 300 mg (q4w) 
Type 
Biological/Vaccine 
Other 
Dose formulation 
• 
Dupilumab 300 mg: a 150 mg/mL 
dupilumab solution in a pre-filled 
syringe to deliver 300 mg in 2 mL. 
 
 
or 
• 
Dupilumab 200 mg: a 175 mg/mL 
dupilumab solution in a pre-filled 
syringe to deliver 200 mg in 
1.14 mL. 
• 
Placebo matching dupilumab 300 mg will 
be supplied as an identical formulation to 
the active 300 mg formulation without 
dupilumab, in a pre-filled syringe to deliver 
placebo in 2 mL. 
or 
• 
Placebo matching dupilumab 200 mg will 
be supplied as an identical formulation to 
the active 200 mg formulation without 
dupilumab, in a pre-filled syringe to deliver 
placebo in 1.14 mL.  
Unit dose strength(s) 
300 mg or 200 mg 
0 mg  
Dosage level(s) 
300 mg every 14 ±3 days after an initial 
loading dose of 600 mg  
or 
200 mg every 14 ±3 days after an initial 
loading dose of 400 mg 
or  
300 mg every 28 ±3 days after an initial 
loading dose of 600 mg 
0 mg every 14 ±3 days or 28 ±3 days after an initial 
loading dose of 0 mg  
Route of 
administration 
Subcutaneous 
Subcutaneous 
IMP and NIMP 
IMP 
IMP 
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ARM name 
Dupilumab 
Placebo 
Packaging and 
labeling 
Each dose of dupilumab will be supplied as 
1 glass pre-filled syringe packed in a patient kit 
box. Both glass pre-filled syringe and box will 
be labeled as required per country 
requirement 
Each dose of placebo will be supplied as 1 glass 
pre-filled syringe packed in a patient kit box. Both 
glass pre-filled syringe and box will be labeled as 
required per country requirement 
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
During the 24-week treatment period, the investigational medicinal product (IMP) is administered 
every 14 ±3 days (q2w) or 28 ±3 days (q4W) for children <30 kg and ≥15 kg. 
The Investigator or delegate will train the participant (or parent(s)/legally authorized 
representative/caregiver) how to prepare and inject IMP at Visit 2. The site staff will inject the 
first dose of the 2 injections. The participant (or parent/legally authorized 
representative/caregiver) will perform the second injection under the supervision of the 
Investigator or delegate. This training must be documented in the participant’s study file. At 
subsequent study drug administrations, participants are allowed to self-inject IMP at home. For 
children ≥6 to <12 years, no self-administration of IMP is allowed by the participant, but 
parent(s)/caregiver(s)/legally authorized representative(s) who are trained by the Investigator or 
designee to prepare and administer IMP may perform home administration of IMP. 
When the participant has a study visit, the IMP will be administered following clinical procedures 
and blood collection. Participants should be monitored for at least 30 minutes. The monitoring 
period may be extended as per country specific or local site-specific requirements. 
If the participant (or parent/legally authorized representative/caregiver) is unable or unwilling to 
administer IMP, injections can be performed at the site by way of unscheduled visits; or 
arrangements can be made for qualified site personnel and/or health care professionals 
(eg, visiting nurse service) to administer IMP for the doses that are not scheduled to be given at 
the study site.  
Subcutaneous injection sites should alternate between the upper thighs, 4 quadrants of the 
abdomen or the upper arms, so that the same site is not injected twice during consecutive 
administrations. Injection in the upper arms can only be done by a trained person (parent/legally 
authorized representative/caregiver trained by Investigator or Delegate) or health care professional 
but not the participants themselves. The IMP injection should be avoided in areas where 
participants have urticaria or angioedema. 
Participant/parent/legally authorized representative/caregiver should be trained by the site staff to 
recognize potential signs and symptoms of hypersensitivity reaction in order to 
self-monitor/monitor at home for at least 30 minutes (or longer per country specific or local 
site-specific requirements) following injection. In case of hypersensitivity symptoms the 
participant should contact healthcare provider/emergency. 
For doses not given at the study site, paper diaries will be provided to record information related 
to the injections. The paper diary will be kept as source data in the patient’s study file. 
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6.1.2 Noninvestigational medicinal product(s) 
Participants should continue their established standard of care background therapy with a 
long-acting non-sedating H1-AH, at up to 4-fold the recommended dose. If participants are on 
a dose higher than 4-fold the recommended dose at the screening visit (Visit 1), the Investigator 
can adjust the participant dose within the stipulated range at the screening visit (Visit 1). 
Participants should continue to take the same daily dose throughout the study unless they 
experience a flare for which rescue therapy may be initiated. Please refer to Section 6.5.1 for 
rescue therapy. The following list of H1-AH is allowed and noted with their recommended dose: 
•
Cetirizine 10 mg once per day (qd).
•
Levocetirizine dihydrochloride 5 mg qd
•
Fexofenadine 60 mg twice per day or 180 mg qd
•
Loratadine 10 mg qd
•
Desloratadine 5 mg qd
•
Bilastine 20 mg qd
•
Rupatadine 10 mg qd
•
Other H1-AH after discussion with the Sponsor
For other information related to H1-AH including safety precautions, please refer to the National 
Product labeling. 
Background therapy will be supplied by Sponsor’s local affiliate as locally required or by sites. 
Reimbursement will be provided when deemed necessary and as per country regulation. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Storage and handling 
1. The Investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study intervention received and any discrepancies are
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only authorized
site staff may supply or administer study intervention. All study intervention must be
stored in a secure, environmentally controlled, and monitored (manual or automated) area
in accordance with the labeled storage conditions with access limited to the Investigator
and authorized site staff.
3. The Investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance
(ie, receipt, reconciliation, and final disposition records).
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Responsibilities 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.7). A potential 
defect in the quality of IMP may be subject to initiation of a recall procedure by the Sponsor. 
In this case, the Investigator will be responsible for promptly addressing any request made by the 
Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to randomized study intervention using an IRT. The 
Investigator will be questioned during interactive voice response system (IVRS) phone 
call/interactive web response system (IWRS) web module if he/she wishes to enroll the patient in 
Study A or Study C, or Study B. Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information and directions for the IWRS will be 
provided to each site. 
At screening visit (Visit 1), the Investigator or designee will contact the IRT system to receive the 
participant number. If a patient who had previously failed screening is approached for 
rescreening, a new ICF must be signed. In such case, a new patient number will be assigned by 
IRT. 
Methods of assigning patients to treatment group  
The randomized intervention kit number list is generated centrally by Sanofi and IMPs 
(dupilumab 300 mg, dupilumab 200 mg, or their matching placebo) are packaged in accordance 
with this list. The randomization and intervention allocation are performed centrally by an IRT. 
The IRT generates the participant randomization list and allocates the intervention number and the 
corresponding intervention kits to the participants according to it. 
Participants will be randomized in a 1:1 ratio treatment arm described in Table 3. 
The randomization will be stratified first by age (adults versus adolescents versus children in 
Study A and Study C and adults versus adolescents in Study B; up to approximately 5% of total 
sample size for children and approximately 5% of total sample size for adolescents in Study A and 
Study C; up to approximately 5% of total sample size for adolescents in Study B). In adults, 
randomization will be stratified further by country (Study A, B and C) and presence of 
angioedema at baseline (Study C only). In adolescents/children ≥6 to <12 years of age, 
randomization will not be stratified further. In Study A, overall 52% of participants received  
H1-AH at recommended doses as background therapy, and 45% of participants presented with 
angioedema at baseline. To maintain consistency between the study population in studies A and 
C, and reflect the real-life distribution of patients with angioedema and uncontrolled by both 
standard dose or maximal H1-AH therapy, it is planned that Study C would include not more than 
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approximately 50% (n=75) of participants having their H1-AH therapy at recommended doses 
(for more details please see Section 6.1.2), and not less than approximately 30% (n=45) but not 
more than approximately 45% (n=68) of participants presenting with angioedema at baseline.  
It is anticipated that approximately 30%-40% of enrolled participants will have angioedema. 
A randomized participant is defined as a participant who has been allocated to a randomized 
intervention regardless whether the treatment was administered or not (ie, participant registered 
by the IRT). A participant cannot be randomized more than once in the study. 
Investigational medicinal products will be dispensed at the study visits summarized in the 
Schedule of activities (SoA).  
Returned IMP should not be re-dispensed to the participants. 
Methods of blinding 
Dupilumab 300 mg/200 mg and placebo matching dupilumab 300 mg/200 mg will be provided in 
identically matched 2 mL/1.14 mL pre-filled syringes that are visually indistinguishable for each 
dose. Syringes and box will be labeled with a treatment kit number. While these are double-blind 
trials with regard to the treatment with either dupilumab or placebo, they are not blinded to weight 
based dose levels, due to the different volume size (2 mL versus 1.14 mL) of the dose level of 
dupilumab (300 mg/matching placebo or 200 mg/matching placebo) that will be used for the 
different weight categories for adolescents and children ≥6 to <12 years of age. In addition, in 
children, the study is not blinded to dose regimen due to the different frequency of IMP 
administration (q4w versus q2w). 
Code breaking 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s treatment 
assignment is warranted (eg, in case of available antidote). Participant safety must always be the 
first consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, he/she may, at his/her discretion, contact the Sponsor to discuss the situation prior to 
unblinding a participant’s treatment assignment unless this could delay emergency treatment for 
the participant. If a participant’s treatment assignment is unblinded, the Sponsor must be notified 
within 24 hours of this occurrence. The date and reason for the unblinding must be recorded. 
6.4 
STUDY INTERVENTION COMPLIANCE  
• Investigator or his/her delegate must ensure that IMP will be administered to each 
participant according to the labeling instructions. 
• IMPs accountability: 
- 
IMPs are returned by the participant at each visit. In case of DTP process, the 
intervention units can be returned by the carrier (if defined in the contract). 
- 
The Investigator or his/her delegate counts the number of remaining kits/pre-filled 
syringes and fills in the IMP accountability and inventory forms. 
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- 
The Investigator or his/her delegate records the dosing information on the appropriate 
pages of the electronic case report form (eCRF). 
- 
The monitor in charge of the study then checks the eCRF data by comparing them with 
the IMP which he/she has retrieved and source documents. 
- 
Paper diary will be dispensed to the participants for indicating the IMP administration 
at home.  
Participant compliance with study intervention will be assessed at each visit. Compliance will be 
assessed by kit/pre-filled syringe. Deviation(s) from the prescribed dosage regimen should be 
recorded in the eCRF. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
Long-acting non-sedating H1-AH, at up to 4-fold the recommended dose, are allowed as 
background medication and on demand as recue medication (for rescue therapy in participants in 
Japan, please see Appendix 11 Section 10.11). See Section 6.1.2 and Section 6.5.1 for details. 
The concomitant use of the following therapies is prohibited during the entire study. Study 
treatment will need to be discontinued in participants receiving these treatments: 
• Systemic immunosuppressants (immunosuppressive/immunomodulating drugs) 
eg, systemic corticosteroids (oral or parenteral [intravenous, intramuscular, SC]), 
cyclosporine, mycophenolate-mofetil, interferon gamma, Janus kinase inhibitors, 
azathioprine, methotrexate, hydroxychloroquine, dapsone, sulfasalazine, colchicine, etc.  
Note: a short course of OCS is allowed as rescue therapy (see Section 6.5.1) 
• Antifibrinolytic tranexamic acid and epsilon-aminocaproic acid 
• Other monoclonal antibodies (which are biological response modifiers) 
• Phototherapy, including tanning beds 
• IVIG 
• Plasmapheresis 
• Other investigational drugs. 
The concomitant use of following therapies is prohibited during the entire study but study 
treatment will not need to be discontinued in participants receiving these treatments in violation of 
the protocol: 
• Topical corticosteroids  
• Topical calcineurin inhibitors  
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• Topical and oral antihistamines (other than those allowed as background therapy)  
• Routine doses of doxepin (daily or every other day during 5 or more consecutive days)  
• LTRAs and H2 receptor antagonists, unless stable and taken for diseases other than CSU. 
6.5.1 Rescue medicine  
All participants on 1- to 3-fold the approved non-sedating H1-AH dose (maintenance dose used at 
screening) will be allowed to take additional doses of their H1-AH medications as rescue therapy 
as long as they do not exceed 4-fold the recommended dose during the screening, treatment, and 
follow-up periods. If symptoms are still uncontrolled after increase of H1-AH to the maximum 
allowed dose, participants can take a short course of OCS as rescue therapy during the treatment 
and follow-up periods. The participants on stable dose of 4-fold the approved H1-AH dose will be 
allowed to take a short course of OCS as rescue therapy during the treatment and follow-up 
periods. In order to ensure consistency, when possible, it is recommended to use OCS for 5 to 
7 days with a starting dose of oral prednisone 40 mg (or clinically comparable OCS) followed by 
taper per the Investigator’s judgment. 
For rescue medication in participants in Japan, please see Appendix 11 (Section 10.11). 
The initial maintenance antihistamine dose should remain stable throughout the study, and 
participants should continue their maintenance dose once rescue treatment is no longer required. 
The use of permitted rescue medications should be delayed, if possible, for at least 8 weeks 
following the initiation of the investigational treatment. The date and time of rescue medication 
administration as well as the name and dosage regimen of the rescue medication must be 
recorded.  
For other information related to H1-AH and OCS including safety precautions please refer to the 
National Product labeling. 
6.6 
DOSE MODIFICATION  
No change in IMP dose is allowed. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
The Sponsor will not be responsible for intervention after the EOS Visit. Intervention after the 
EOS Visit will be at the discretion of the Investigator or treating physician. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant should complete 
early treatment discontinuation visit with all assessments planned for the end of treatment (EOT) 
Visit. See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study 
intervention. 
The participants may withdraw from treatment with the IMP if he or she decides to do so, at any 
time and irrespective of the reason, or this may be the Investigator’s decision. All efforts should 
be made to document the reason(s) for treatment discontinuation and this should be documented 
in the eCRF. 
Participants must be permanently withdrawn from the study treatment for the following reasons: 
• At their own request or at the request of their legally authorized representative (legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective participant to the patient’s 
participation in the procedure(s) involved in the research). 
• If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
participant’s well-being. 
• At the specific request of the Sponsor. 
• In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor. 
• Any code broken requested by the Investigator will lead to permanent discontinuation of 
study intervention. 
• Pregnancy. 
• Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (see Section 10.8). 
• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin. 
• Any opportunistic infection or other infections whose nature or course may suggest an 
immunocompromised status (see Section 10.9). 
• Serum alanine aminotransferase (ALT) >3 × Upper Limit of Normal (ULN) and total 
bilirubin >2 × ULN (see Section 10.6). 
• Serum ALT >5 × ULN if baseline ALT ≤2 × ULN or ALT >8 × ULN if baseline 
ALT >2 × ULN (see Section 10.6). 
• If the participant develops a medical condition that requires use of prohibited medication 
(see Section 6.5). 
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See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation within a reasonable timeframe as assessed by the Investigator before making 
a decision of definitive discontinuation of the IMP for the concerned participant. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
Participants who discontinue the study intervention prematurely (prior to completing the 24-week 
treatment period) will perform, as soon as possible, the early treatment discontinuation Visit with 
all assessments normally planned for the EOT Visit (Visit 4), to assure a complete clinical 
assessment in close temporal proximity to the premature termination of study treatment is 
available. 
In addition, and to allow assessment of participant outcomes over the stipulated study period, 
participants will be asked and encouraged to complete all remaining study treatment visits, and 
participate in safety follow-up according to the visit schedule with a ±3 day window. Under 
exceptional circumstances when a participant cannot come to the site for a scheduled visit, 
a phone contact can be made. During the phone contact, at least information about AEs, 
concomitant medication and status of urticaria should be collected. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs.  
In addition, if participants become infected while receiving treatment with dupilumab and do not 
respond to antihelminthic treatment, treatment with dupilumab should be temporarily 
discontinued until infection resolves. 
If the participant misses more than 2 consecutive doses, the participant will be permanently 
discontinued from the study treatment. 
For all temporary intervention discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the eCRF. 
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
A participant may withdraw from the study at any time at his/her own request, or if his/her 
parent(s)/caregiver(s)/legally authorized representative(s) decide to do so, or may be withdrawn at 
any time at the discretion of the Investigator for safety, behavioral, compliance, or administrative 
reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted. Refer to SoA (Section 1.3) for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants, or their parent(s)/caregiver(s)/legally authorized representative(s) wish to withdraw 
consent for participation into the study, the participants will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
The participants who withdraw from the study intervention should be explicitly asked (or their 
parent(s)/caregiver(s)/legally authorized representative(s)) about the contribution of possible AEs 
to their decision, and any AE information elicited must be documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
Follow-up Visits and from withdrawal of consent for non-participant contact follow-up, 
(eg, medical record checks). The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be re-randomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused. 
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7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
• Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1 (Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
Study assessments and procedures described below are common to Study A, Study B, and 
Study C. 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Section 1.3). 
• Patient-Reported Outcome (PRO) questionnaires should be completed by the participants 
before the consultation and/or clinical tests, in a quiet place. The questionnaires should be 
completed by the participants themselves, independently from their physician, the study 
nurse, or any other medical personnel and without any help from friends or relatives. 
• Adolescents/children completing the questionnaires (UAS, AAS, UCT, Chronic Urticaria 
Quality of Life Questionnaire [CU-Q2oL], 5-level EuroQol 5 dimensional questionnaire 
[EQ-5D-5L] [≥16 years old], EuroQol 5-dimensional questionnaire youth [EQ-5D-Y] 
[≥6 to <16 years old], PGIS, PGIC, CDLQI [≥6 to <16 years old] and DLQI [≥16 years 
old]) may be helped by their parents/caregivers for the reading and the understanding of 
the instructions, a word or a question of the questionnaires if they encounter difficulties to 
answer. Adolescents and children should answer the question themselves; 
parents/caregivers should not influence nor interpret their child's answer. 
Parent(s)/caregiver(s)/ legally authorized representative(s) should not select any of the 
response choices on behalf of their child. 
• The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 168 mL. The 
maximum amount of blood collected expected as per schedule of activities from each 
adolescent over the duration of the study will not exceed 101 mL. The maximum amount 
of blood collected from each child will be compliant with the European guideline (27). 
The maximum amount of blood collected per each visit from each child aged ≥6 to 
<12 years will not exceed 11 mL per visit and the total maximum amount of blood 
collected expected as per schedule of activities for each child over the duration of the 
study will not exceed 47 mL. Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples. 
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• In light of the public health emergency related to COVID-19 (Coronavirus disease 2019) 
(or in case of any other pandemic requiring public health emergency), the continuity of 
clinical study conduct and oversight may require implementation of temporary or 
alternative mechanisms eg, phone contact, virtual visits, online meetings, use of local 
clinic or laboratory locations, and home visits by skilled staff. Implementation of such 
mechanisms may differ country by country, depending on country regulations and local 
business continuity plans.  Additionally, no waivers to deviate from protocol enrollment 
criteria due to COVID-19 (or any other pandemic) will be granted. All temporary 
mechanisms utilized, and deviations from planned study procedures are to be documented 
as being related to COVID-19 (or any other pandemic) and will remain in effect only for 
the duration of the public health emergency. 
8.1 
EFFICACY ASSESSMENTS  
Efficacy data will be collected via electronic devices. 
The e-diary is used for daily recording of PRO such as the UAS7 and AAS7 questionnaires, and 
use of H1-AH medication. This device will be dispensed at screening visit (Visit 1), including 
instructions for use and participant(s)/parent(s)/caregiver(s)/legally authorized representative(s) 
will be instructed on the use of the device. 
Recorded information will be downloaded from this device daily. At the EOS visit, the e-diary 
will be downloaded and returned to the site.  
On regular basis, the site staff should review on vendor´s website the information downloaded 
from participants´ e-diary. They should particularly check status of the disease reviewing UAS7 
and AAS7, as well as compliance to background therapy and overall e-diary compliance. The site 
should follow-up with the subject as appropriate. 
The same questionnaires as for adolescents aged <16 years will be used for children aged ≥6 to 
<12 years. 
For UCT, DLQI (>16 years old)/CDLQI (≥6 to <16 years old), CU-Q2oL, 5-level EuroQol 
5-dimensional questionnaire (EQ-5D-5L) (≥16 years old)/EuroQol 5-dimensional questionnaire 
youth (EQ-5D-Y) (≥6 to <16 years old), PGIC, PGIS, and missed school/work days 
questionnaires, participant(s) will fill in the questionnaires during their site visit on a tablet that 
will be provided to the site. This device is kept at the site during the study. 
8.1.1 Urticaria activity score  
The Urticaria Activity Score (UAS) is a validated PRO measure. The daily UAS is the sum of the 
daily Hive Severity Score (HSS, ranging from 0 = None to 3 = more than 50 hives) and the daily 
Itch Severity Score (ISS, ranging from 0 = None to 3 = intense), the 2 key urticaria signs and 
symptoms which are wheals and itch. The daily UAS scores range from 0 to 6 point/day. Daily 
UAS scores are summed over 7-day period to create the UAS7, ranging from 0 to 42, and is 
composed of the HSS7 and ISS7 components. The UAS7 is an established and widely accepted 
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PRO tool to prospectively measure CSU activity (28). It has been used in most clinical trials in 
CSU in the recent years as a main outcome parameter and medical practice (3, 18). A minimal 
important difference (MID) value ranging from 9.5 to 10.5 has been defined to help interpretation 
of the change in score in CSU participants (29, 30, 31). 
Participants will complete the UAS as described in the SoA (Section 1.3). The assessment tool is 
provided in Section 10.7.1. 
8.1.2 Angioedema activity score  
The Angioedema Activity Score (AAS) is a validated PRO measure that assesses angioedema 
activity (20). The AAS is a diary in which participants document on a daily basis the presence or 
absence of angioedema during the past 24 hours. If angioedema is present, participants answer 
5 additional questions about the time of the day the swelling episode occurred, and the severity 
and impact on daily functioning and appearance this swelling episode has had. Each AAS item is 
scored between 0 and 3 points, that is, the minimum and maximum daily AASs are 0 and 
15 points. The daily AASs are summed up to 7-day scores (AAS7), with 7-day scores ranging 
from 0 to 105 (20). A MID of the AAS7 of around 8 points has been established (20). 
Participants will complete the AAS as described in the SoA (Section 1.3). The assessment tool is 
provided in Section 10.7.2.  
8.1.3 Urticaria control test  
The Urticaria Control Test (UCT) is a validated PRO measure for assessing urticaria control (20) 
based on 4 items (severity of pruritus and wheals urticaria symptoms; frequency of treatment 
being not sufficient; QoL impairment; overall urticarial control). Each item is rated on a 5-point 
Likert-type scale (scored with 0 to 4 points). Low scores indicate high disease activity and low 
disease control. The UCT total score is calculated by adding all 4 individual item scores. 
Accordingly, the minimum and maximum UCT scores are 0 and 16, with a score of 16 points 
indicating complete disease control (20). 
Participants will complete the UCT as described in the SoA. The assessment tool is provided in 
Section 10.7.3. 
8.1.4 Dermatology life quality index and children’s dermatology quality life quality index  
The DLQI is a PRO developed to measure dermatology-specific HRQoL in adult participants 
(22). The instrument comprises 10 items assessing the impact of skin disease on participants’ 
HRQoL over the previous week. The items cover symptoms, leisure activities, work/school or 
holiday time, personal relationships including intimate, the side effects of treatment, and 
emotional reactions to having a skin disease. It is a validated questionnaire used in clinical 
practice and clinical trials (32). Response scale is a 4-point likert scale (0 = “not at all” and  
3 = “very much”) for 9 items. The remaining 1 item about work/studying asks whether work/study 
has been prevented and then (if “No”) to what degree the skin condition has been a problem at 
work/study; the item is rated on a 3-point Likert scale (‘Not at all’ to ‘A lot’). Overall scoring 
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ranges from 0 to 30, with a high score indicative of a poor HRQoL. Using an integrated analysis 
of distribution and anchor-based approaches using the change in DLQI total score and participant-
assessed itch severity scores, the MID for the DLQI in participants with chronic idiopathic 
urticaria was reported to be in the range of 2.24 to 3.10 points (33). 
The Children’s Dermatology Quality Life Quality Index (CDLQI) is a validated questionnaire 
designed to measure the impact of skin disease on children’s HRQoL (23). Participants provide 
responses to 10 questions (symptoms feelings associated with disease, the impact of the disease 
on leisure, school or holidays, personal relationships, sleep, and side effects of treatment for the 
skin disease). The instrument has a recall period of 7 days. Nine of the 10 questions are scored on 
a 4-point likert scale ranging from 0 = Not at all/question unanswered to 3 = Very much. Question 
7 has an additional possible response (prevented school), which is assigned a score of 3. The 
CDLQI total score is the sum of the score of each question with a maximum of 30 and a minimum 
of 0. The higher the score, the greater the impact is on the child’s HRQoL.  
Participants will complete the DLQI (≥16 years old) or CDLQI (≥6 to <16 years old) as described 
in the SoA (Section 1.3). The assessment tools are provided in Section 10.7.4 and Section 10.7.5.  
8.1.5 Chronic urticaria quality of life questionnaire  
The CU-Q2oL is a disease-specific instrument used to assess the QoL in adult participants with 
CSU (34). The CU-Q2oL is a 23-item, self-administered questionnaire that includes 6 QoL 
dimensions: pruritus, swelling, impact on life activities, sleep problems, limits, and looks. Each 
item is scored on a 5-point Likert scale (1 = not at all, 5 = extremely) where participants indicate 
how troubled they are within each dimension. The individual items are summed to generate the 
overall CU-Q2oL score, which is then converted to a 0 to 100 scale; higher scores indicate greater 
QoL impairment. 
Participants will complete the CU-Q2oL as described in the SoA (Section 1.3). The assessment 
tool is provided in Section 10.7.6.  
8.1.6 Patient Global Impression of Change of CSU disease and Patient Global Impression 
of Severity of CSU disease  
The Patient Global Impression of Change (PGIC) is a 1-item questionnaire that asks the 
participant to provide the overall self-assessment of change in their CSU on a 7-point scale, 
compared to just before participant started taking the study treatment. Response choices 
are: 0 = “Very much better”, 1 = “Moderately better”, 2 = “A little better”, 3 = “No change”, 
4 = “A little worse”, 5 = “Moderately worse”, 6 = “Very much worse”.  
The Patient Global Impression of Severity (PGIS) is a 1-item questionnaire that asks participants 
to provide the overall self-assessment of their participant’ disease severity on a 4-point scale for 
the past week. Response choices are: 1 = “none”, 2 = “Mild”, 3 = “Moderate”, 4 = “Severe”. 
Participants will complete the 2 items as described in the SoA (Section 1.3). The items are 
provided in Section 10.7.7 and Section 10.7.8.  
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8.1.7 EuroQOL 5 dimensions questionnaire  
The Euroqol-5 dimensions (EQ-5D) is a standardized PRO 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 adult version of the questionnaire is adapted to patients aged 16 and 
older. The EQ-5D consists of 2 parts: the descriptive system and the EQ visual analogue scale 
(EQ VAS). The EQ-5D 5L descriptive system comprises the following 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels of 
perceived problems: “no problem”, “slight problems”, “moderate problems, severe problems, and 
inability to do the activity (35). The respondent is asked to indicate his/her health state by ticking 
(or placing a cross) in the box against the most appropriate statement 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 
EQ VAS records the respondent’s self-rated health on a vertical, VAS 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 EQ-5D Youth version (EQ-5D Y) will be administered to children ≥6 to <12 years old and 
adolescents 12 to 15 years old (36). The EQ-5D-Y is based on the EQ-5D-3L and essentially 
consists of 2 pages: the EQ-5D descriptive system and the EQ VAS. The EQ-5D-Y descriptive 
system comprises the following 5 dimensions: mobility, looking after myself, doing usual 
activities, having pain or discomfort and feeling worried, sad or unhappy. Each dimension has 
3levels: no problems, some problems and a lot of problems. The EQ VAS records the younger 
patient’s self-rated health on a vertical VAS where the endpoints are labelled “The best health you 
can imagine” and “The worst health you can imagine”.  
Participants will complete the questionnaire as described in the SoA (Section 1.3). The assessment 
tool is provided in Section 10.7.9 and Section 10.7.10. 
8.1.8 Missed school/work days  
Participants who are employed or enrolled in school will be asked to report the number of sick 
leave/missed school days since the last study assessment. 
Participants will complete the questionnaire as described in the SoA (Section 1.3). The assessment 
tool is provided in Section 10.7.11.  
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
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8.2.1 Physical examinations  
• A complete physical examination will include skin, nasal cavities, eyes, ears, respiratory, 
cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems.  
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new adverse 
event. 
8.2.2 Vital signs  
• Vital signs will be measured in a semi-supine or sitting position after 5 minutes rest and 
will include axillary or oral temperature (same method of temperature measurement 
should be used during the course of the study), systolic and diastolic blood pressure, and 
pulse and respiratory rate. Blood pressure and pulse measurements should be assessed 
using the same arm with a completely automated device. Manual techniques will be used 
only if an automated device is not available. 
• Body weight (kg) will be measured at screening (Visit 1) and at EOT/EOS visits. Height 
will be measured at screening visit (Visit 1). Height and weight should be measured with 
indoor clothing but without shoes. 
8.2.3 Electrocardiograms  
• 
Single standard 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals. The ECG should be recorded after 10 minutes of rest in the supine 
position. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or Medical Monitor. 
• If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified, and the Sponsor notified. 
• All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
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• If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described in Section 10.3, even if not fulfilling a seriousness criterion, using the 
corresponding pages in the CRF (to be sent) or screens in the e-CRF. 
• Anaphylactic reactions 
• Systemic hypersensitivity reactions 
• Helminthic infections 
• Any severe type of conjunctivitis or blepharitis  
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms) 
• Significant ALT elevation  
- 
ALT >5 × the ULN in participants with baseline ALT ≤2 × ULN;  
or  
- 
ALT >8 × ULN if baseline ALT >2 × ULN. 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/non-investigational medicinal 
product (NIMP) 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills 1 of the seriousness criteria 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined.  
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
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• Symptomatic overdose (serious or nonserious) with IMP/NIMP  
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least 
twice the intended dose during an interval of less than 11 days. The circumstances 
(ie, accidental or intentional) should be clearly specified in in the overdose form. 
- 
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least 
twice the maximum prescribed daily dose, within the intended therapeutic interval. 
“The circumstances (ie, accidental or intentional) should be clearly specified in the 
overdose form”. 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse event will be reported by the participant (or, when appropriate, by a caregiver, parent, 
surrogate, or the participant's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs, serious or nonserious, will be collected from the signing of the ICF until the EOS visit at 
the time points specified in the SoA (Section 1.3). 
All SAEs and AESIs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE/AESI data to the Sponsor within 24 hours of it 
being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor.  
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and 
non-serious AEs of special interest (as defined in Section 8.3), will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). Further information on follow-up procedures is given in Appendix 3 
(Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• Adverse events that are considered expected will be specified in the reference safety 
information. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.  
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and up to the EOS Visit or within 
12 weeks after last study intervention, whichever was later. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
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8.3.6 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
The CSU should be reported as an AE or SAE only if judged by the Investigator to have 
unexpectedly worsened in severity and/or frequency or change in nature any time during the 
study. If the participant has a preexisting medical history of angioedema and this condition 
worsens during the study, it should be reported as an AE or SAE. Any new onset of angioedema 
in the participant with no prior occurrence should also be reported as an AE or SAE. 
Any other AE not listed as an expected event in the IB or in this protocol will be considered 
unexpected. 
8.3.7 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form, within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.3.8 Patients with angioedema  
Patients with CSU can have angioedema as part of their symptoms. Participants will be provided 
emergency contact information and advised to contact a physician, in case of new occurrence of 
angioedema or worsening of preexisting angioedema. 
8.4 
TREATMENT OF OVERDOSE  
Symptomatic overdose with IMP/NIMP is considered as an AESI (defined in Section 8.3). 
No antidote is available for dupilumab. The Sponsor does not recommend specific treatment for 
an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
dupilumab can no longer be detected systemically (at least 98 days). 
3. Obtain a plasma sample for PK analysis as soon as possible from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case basis). 
4. Document appropriately in the eCRF. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the participant. 
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8.5 
PHARMACOKINETICS  
8.5.1 Systemic drug concentration and anti-drug antibodies  
8.5.1.1 Sampling time  
Blood samples will be collected for determination of functional dupilumab and anti-dupilumab 
antibodies in serum as specified in the SoA (Section 1.3). Special procedures for collection, 
storage, and shipping of serum are described in separate operational manuals. The date of 
collection should be recorded in the participant e-CRF.  
8.5.1.2 Handling procedures  
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of handling procedure for samples used in the determination of 
systemic drug concentration and ADA is provided in Table 4. 
Table 4 - Summary of handling procedures  
 
8.5.1.3 Bioanalytic method  
Serum PK and ADA samples will be assayed using validated methods as described in Table 5. 
Table 5 - Summary of bioanalytical methods for functional dupilumab and anti-dupilumab 
antibodies  
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In the event of any SAE, any AE of severe injection site reaction lasting longer than 24 hours, or 
any AESI of anaphylactic reaction or systemic allergic reaction that is related to IMP and require 
treatment, PK and ADA samples will be collected at or near the onset of the event for any 
additional analysis if required or for archival purposes. The exact date and time of sample 
collection must be recorded and entered into the database by the central laboratory. 
An unscheduled systemic drug concentration page in the eCRF must be completed as well. If 
necessary for safety monitoring, additional ADA and PK samples may be collected after the EOS 
visit until resolution of AE. 
Specifically for PK, any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member and then 
archived in the Sponsor and site study files but will not constitute a protocol amendment. The 
IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the ICF. 
8.6 
PHARMACODYNAMICS  
See Section 8.8 for IgE measurement. No other pharmacodynamic parameters will be evaluated in 
this study.  
8.7 
GENETICS  
For those participants who consent to the optional pharmacogenetic/pharmacogenomic sample 
collection section of the ICF, blood samples for exploratory genetic analysis of DNA or RNA will 
be collected and stored for possible future use. Participation is optional. Participants who do not 
wish to participate in the genetic research may still participate in the study. Adolescents/children 
will not participate in the optional genetic research. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
Details on processes for collection and shipment and destruction of these samples can be found in 
a laboratory manual. 
8.8 
BIOMARKERS  
• Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in 
this study as specified in the SoA (Section 1.3): 
- 
Venous blood samples will be collected for measurement of serum total IgE, which 
will be measured using a validated quantitative method.  
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• Optional samples for biomarker research that should be collected from participants in the 
study where possible are the following: 
- 
Serum and plasma (except pediatric participants) 
- 
Serum and plasma will be collected and stored for analysis of potential biomarkers 
of drug response, disease activity, safety, and the Type 2 inflammation pathway. 
- 
Skin biopsy (sub-study) (except pediatric participants) 
- 
For skin biopsies, gene expression and immunohistological analyses may be used 
to investigate drug response, disease activity, and the Type 2 inflammatory 
pathway. Two biopsies will be taken from each participant, 1 from lesion and 
1 from non-lesion at the timepoints specified in the SoA. 
- 
Basophil activation test (sub-study) (except pediatric participants in Study A and Study 
B, and all Study C participants) 
- 
Blood will be collected for assessment of basophil activation using a validated 
assay. 
Plasma, serum, and skin biopsy samples may be stored for a maximum of 5 years and DNA or 
RNA samples for 15 years (or according to local regulations) following the last participant’s last 
visit for the study at a facility selected by the Sponsor. 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS  
Number of missed school/work days collection is described in Section 8.1.8. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
In Studies A (omalizumab naïve), B (omalizumab intolerant or incomplete responders), and C 
(omalizumab naïve) the statistical hypotheses for comparing dupilumab against placebo on the 
primary endpoint of change from baseline in ISS7 at Week 24 (except EU and EU reference 
countries), and the primary endpoint of change from baseline in UAS7 at Week 24 for EU and EU 
reference countries are as follows: 
• Null hypothesis H0: No treatment difference between dupilumab and placebo. 
• Alternative hypothesis H1: There is a treatment difference between dupilumab and 
placebo. 
The statistical hypotheses to be tested on secondary endpoints can be specified similarly as those 
on the primary endpoint.  
9.2 
SAMPLE SIZE DETERMINATION  
The total anticipated number of participants across the 3 studies is approximately 384 randomized 
participants. 
For Study A (omalizumab naïve): An effect size of 0.7 or higher is assumed. An absolute change 
of 5 in ISS7 score is considered the minimal clinically important difference (MCID) and an 
absolute change of 10 in UAS7 score is considered the MCID. Based upon an SD of 7, a change 
of 5 in the ISS7 would correspond to an effect size of approximately 0.7. Based upon an SD of 14, 
a change of 10 in the UAS7 would correspond to an effect size of approximately 0.7. Based on 
this assumption, plus the assumption of a 15% dropout rate and inclusion of children, it is 
estimated that 65 participants per group will provide 96% power to detect an effect size of 0.7 or 
higher between the dupilumab arm and placebo using a 2-sided t-test with alpha = 0.05. This 
sample size estimate applies to both ISS7 (primary endpoint for all countries except EU and EU 
reference countries) and UAS7 (primary endpoint for EU and EU reference countries). 
For Study B (omalizumab intolerant or incomplete responders): An effect size of 0.7 or higher is 
assumed. An absolute change of 5 in ISS7 score is considered the MCID and an absolute change 
of 10 in UAS7 score is considered the MCID. Based upon an SD of 7, a change of 5 in the ISS7 
would correspond to an effect size of approximately 0.7. Based upon an SD of 14, a change of 
10 in the UAS7 would correspond to an effect size of approximately 0.7. Based on this 
assumption, plus the assumption of a 15% dropout rate, it is estimated that 52 participants per 
group, will provide 90% power to detect an effect size of 0.7 or higher between the dupilumab 
arm and placebo using a 2-sided t-test with alpha = 0.05. This sample size estimate applies to both 
ISS7 (primary endpoint for all countries except EU and EU reference countries) and UAS7 
(primary endpoint for EU and EU reference countries).  
 
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Considering the reduced drop-out rate of 10% observed during the study, an interim analysis will 
be performed when the first 80 randomized participants would have completed their Week 24 visit 
by the interim analysis cut-off date. Using the O’Brien-Fleming approach with information 
fraction 0.77 and overall type-I error controlled at 0.05, the alpha spending at this interim analysis 
will be 0.021, and the alpha spending at the final analyses when all 104 participants complete the 
study will be 0.043. 
At the Study B interim analysis, it is estimated that 40 participants per group will provide 74% 
power to detect a treatment effect of 5 or higher with SD 7 and minimal detectable difference 
(MDD) of approximately 3.8 for ISS7 and a treatment effect of 10 or higher with SD 14 and 
MDD of approximately 7.6 for UAS7 between the dupilumab arm and placebo using a 2-sided  
t-test with alpha = 0.021. 
With the decision process outlined in Section 9.5, the overall power for the study will be 
approximately 88%. 
For Study C (omalizumab naïve): Assumptions for sample size calculations for Study C were 
made by considering Study A results. An effect size of 0.564 or higher is assumed. Based upon an 
SD of 7.5 (pooled SD from the observed data in Study A), a treatment difference of 4.23 in the 
ISS7 would correspond to an effect size of approximately 0.564. Based upon an SD of 14.3 
(pooled SD from the observed data in Study A), a treatment difference of 8.53 in the UAS7 would 
correspond to an effect size of approximately 0.597. Based on this assumption, plus the 
assumption of a 10% dropout rate, it is estimated that 75 participants per group will provide 90% 
power to detect an effect size of 0.564 or higher between the dupilumab arm and placebo using a 
2-sided t-test with alpha = 0.05. This sample size estimate applies to both ISS7 (primary endpoint 
for all countries except EU and EU reference countries) and UAS7 (primary endpoint for EU and 
EU reference countries). 
The sample size calculations and the alpha spending by O’Brien-Fleming approach were 
calculated by nQuery Advisor and nTerim 4.0. 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis which will be conducted separately for each study (A, B and C), the 
following populations are defined separately for each study (A, B and C) (Table 6): 
Table 6 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF 
Randomized 
The randomized population includes all participants with a treatment kit number allocated 
and recorded in the IRT database, and regardless of whether the treatment kit was used or 
not. 
Participants treated without being randomized will not be considered randomized and will 
not be included in any efficacy population. 
Intent-to-treat (ITT) 
All randomized participants analyzed according to the treatment group allocated by 
randomization. 
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Population 
Description 
Intent-to-treat24 (ITT24)  
(For Study B interim analysis) 
All participants who were randomized at least 24 weeks before the interim analysis cut-off 
date and would have completed the Week 24 visit by the cut-off date of interim analysis. 
The exact interim analysis cut-off date will be specified in the SAP, which will be finalized 
before the interim analysis.  
Efficacy 
The ITT population (ITT24 for Study B interim analysis). 
Safety 
All participants randomly assigned to study intervention and who take at least 1 dose of 
study intervention. Participants will be analyzed according to the intervention they actually 
received.  
Randomized participants for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized.  
For participants who accidentally receive different treatment from the planned, the actual 
intervention allocation for as-treated analysis will be the dupilumab group. 
The pharmacodynamic (PD) analyses will be performed on the safety population. 
Pharmacokinetic (PK) 
The PK population includes all participants in the safety population with at least one non-missing 
result for functional dupilumab concentration in serum after first dose of the study treatment. 
Participants will be analyzed according to the intervention actually received. 
Antidrug antibody (ADA) 
ADA population includes all participants in the safety population who have at least one non-
missing ADA result after first dose of the study treatment. Participants will be analyzed according 
to the intervention actually received. 
Abbreviations: ADA = antidrug antibody; ICF = Informed consent form, IRT = Interactive response technology; PD = Pharmacodynamic 
9.4 
STATISTICAL ANALYSES  
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses, and procedures for accounting for missing, unused, and 
spurious data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. 
9.4.1 Efficacy analyses  
Table 7 - Efficacy analyses  
Endpoint 
Statistical analysis methods 
Primary 
Primary endpoint: 
Change from baseline in ISS7 at Week 24 (except EU 
and EU reference countries)  
 
Primary endpoint for EU and EU reference countries: 
Change from baseline in UAS7 at Week 24 
 
The primary efficacy endpoint will be analyzed using a hybrid 
method of the worst-observation carried forward (WOCF) and 
multiple imputation. For participants taking selected prohibited 
medications and/or rescue medications (details of selection will be 
specified in the statistical analysis plan), their data after the 
medication usage will be set to missing, and the worst 
postbaseline value on or before the time of the medication usage 
will be used to impute missing Week 24 value (for participants 
whose postbaseline values are all missing, the baseline will be 
used to impute). Participants who discontinue the treatment 
prematurely are encouraged to follow the planned clinical visits 
and in these participants who did not take the selected prohibited 
medications and/or rescue medications, all data collected after 
treatment discontinuation will be used in the analysis. For these 
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Endpoint 
Statistical analysis methods 
participants, missing data may still happen despite all efforts have 
been tried to collect the data after treatment discontinuation. For 
participants who discontinue due to lack of efficacy, all data 
collected after discontinuation will be used in the analysis, and a 
WOCF approach will be used to impute missing Week 24 value if 
needed. For participants who discontinue not due to lack of 
efficacy, a multiple imputation approach will be used to impute 
missing Week 24 value, and this multiple imputation will use all 
participants excluding participants who have taken the selected 
prohibited medications and/or rescue medications on or before 
Week 24 and excluding participants who discontinue due to lack of 
efficacy on or before Week 24. Each of the imputed complete data 
will be analyzed by fitting an analysis of covariance model with the 
baseline value of the primary endpoint, treatment group, presence 
of angioedema at baseline, and region (combined countries) as 
covariates. Statistical inference obtained from all imputed data will 
be combined using Rubin’s rule. Descriptive statistics including 
number of subjects, mean, standard error, and least squares (LS) 
mean changes (and standard error) score will be provided. In 
addition, difference of the dupilumab group against placebo in LS 
means and the corresponding 95% confidence intervals (CI) will 
be provided along with the p-values.  
Sensitivity analysis 
Tipping point analyses and other sensitivity analyses will be 
performed to confirm robustness of the results with respect to the 
missing data handling. Details of the sensitivity analyses will be 
provided in the SAP. 
Subgroup analysis 
To assess the consistency in treatment effects across different 
subgroup levels, subgroup analyses will be performed for the 
primary efficacy endpoint with respect to age group, gender, 
region, and other factors that will be specified in the SAP. 
Secondary 
Change from baseline in UAS7 at Week 12 and Week 24 
(except EU and EU reference countries) 
Change from baseline in HSS7 at Week 12 and Week 24 
Change from baseline in ISS7 at Week 12 and Week 24 
(in EU and EU reference countries) 
Change from baseline in AAS7 at Week 12 and Week 24 
Change from baseline in UCT at Week 12 and Week 24 
Change from baseline in DLQI /CDLQI at Week 12 and 
Week 24 
PGIC at Week 12 and Week 24 
Change from baseline in PGIS at Week 12 and Week 24 
Change from baseline in ISS at all time points 
These endpoints will be analyzed using the same approach as for 
the primary endpoint of change from baseline in ISS7 at Week 24. 
 
Detailed analyses will be described in the SAP finalized before 
database lock. 
Secondary 
Proportion of ISS7 MID responders at Week 12 and 
Week 24 
Proportion of patients with UAS7 ≤6 at Week 12 and 
Week 24 
Proportion of patients with UAS7 = 0 at Week 12 and 
Week 24 
These responder endpoints will be analyzed using the 
Cochran-Mantel-Haenszel test adjusted by baseline disease 
severity, presence of angioedema at baseline, and region. The 
baseline disease severity will be defined according to UAS7 <28 or 
≥28. Comparisons of the response rates between dupilumab dose 
and placebo will be derived. 
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Endpoint 
Statistical analysis methods 
Proportion of well-controlled patients (UCT ≥12) at Week 
12 and Week 24 
Participants who receive selected prohibited medications and/or 
rescue medications will be considered as non-responders for time 
points after the medication usage. For other participants, all 
available data including those collected during the off-treatment 
period will be used to determine the responder/non-responder 
status. Missing data will be considered as non-responders. 
Secondary 
Time to ISS7 MID response 
Proportion and time to event of patients receiving OCS 
for CSU during the planned treatment period 
These time-to-event endpoints will be analyzed using the Cox 
proportional hazards model, including treatment, the 
corresponding baseline value, presence of angioedema at 
baseline, and region as covariates. The estimates of the hazard 
ratio between dupilumab dose and placebo will be derived. 
Exploratory 
Will be described in the SAP finalized before database lock. 
Within each study, Study A and Study C (omalizumab naïve) and Study B (omalizumab intolerant 
or incomplete responders), the multiplicity procedure is proposed to control the overall Type-I 
error rate for testing the primary endpoint and the key secondary endpoints. Detailed hierarchical 
testing procedure will be defined in each study SAP.  
Study A and Study C are each considered positive when the primary endpoint achieves statistical 
significance with 2-sided significance level 0.05 for that study.  
For study B, an interim analysis will be performed using the O’Brien-Fleming approach with 
information fraction 0.77 and overall type-I error controlled at 0.05, the alpha spending at this 
interim analysis will be 0.021, and the alpha spending at the final analyses when all 104 
participants complete the study will be 0.043. The decision process that applies to this interim 
analysis is outlined in Section 9.5. 
Multiplicity adjustment for the other efficacy endpoints will be described in the study SAP. 
9.4.2 Safety analyses  
All safety analyses will be performed on the safety population. The summary of safety results will 
be presented by treatment group. The baseline value is defined generally as the last available 
value before randomization. 
Table 8 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
AE, SAE, AE 
leading to death, 
AE leading to 
permanent 
treatment 
discontinuation 
Adverse event incidence tables will present by system organ class (SOC) (sorted by internationally 
agreed order), high-level group term (HLGT), high level term (HLT) and preferred term (PT) sorted in 
alphabetical order for each treatment group, the number (n) and percentage (%) of participants 
experiencing an AE. Multiple occurrences of the same event in the same participant will be counted only 
once in the tables within a treatment phase. The denominator for computation of percentages is the 
safety population within each treatment group. 
Proportion of participants with at least 1 treatment-emergent adverse event (TEAE), treatment-emergent 
SAE, TEAE leading to death, and TEAE leading to permanent treatment discontinuation will be tabulated 
by treatment group. In addition, TEAEs will be described according to maximum intensity and relation to 
the study intervention. Serious AEs and AEs leading to study discontinuation that occur outside the 
treatment-emergent period will be summarized separately. 
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Endpoint 
Statistical Analysis Methods 
AESI and other AE 
groupings 
Incidence of each type of AESI and other AE groupings will be tabulated by treatment group. For each 
type of AESI, the following analysis will be generated. 
• 
A summary of the number (%) of participants with 
- 
Any TEAE 
- 
Any SAE (regardless of treatment-emergent status) 
- 
Any treatment-emergent SAE 
- 
Any AE leading to death 
- 
Any TEAE leading permanent treatment discontinuation 
- 
Any TEAE related to study intervention reported by the Investigator 
- 
Any TEAE by maximum intensity, corrective treatment, and final outcome 
• 
Kaplan-Meier (K-M) estimates of probability of having at least one TEAE at specific time points, 
and K-M curve to depict the course of event onset over time.  
The method to identify AESIs and other AE groupings will be specified in the SAP. 
Death 
The following deaths summaries will be generated: 
• 
Number (%) of participants who died by study period (TEAE, on-study) summarized on the 
safety population by treatment received.  
• 
Death in nonrandomized participants or randomized and not treated participants. 
• 
TEAE leading to death (death as an outcome on the AE eCRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT, and PT showing number (%) of participants sorted 
by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT. 
Laboratory 
parameters 
Results and change from baseline for the parameters will be summarized by treatment group for baseline 
and each post baseline time point, endpoint, minimum and maximum value. Summary statistics will 
include number of participants, mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The following definitions will be applied to laboratory parameters. 
• 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds 
based on literature review and defined by the Sponsor for clinical laboratory tests. 
• 
PCSA criteria will determine which participants had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, including 
unscheduled or repeated evaluations. The number of all such participants will be the numerator 
for the on-treatment PCSA percentage.  
The proportion of participants who had at least one incidence of PCSA at any time during the treatment 
emergent period will be summarized by treatment group. Shift tables showing changes with respect to 
the baseline status will be provided. 
9.4.3 Other analyses  
Pharmacokinetic, immunogenicity, PD, and biomarker exploratory analyses will be described in 
the SAP finalized before database lock. The population PK and PD analyses might be presented 
separately from the main clinical study report (CSR). 
Data collected regarding the impact of the COVID-19 or other pandemics, on the participants will 
be summarized (eg, discontinuation due to COVID-19). Any additional analyses and methods 
required to investigate the impact of COVID-19 or other pandemics pandemic requiring public 
health emergency on the efficacy (eg, missing data due to COVID-19) and safety will be detailed 
in the SAP. 
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9.5 
INTERIM ANALYSES  
The database locks will be implemented separately for Study A (omalizumab naïve), Study B 
(omalizumab intolerant or incomplete responders), and Study C (omalizumab naïve). 
No interim analysis is planned for Study A and Study C. 
For each Study A and Study C, a primary database lock will be performed when all randomized 
participants have completed their treatment phase. Final analyses in the CSR will be based on all 
data collected up to this database lock. The database will be updated at the end of the study for all 
participants to include the post-treatment follow-up information and updates for the events 
previously ongoing at the time of the primary lock. Additional data between this database lock 
and last participant completing last visit will be summarized in a CSR addendum. 
For Study B, an interim analysis (IA) will be performed when the first 80 randomized participants 
would have completed their 24-week treatment period by the interim analysis cut-off date. This 
interim analysis will use the O’Brien-Fleming approach with information fraction 0.77 and overall 
type-I error controlled at 0.05, with an alpha spending at the interim analysis of 0.021, and an 
alpha spending at the final analysis (when all 104 participants complete the study) of 0.043. 
The possible outcomes from this interim analysis are summarized below and in Table 9: 
Efficacy at IA: 
• 
In case p-value at interim analysis is ≤0.021 in ISS7 and UAS7, Study B is considered 
“Efficacy at IA for ISS7 and UAS7” (as shown in Table 9).  
• 
In case p-value at interim analysis is ≤0.021 for ISS7 and >0.1 for UAS7, Study B is 
considered “Efficacy at IA for ISS7” (as shown in Table 9). 
In case of “Efficacy at IA”, the cut-off date for the interim analysis will be considered as the 
primary database lock, the study treatment will continue, and a final database lock will occur 
when all participants have completed the last visit in the study. Additional data between this 
database lock and last participant completing last visit will be summarized in a CSR 
addendum. 
Stop for futility:  
• 
In case p-value at interim analysis is >0.1 for ISS7 and UAS7, Study B is considered “Stop 
for futility” (as shown in Table 9). 
In case of stop for futility, enrollment of additional patients will stop for Study B if 
104 patients have not been enrolled and the study treatment will be stopped for all current 
participants. Additional data between this database lock and last participant completing last 
visit will be summarized in a CSR addendum. 
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Continue up to EOT for the primary analysis:  
• For all other situations the decision is to continue the study (as shown in Table 9) until 
104 participants (52 participants per group) complete the study treatment and the final 
analysis will be conducted with an alpha 0.043.  
In this case Study B will continue up to the EOT for the primary analysis, a second database lock 
will be performed when all randomized participants have completed their treatment phase and a 
final database lock will occur when all participants have completed the last visit in the study. 
Table 9 - Possible outcomes from the Study B interim analysis  
UAS7 
(treatment effect) 
ISS7 (treatment effect) 
≤0.021 
p >0.021 and p ≤0.1  
p >0.1 
≤0.021 
Efficacy at IA for ISS7 
and UAS7  
Continue up to EOT for final analysis 
Continue up to EOT for final 
analysis 
p >0.021 and p ≤0.1 
Continue up to EOT 
for final analysis 
Continue up to EOT for final analysis 
Continue up to EOT for final 
analysis 
p >0.1 
Efficacy at IA for ISS7 
Continue up to EOT for final analysis 
Stop for futility 
To maintain study integrity with respect to the subsequent visits and analyses after the Study B 
interim analysis, a dissemination plan will be written. This plan will clearly identify 
two independent study teams and an independent committee (including a statistician). Details of 
the process will be described in the Study SAP. 
The independent committee will be in charge of analyzing and reviewing the interim analysis and 
providing guidance about the above described scenarios (continue, success or futility).  
Two independent study teams will be put in place. Specific steps will be setup to maintain the 
blind of the study to all individuals involved in the conduct of the study and/or analysis, and to 
protect the overall blinding and integrity of the study data, after the interim analysis has been 
performed. Details will be provided in the dissemination plan. 
9.5.1 Data Monitoring Committee  
Due to extensive safety record of the post-marketed IMP (dupilumab), it is not planned to have 
a Data Monitoring Committee for this study. 
9.5.2 Unblinding plan  
The unblinding plan will be detailed in the SAP or in a separate unblinding plan. 
 
 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. 
- 
Applicable ICH-GCP Guidelines. 
- 
Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant (and the parent of adolescent/child) or his/her legally authorized representative 
and answer all questions regarding the study. All participants should be informed to the 
fullest extent possible about the study, in language and terms they are able to understand. 
• It is the responsibility of the Investigator or designee (if acceptable by local regulations) to 
obtain written informed assent form (IAF) from each participant ≥6 years of age, and 
written ICF from each participant's parent(s)/caregiver(s)/legally authorized 
representative(s), prior to the participant's participation in the study, and prior to initiating 
any screening procedures. The written IAF/ICF should be signed and dated by the 
participant(s) and parent(s)/caregiver(s)/legally authorized representative(s), respectively.  
• Participants must be informed that their participation is voluntary. Participants (and 
parents of adolescents/children) or legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. Adolescents and 
children will sign simplified informed consent (IAF). If during the study the adolescent 
reaches the age of majority he/she needs to re-consent. 
• The ICF and possibly the IAF used by the Investigator for obtaining the informed consent 
of the participant and parent(s) or the participant’s legally acceptable representative must 
be reviewed and approved by the Sponsor prior to submission to the appropriate IRB/IEC 
for approval/favorable opinion. 
• For the children/adolescents’ participation, local law must be observed in deciding 
whether one or both parents/ legally authorized representatives’ consent is required. If 
only one parent or legally authorized representative signs the consent form, the 
Investigator must document the reason for only one parent or legally authorized 
representative’s signature. 
• In addition, children/adolescents will assent as detailed below or will follow the Ethics 
Committee (IRB/IEC) approved standard practice for pediatric participants at each 
participating center (age of assent to be determined by the IRBs/IECs or be consistent with 
the local requirements): 
- 
Participants who can read the IAF will do so before writing their name and dating or 
signing and dating the form. 
- 
Participants who can write but cannot read will have the IAF read to them before 
writing their name on the form. 
• The original of each completed IAF/ICF must be retained by the Investigator as part of the 
participant’s study record and a copy of the signed assent/consent form must be given to 
the participant(s)/participant’s parent(s)/caregiver(s)/legally authorized representative(s). 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
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Participants who are rescreened are required to sign a new ICF. 
For adults only, adults will have the option to provide consent for the use of remaining mandatory 
samples as well as any remaining additional serum/plasma samples for optional exploratory 
research. The Investigator or authorized designee will explain to each participant the objectives of 
the exploratory research. Participants will be told that they are free to refuse to participate and 
may withdraw their consent at any time and for any reason during the storage period. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation). 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
“Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on afro American population for the Food and Drug Administration or on 
Japanese population for the Pharmaceuticals and Medical Devices Agency in Japan)”. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.5 Committees structure  
There will be no study committees. 
10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinical trial register (eu.ctr), and sanofi.com, as well as 
some national registries. 
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In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
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10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in Study Reference Manual. 
10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
- 
Total number of participants included earlier than expected. 
10.1.10 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
The tests detailed in Table 10 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central analysis 
is obtained at the same time. Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be entered into 
the CRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.  
Table 10 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
 
 
Blood urea nitrogen 
 
Creatinine 
 
Glucose [fasting or nonfasting] 
 
Potassium 
 
Lactate dehydrogenase 
 
Uric acid 
Total cholesterol 
 
Sodium 
 
Calcium 
Chloride 
Bicarbonate 
Creatine Phosphokinase 
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total bilirubin 
 
Total protein 
Albumin 
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Laboratory assessments 
Parameters 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, and ketones [bilirubin, urobilinogen, nitrite, and 
leukocyte esterase] by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other screening tests 
• 
For women of childbearing potentialb: serum pregnancy test at screening visit 
(Visit 1) and urine pregnancy tests every 4 weeks during the study. A negative 
result must be obtained at V1 and at V2 prior to randomization. In case of 
positive urine test the study treatment will be withheld and a serum pregnancy 
test to confirm the pregnancy should be performed as soon as possible. 
Pregnancy testing should be done monthly, female participants will be supplied 
with dipsticks for months with no site visits planned. In female participants who 
discontinue the study intervention the pregnancy testing should continue for 
minimum of 12 weeks after the last dose of study intervention). 
• 
Hepatitis serologic testing at screening visit (Visit 1): hepatitis B surface antigen 
(HBs Ag), hepatitis B surface antibody (HBs Ab), hepatitis B core antibody 
(HBc Ab), and hepatitis C virus antibodies (HCV Ab). In case of results showing 
HBs Ag (negative) and HBc Ab (positive), an HBV DNA testing will be performed 
and should be confirmed negative prior to randomization. In case of results 
showing HCV Ab (positive), an HCV RNA testing will be performed and should 
be confirmed negative prior to randomization. 
• 
HIV serologic testing at screening visit (Visit 1): Human Immunodeficiency Virus 
(HIV) screen (Anti-HIV-1 and HIV-2 antibodies) 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Section 10.6. All events of [insert criteria related to ALT, bilirubin, International normalized ratio etc] which may indicate severe 
liver injury (possible Hy’s Law) must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).  
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded. 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
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• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event 
is serious. When in doubt as to whether “hospitalization” occurred or was necessary, 
the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
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- 
Examples of such events include invasive or malignant cancers, 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. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Sponsor’s representative in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
Sponsor’s representative. In such case, care should be taken to ensure that the patient's 
identity is protected and the patient's identifiers in the study are properly mentioned on any 
copy of a source document provided to the Company. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
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• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology, if available.  
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
REPORTING OF SAES 
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the protocol. 
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SAE reporting to the Sponsor via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
Documented hysterectomy 
Documented bilateral salpingectomy 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 consecutive months without 
an alternative medical cause. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. 
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CONTRACEPTION GUIDANCE 
Female participants of childbearing potential are eligible to participate if they agree to use 
a highly effective method of contraception consistently and correctly as described below. 
 
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation  
• 
Oral  
• 
Intravaginal  
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly effective methods that are user independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used. 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
 
COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive dupilumab. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
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Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of 
a participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as 
an AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described 
in Section 8.3.4 of the protocol. While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention.  
10.5 
APPENDIX 5: GENETICS  
• Use/Analysis of DNA and RNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; safety, mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants. 
• DNA and RNA samples will be used for research related to dupilumab or chronic 
spontaneous urticaria and related diseases. They may also be used to develop tests/assays 
including diagnostic tests related to dupilumab or related drugs and atopic/allergic 
diseases. Genetic research may consist of the analysis of 1 or more candidate genes or the 
analysis of genetic markers throughout the genome [including whole-exome sequencing, 
whole-genome sequencing, and DNA copy number variation. Transcriptome sequencing 
(or other methods for quantitating RNA expression) may also be performed.  
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand study disease or related conditions. 
• The Sponsor will store the DNA and RNA samples in a secure storage space with 
adequate measures to protect confidentiality. 
• The samples will be retained while research on study intervention or study interventions of 
this class or indication continues but no longer than 15 years or other period as per local 
requirements. 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND 
FOLLOW UP ASSESSMENTS  
 
*If unable to retest in 72 hours, use original laboratory results to decide on further reporting/monitoring/discontinuation. 
Note: 
“Baseline” refers to ALT sampled at Baseline Visit; or if baseline value unavailable, to the latest ALT sampled before the Baseline 
Visit. The algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.3 for guidance on safety reporting. 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or episode of 
arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances suggesting hepatic 
encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to normal/baseline or clinical 
resolution.
8.
FREEZE serum sample (5ml x 2)
9.   In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
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Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting adverse events in Section 10.3 is met. 
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10.7 
APPENDIX 7: CLINICIAN-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES  
10.7.1 Urticaria activity score (UAS)  
 
 
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10.7.2 Angioedema activity score (AAS)  
 
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10.7.3 Urticaria control test (UCT)  
 
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10.7.4 Dermatology life quality index (DLQI)  
 
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10.7.5 Children’s dermatology life quality index (CDLQI)  
 
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10.7.6 Chronic urticaria quality of life questionnaire (CU-Q2OL)  
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10.7.7 Patient Global Impression of Change (PGIC)  
10.7.8 Patient Global Impression of Severity (PGIS)  
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10.7.9 EuroQol 5-dimensional questionnaire Youth (EQ-5D-Y)  
 
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10.7.10 
5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L)  
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© EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research 
Foundation 
 
Disclaimer: This is a preview of the EQ-5D instrument. It demonstrates the text, questions and response options 
included in this version. This preview does not represent the final product and should not be used as an official EQ-
5D instrument. 
 
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10.7.11 
Missed school/work days  
 
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10.8 
APPENDIX 8: DEFINITION OF ANAPHYLAXIS  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death (37)”. 
Clinical criteria for diagnosing anaphylaxis 
 
10.9 
APPENDIX 9: LIST OF OPPORTUNISTIC INFECTIONS  
• Aspergillosis 
• Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers) 
• Candidiasis - only systemic or extensive mucosal or cutaneous candidiasis  
• Coccidioides immitis (endemic south-western US and Central and South America) 
• Cryptococcus 
• Cytomegalovirus 
• Herpes Simplex (disseminated) 
• Herpes Zoster (disseminated; ophthalmic; involvement of 2 or more dermatomes) 
• Histoplasmosis (pulmonary or disseminated; most common tropical areas 
Tennessee-Ohio-Mississippi river basins) 
• Listeriosis 
• Mycobacterium TB 
• Mycobacterium avium 
• NonTB mycobacteria 
• Pneumocystis pneumonia 
This list is indicative and not exhaustive. 
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10.10 APPENDIX 10: LIST OF PROHIBITED LIVE ATTENUATED VACCINES  
• Bacillus Calmette-Guérin (BCG) antituberculosis vaccine 
• Chickenpox (Varicella) 
• Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection 
is permitted 
• Measles (Rubeola) 
• Measles-mumps-rubella combination 
• Measles-mumps-rubella-varicella combination 
• Mumps 
• Oral polio (Sabin) 
• Oral typhoid 
• Rotavirus 
• Rubella 
• Smallpox (Vaccinia) 
• Varicella Zoster (shingles) 
• Yellow fever 
This list is indicative and not exhaustive. 
10.11 APPENDIX 11: COUNTRY-SPECIFIC REQUIREMENTS  
10.11.1 Amendment for Japan  
Section 6.5.1 Rescue medicine (see Section 6.5.1). 
Use of H1-AH antihistamines for CSU treatment 
In Japan, patients with CSU who are not well controlled on approved H1-AH dose may escalate 
the H1-AH dose only up to 2-fold the approved dose. 
All participants entering the study will be on up to 2-fold the approved dose of the non-sedating 
H1-AH. Participants will continue to take the same daily maintenance dose throughout the study 
unless they experience a flare, in which case rescue therapy may be initiated. 
Rescue therapy  
All participants on the approved non-sedating H1-AH dose (maintenance dose used at screening) 
will be allowed to take additional doses of their H1-AH medications as rescue therapy as long as 
they do not exceed 2-fold the approved dose during the screening, treatment, and follow-up 
periods. If symptoms are still uncontrolled after increase of H1-AH to the maximum allowed 
dose, participants can take a short course of OCS as rescue therapy during the treatment and 
follow-up periods.  
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The participants on maintenance dose of 2-fold the approved H1-AH dose will be allowed to take 
a short course of OCS as rescue therapy during the treatment and follow-up periods.  
In order to ensure consistency, when possible, it is recommended to use a short course of OCS for 
5 to 7 days with a starting dose of oral prednisone 40 mg (or clinically comparable OCS) followed 
by taper per the Investigator’s judgment. 
The initial maintenance antihistamine dose should remain stable throughout the study, and 
participants should continue their maintenance dose once rescue treatment is no longer required. 
The use of permitted rescue medications should be delayed, if possible, for at least 8 weeks 
following the initiation of the investigational treatment. The date and time of rescue medication 
administration as well as the name and dosage regimen of the rescue medication must be 
recorded.  
For other information related to H1-AH and OCS including safety precautions please refer to the 
National Product labeling. 
10.11.2 Amendment for France  
Section 5.1 Inclusion criteria (See Section 5.1). 
Children aged ≥6 to <12 years will not be recruited in France. 
Additionally, all references to the ≥6 to <12 years age group in this protocol will not be applicable 
in France. 
10.12 APPENDIX 12: ABBREVIATIONS  
 
AAS: 
angioedema activity score  
AAS7: 
angioedema activity score over 7 days 
ADR: 
adverse drug reaction 
AEs: 
adverse event(s) 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
CDLQI: 
children's dermatology quality life quality index 
CIU: 
chronic idiopathic urticaria 
COVID-19: 
Coronavirus disease 2019 
CRF: 
case report form 
CRSwNP: 
chronic rhinosinusitis with nasal polyposis 
CSU: 
chronic spontaneous urticaria  
CU-Q2oL: 
chronic urticaria quality of life questionnaire  
DLQI: 
dermatology life quality index 
DNA: 
deoxyribonucleic acid 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
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e-diary: 
electronic diary 
EoE: 
eosinophilic esophagitis 
EOS: 
end of study 
EOT: 
end of treatment 
EQ VAS: 
EQ visual analogue scale 
EQ-5D: 
Euroqol-5 dimensions 
EQ-5D-5L: 
5-level EuroQol 5-dimensional questionnaire 
EQ-5D-Y: 
EuroQol 5-dimensional questionnaire youth 
FcεRI: 
Fc gamma receptor 
GCP: 
Good Clinical Practice 
H1-AH: 
H1-antihistamines 
HBc Ab: 
hepatitis B core antibody 
HBs Ag: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HCV: 
hepatitis C virus 
HCV Ab: 
hepatitis C virus antibody 
HIV: 
human immunodeficiency virus 
HRQoL: 
health-related quality-of-life 
HSS7: 
weekly hives severity score 
IAF: 
informed assent form 
IB: 
investigator’s brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IEC: 
Independent Ethics Committee 
IgE: 
immunoglobulin E 
IL: 
interleukin 
IL-13: 
interleukin-13 
IL-4: 
interleukin-4 
IL-4R: 
interleukin-4 receptor 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ISS7: 
weekly itch severity score 
IVIG: 
intravenous immunoglobulin 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LTE4: 
leukotriene E4 
LTRA: 
leukotrine receptor antagonist 
mAb: 
monoclonal antibody 
MARCO: 
Margin Consolidated 
MID: 
minimal important difference 
NIMP: 
non-investigational medicinal product 
OCS: 
oral corticosteroids 
PD: 
pharmacodynamics 
PGDM: 
prostaglandin D2 metabolite 
PGIC: 
Patient Global Impression of Change 
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PGIS: 
Patient Global Impression of Severity 
PRO: 
patient-reported outcome 
q4w: 
every 4 weeks 
qd: 
once per day 
RNA: 
ribonucleic acid 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SoA: 
schedule of activities 
TB: 
tuberculosis 
Th2: 
T-helper 2 
UAS7: 
weekly urticaria activity score 
ULN: 
upper limit of normal 
WOCBP: 
women of childbearing potential 
 
10.13 APPENDIX 10: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.13.1 Amended protocol 01 (10 February 2020)  
This amended protocol01 (Amendment 01) was considered to be nonsubstantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
Overall Rationale for the Amendment  
The primary purpose of this amendment was to incorporate recommendation from Japanese 
Institutional Review Boards (IRB) clinical trial review to align H1-antihistamines (H1-AH) 
medication intake for Japanese participants with the Japanese local guidelines for treatment of 
chronic spontaneous urticaria (CSU).  
Protocol amendment summary of changes table 
Section # and 
name 
Description of change 
Brief rationale 
Table of Contents 
Document History was added 
As per request from the Japanese 
IRB during the review of the clinical 
trial application, the text is modified to 
be aligned with Japanese local 
guidelines for treatment of CSU. In 
Japan, patients with CSU who are not 
well controlled on approved H1-AH 
dose may escalate the H1-AH dose 
4.1 Overall design 
Modification of H1-AH medicine intake for Japanese patients: 
Reference provided to Section 10.11 that describes Local 
Japanese requirements 
6.5 Concomitant 
therapy 
Reference provided to Section 10.11 that describes Local 
Japanese requirements 
6.5.1 Rescue medicine 
Reference provided to Section 10.11 that describes Local 
Japanese requirements 
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Section # and 
name 
Description of change 
Brief rationale 
10.11 Appendix 11: 
Country-Specific 
Requirements 
Rescue therapy with H1-AH is modified for Japanese patients. 
H1-AH that is used as background therapy can be increased 
during time of flare to 2-fold only. If the symptoms persist or if 
the participant is already on a baseline 2-fold the approved 
dose of H1-AH at time of flare, the patient can only be rescued 
by a short course of oral corticosteroids (OCS). No further 
increase in H1-AH is allowed. 
only up to 2-fold the approved dose 
as per local guidelines. 
10.13.2  Amended protocol 02 (30 April 2020)   
This amended protocol 02 (Amendment 02) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to increase the sample size of Study A (omalizumab 
naïve population) based on recommendation from Food and Drug Administration (FDA) to power 
the studies using conservative assumptions with regards to treatment effect and variability and to 
include children aged ≥6 to <12 years (for Study A only), and to switch the primary and the key 
secondary endpoints to establish the weekly urticaria activity score (UAS7) as the primary 
endpoint for European Union (EU) and EU reference countries based on recommendations from 
European Medicines Agency (EMA). 
Protocol amendment summary of changes table 
Section # and name 
Description of change 
Brief rationale 
Title page 
NCT and WHO identifiers were added. 
This change is to add 
administrative details. 
1.1 Synopsis  
3. Objectives and 
endpoints 
In the primary objective, “adult and adolescent participants with 
CSU” was changed to “study participants”. 
This change is to simplify the 
wording of the primary objective 
with population of adults, 
adolescents and children aged ≥6 
to <12 years included in the 
primary analyses. 
1.1 Synopsis  
3. Objectives and 
endpoints 
3.1 Appropriateness of 
measurements 
4.2 Scientific rationale for 
study design 
9.1 Statistical hypotheses 
9.4.1 Efficacy analyses 
1. 
The primary endpoint was changed for EU and EU reference 
countries as follows: 
“For EU and EU reference countries only:  Change from 
baseline in weekly urticaria activity score (UAS7, composite 
patient reported itch and hive score) at Week 24”. 
2. 
Change from baseline in ISS7 “at Week 24 (in EU and EU 
reference countries)” was changed to key secondary 
endpoint for EU and EU reference countries. 
According to EMA Scientific 
Advice, UAS7 was appointed as 
the primary endpoint in the EU 
and EU reference countries. 
 
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Section # and name 
Description of change 
Brief rationale 
1.1 Synopsis  
1.3 Schedule of activities 
3.Objectives and endpoints 
8. Study assessments and 
procedures 
8.1 Efficacy assessments 
8.1.4 Dermatology life 
quality index and children’s 
dermatology quality life 
quality index 
The wording was modified for Children’s Dermatology Life Quality 
Index (CDLQI) lower age limit from ≥6 to <16 years old as follows: 
“CDLQI in patients ≥6 to <16 years old at Week 12 and Week 24”. 
The following text was added: 
“The same questionnaires as for adolescents aged <16 years will 
be used for children aged ≥6 to <12 years”. 
Patient’s age is updated for the 
completion of CDLQI 
questionnaire due to inclusion of 
children aged ≥6 to <12 years (for 
Study A). They will use CDLQI as 
well as adolescents younger than 
16 years. The CDLQI is a tool 
that has been validated in 
children. 
1.1 Synopsis  
6.3 Measures to minimize 
bias: Randomization and 
Blinding 
The following wording was added: “and children ≥6 to <12 years of 
age. In addition, in children, the study is not blinded to dose 
regimen due to the different frequency of IMP administration (q4w 
versus q2w)”. 
The text was implemented due to 
the inclusion of children aged ≥6 
to <12 years in the study.  
1.1 Synopsis 
1.2 Schema 
4.1 Overall design 
9.2 sample size 
determination 
The total anticipated number of participants across the 2 studies 
changed from “184” to “approximately 234” randomized 
participants. 
The number of participants per study arm required for the sample 
size estimate for Study A changed from “40” to “65”, the overall 
number of participants for Study A changed from “80” to “130”. 
The following terms “and up to approximately 5% of participants 
enrolled will be children ≥6 to <12 years of age (both children and 
adolescents recruited in some selected countries)” were added. 
Based on the changes in sample 
size estimate and inclusion of 
children aged ≥6 to <12 years, 
the sample size increased from 
40 to 65 participants per arm for 
Study A.  
 
1.1 Synopsis 
4.1 Overall design 
5.1 Inclusion criteria (I 07.) 
In the definition of the omalizumab incomplete responders, the 
term “at least” was added before the dose of omalizumab, and the 
wording was changed to “Omalizumab incomplete responders are 
defined as participants treated with at least 300 mg (q4w) 
omalizumab for at least 3 months (minimum of 3 injections) and 
who have had an inadequate response resulting in omalizumab 
discontinuation, as confirmed by Investigator assessment”. 
This is to clarify that patients, 
intolerant or with incomplete 
response to omalizumab, who 
took omalizumab doses higher 
than 300 mg are also eligible for 
the study. 
1.1 Synopsis 
1.2 Schema 
2.1 Study rationale 
4.1 Overall design 
4.3 Justification for dose 
6.1.1 Investigational 
medicinal product(s) 
The following wording was added:  
-  “Study A: Children ≥6 to <12 years of age: 200 mg q2w for 
children ≥30 kg at screening and 300 mg q4w for children <30 
kg and ≥15 kg at screening”. 
The dose regimen was changed by adding “q4w” for dupilumab 
and placebo, as follows: “1 injection q2w/q4w after an initial loading 
dose (2 injections) on Day 1”. 
The new text was implemented to 
reflect inclusion of children aged 
≥6 to <12 years in the Study A 
only. Different schemes of IMP 
administration will be used in 
children depending on their 
weight (≥30 or <30 kg and 
≥15 kg). 
1.1 Synopsis 
4.1 Overall design 
6.3 Measures to minimize 
bias: Randomization and 
Blinding 
The randomization was changed to the following wording: “The 
randomization will be stratified first by age (adults versus 
adolescents versus children in Study A and adults versus 
adolescents in Study B; up to approximately 5% of total sample 
size for children in Study A and approximately 5% of total sample 
size for adolescents in Studies A and B, separately). In adults, 
randomization will be stratified further by country. In 
adolescents/children ≥6 to <12 years of age, randomization will not 
be stratified further”. 
This is to clarify the stratification 
of the randomization by age with 
3 strata for Study A (adults, 
adolescents and children) and 
2 strata in study B (adults and 
adolescents). 
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Brief rationale 
1.1 Synopsis 
4.1 Overall design 
6.3 Measures to minimize 
bias: Randomization and 
Blinding 
It is anticipated that approximately 30%-40% of enrolled 
participants will have angioedema. 
This is to clarify that it is intended 
to enroll approximately 30-40% of 
patients with angioedema in the 
study in order to have a sufficient 
number of patients to assess 
effect of study intervention on 
CSU with angioedema.  
1.1 Synopsis 
9.2 Sample size 
determination 
The following wordings were added to the sample size 
determination for study A: “An effect size of 0.7 or higher is 
assumed. An absolute change of 5 in ISS7 score is considered the 
minimal clinically important difference (MCID) and an absolute 
change of 10 in UAS7 score is considered the MCID. Based upon 
an SD of 7, a change of 5 in the ISS7 would correspond to an 
effect size of approximately 0.7. Based upon an SD of 14, a 
change of 10 in the UAS7 would correspond to an effect size of 
approximately 0.7. Based on this assumption, plus the assumption 
of a 15% dropout rate and inclusion of children, it is estimated that 
65 patients per group will provide 96% power to detect an effect 
size of 0.7 or higher between the dupilumab arm and placebo 
using a  
2-sided t-test with alpha = 0.05. This sample size estimate applies 
to both ISS7 (primary endpoint for all countries except EU and EU 
reference countries) and UAS7 (primary endpoint for EU and EU 
reference countries).” 
UAS7 was added in the sample size section for study B. The 
following wording was added “and an absolute change of 10 in 
UAS7 score is considered the MCID”. “Based upon an SD of 14, a 
change of 10 in the UAS7 would correspond to an effect size of 
approximately 0.7”. “This sample size estimate applies to both 
ISS7 (primary endpoint for all countries except EU and EU 
reference countries) and UAS7 (primary endpoint for EU and EU 
reference countries).” The text was amended to provide specific 
information on statistical considerations towards UAS7 score for A 
and B studies. 
Statistical considerations were updated. The power of the study 
changed from “90%” to “96%”. 
The text was aligned with the 
primary purpose of the 
amendment. The text was also 
amended to provide specific 
information on statistical 
considerations towards UAS7 
score for A and B studies. 
1.1 Synopsis 
9.4.1 Efficacy analyses 
The following covariate “presence of angioedema at baseline” was 
added to the primary endpoint analysis. 
The analysis of covariance will 
take this covariate into account. 
 “By baseline disease severity, presence of angioedema at 
baseline” were added to the Cochran-Mantel-Haenszel (CMH) test 
as covariates for adjustment.  
“The baseline disease severity will be defined according to UAS7 
<28 and ≥28” was added. 
The wording “the corresponding baseline value, presence of 
angioedema at baseline” was added as covariates of the 
time-to-event endpoints analysis using the Cox proportional 
hazards model. 
Covariate and cut-off selections 
were added to clarify the analysis 
of secondary endpoints, such as 
responder and time-to-event 
endpoints. 
1.1 Synopsis 
The wording “including UAS7 and HSS7” was added after “The 
same principle will be applied to handle the missing data for all of 
the weekly outcomes”. 
Missing data handling section 
was amended to indicate that 
such an approach also applies to 
UAS7 and HSS7.  
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Brief rationale 
1.3 Schedule of activities 
In-clinic UAS at V1 and V2 was deleted. 
In-clinic UAS assessment at pre-
defined time points for 
confirmation of eligibility is 
considered less relevant for 
chronic spontaneous urticaria 
(CSU), a condition known with 
high fluctuating disease activity. 
E-diary based UAS7 baseline 
assessment is considered 
sufficient measure for evaluation 
of disease severity. 
1.3 Schedule of activities 
The following terms “except (for study A) for children <30 and 
≥15 kg where it will be administered every 4 weeks. The planned 
last dose is at Week 22 except (for study A) for children <30 kg and 
≥15 kg where it will be administered at Week 20” were added to 
the IMP administration.  
The text was added to implement 
information on dosing for children 
aged ≥6 to <12 years. 
Following footnote was added in the table of Schedule of activities: 
“b Participants who discontinue the study treatment prematurely 
(prior to completing the 24-week treatment period) will perform the 
end of treatment (EOT) assessments at the time of discontinuation 
to assure a complete clinical assessment in close temporal 
proximity to the premature termination of study treatment. In 
addition, to allow assessment of participant outcomes over the 
stipulated study period, participants will be asked and encouraged 
to complete all remaining study visits and participate in all 
assessments according to the visit schedule”. The alphabetical 
presentation of footnotes changed, ie, numbering of footnotes from 
“b” onwards was updated accordingly. 
The text was added to implement 
information on patients who 
prematurely discontinue the 
study. 
Following footnote was changed in the table of Schedule of 
activities from “b Loading dose: 600 mg (2 SC injections) for 
300 mg every 2 weeks (q2w) regimen for adults and adolescents 
≥60 kg OR 400 mg (2 SC injections) for 200 mg q2w for 
adolescents <60 kg” to “c Loading dose on Day 1 of 600 mg  
(2 SC injections of 300 mg) followed by 300 mg every 2 weeks 
(q2w) regimen for adults and adolescents ≥60 kg OR 400 mg 
(2 SC injections of 200 mg) followed by 200 mg q2w for 
adolescents <60 kg and children ≥30 kg (Study A) OR 600 mg 
(2 SC injections of 300 mg) followed by 300 mg q4w for children 
<30 kg and ≥15 kg (Study A) OR matched placebo”. 
The text was added to implement 
information on dosing. 
1.3 Schedule of activities 
3. Objectives and 
endpoints 
8. Study assessments and 
procedures 
8.1.7 EuroQOL 5 
dimensions questionnaire 
The following terms “5-level EuroQol 5 dimensional questionnaire 
[EQ-5D-5L] [≥16 years old], EuroQol  
5-dimensional questionnaire youth [EQ-5D-Y] [≥6 to <16 years 
old]” were added as regards with questionnaires completed for 
children. 
 
The text was added to implement 
information on completion of 
questionnaires for children aged 
≥6 to <12 years. The EQ-5D 
Youth version (EQ-5D Y) will be 
administered to children ≥6 to 
<12years old and adolescents 12 
to 15 years old. 
1.3 Schedule of activities 
8.2.2 Vital signs 
The wordings for vital signs were changed to “Vital signs will be 
measured in a semi-supine or sitting position after 5 minutes rest 
and will include axillary or oral temperature (same method of 
temperature measurement should be used during the course of the 
study)”. 
Oral temperature measurement is 
also allowed as this method is 
widely used in clinical trials. 
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Brief rationale 
1.3 Schedule of activities 
10.2 Appendix 2: CLINICAL 
LABORATORY TESTS 
The following footnote “i” was amended to: “In case of results 
showing HBs Ag (negative), and HBc Ab (positive), an HBV DNA 
testing will be performed and should be confirmed negative prior to 
randomization. In case of results showing HCV Ab (positive), an 
HCV RNA testing will be performed and should be confirmed 
negative prior to randomization”. 
This is to simplify the wording for 
the serological status analysis 
and interpretation. 
1.3 Schedule of activities 
The following wording “a specific written informed consent” was 
changed to “consent” on footnotes “l to p”. 
Wording is changed to allow 
flexibility for country specifications 
and to be aligned with global 
informed consent form (ICF). 
1.3 Schedule of activities 
 
The following wording was added in the footnote “r”: “For 
participants (with exception of adolescents and children) who 
decide to participate and provide consent for the photography, 
photographs will be taken of a representative area of CSU 
involvement for commercial activities. Instructions for taking the 
photographs are provided in the photography reference manual.” 
This is to clarify that CSU 
photographs representative area 
for commercial activities will be 
taken at selected sites at selected 
countries at baseline, Week 12, 
Week 24 and follow-up visit.  
2.3 Benefit/risk assessment 
The following sentence was added: “Moreover, in the AD pivotal 
trial submitted for registration to the US and EU, the efficacy and 
safety of dupilumab in children aged ≥6 to <12 years old with AD 
was comparable to that in older patients”. 
This is to clarify the positioning of 
dupilumab in children aged ≥6 to 
<12 years. 
The following paragraph was added: 
“Based on clinical studies in AD, the safety profile in pediatric 
patients (aged ≥6 to <12 years) appears similar to that of adults 
and adolescents with AD. As of 28 September 2019, 386 children 
aged ≥6 to <12 years had been exposed to dupilumab in AD 
clinical trials, with a total of 339.8 person-years of exposure”. 
This is to implement information 
on experience with dupilumab in 
children aged ≥6 to <12 years in 
pediatric studies in the AD 
indication. 
4.3 Justification for dose 
The following wording was added “The doses proposed for children 
≥6 to <12 years of age are the dose regimens for the same age for 
AD, which have been submitted to the Health Authorities and are 
currently in review”. 
The text was added to implement 
information on dosing for children 
aged ≥6 to <12 years.  
5.1 Inclusion criteria 
I.01 Inclusion criterion was changed to: 
“Study A: Participant must be ≥6 years to 80 years of age at the 
time of signing the informed consent.  
Study B: Participant must be ≥12 years (or the minimum legal age 
for adolescents in the country of the investigational site) to 
80 years of age at the time of signing the informed consent”. 
Note: For those countries where local regulations do not permit 
enrollment of children aged ≥6 to <12 years of age, the recruitment 
will be restricted to those who are ≥12 years of age (or the 
minimum legal age for adolescents in the country of the 
investigational site). For those countries where local regulations do 
not permit enrollment of children aged ≥6 to <12 years and 
adolescents, the recruitment will be restricted to those who are 
≥18 years of age. 
This is to clarify participants’ age 
for each study at the time of 
signing the informed consent. The 
criterion was changed for Study A 
since children aged ≥6 to 
<12 years are newly eligible.  
Participation of children in each 
country is made voluntary and 
depends on local country 
regulations, Health Authorities 
and IRB/EC approval. 
I.06 Inclusion criterion “In clinic UAS>4 prior to randomization (at 
V1 or V2)” was deleted. 
In-clinic UAS assessment at pre-
defined time points for 
confirmation of eligibility is 
considered less relevant for CSU, 
a condition known with high 
fluctuating disease activity.  
E-diary based weekly UAS7 
baseline assessment is 
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considered sufficient measure for 
evaluation of disease severity. 
The inclusion criterion I.10 was changed to ”Participants ≥6 and 
<18 years of age must provide written informed assent, and their 
parent(s)/caregiver(s)/legally authorized representative(s) must 
sign the specific ICF. In countries where legal age of majority is 
˃18 years, a specific ICF must also be signed by the participant’s 
legally authorized representative”. 
This is to clarify that both the child 
and adolescent must provide 
written informed assent and the 
parent(s)/caregiver(s)/legally 
authorized representative(s) must 
sign the specific ICF. 
5.2 Exclusion Criteria 
The wording changed to “weight is less than 30 kg in adults and 
adolescents and 15 kg in children aged ≥6 to <12 years” on E01. 
The E01 criterion is updated. The 
weight limit of <30 kg continues to 
be applicable for adults and 
adolescents. In Study A the 
children aged ≥6 to <12 years 
have a lower limit for inclusion of 
15 kg. 
The wording “and during the screening period” was added to the 
exclusion criterion E08. 
The E08 criterion is updated. 
Patients who had also significant 
infections during the screening 
period are not eligible. 
Omalizumab washout period was amended from 5 to 4 months 
before screening visit (V1).  
The E17 criterion is updated to 
reflect 5 half-lives of omalizumab 
in CSU patients as per 
omalizumab label. The decrease 
in waiting period also provides a 
potential treatment option with the 
study medication for patients with 
a high medical need. 
6.1.1 Investigational 
medicinal product 
The intervention name details were updated and changed to: “For 
adults and adolescents ≥60 kg: Dupilumab 300 mg (q2w) 
For adolescents <60 kg and children ≥6 to <12 years of age ≥30 
kg: Dupilumab 200 mg (q2w) 
For children ≥6 to <12 years of age <30 kg and ≥15 kg: Dupilumab 
300 mg (q4w)”. 
Similar changes were made for the placebo matching dupilumab 
200 mg/300 mg. 
For dupilumab, the following terms were added: “300 mg every 
28 ±3 days after an initial loading dose of 600 mg”. The text was 
aligned for placebo. 
The following terms “or 28 ±3 days (Q4W) for children <30 kg and 
≥15 kg” were added to the IMP administration. 
This is to clarify study 
interventions administered and 
dosage levels for the pediatric 
population. 
“Drug visits” were replaced by “drug administrations”. 
Minor correction is made. 
The following wording is added: “For children ≥6 to <12 years, no 
self-administration of IMP is allowed by the participant, but 
parent(s)/caregiver(s)/legally authorized representative(s) who are 
trained by the Investigator or designee to prepare and administer 
IMP may perform home administration of IMP”. 
This is to clarify that home 
administration of IMP will be 
performed by 
parent(s)/caregiver(s)/legally 
authorized representative(s) for 
children ≥6 to <12 years. 
7.2 Participation 
discontinuation/withdrawal 
from the study 
The following wording was added “or if his/her 
parent(s)/caregiver(s)/legally authorized representative(s) decide to 
do so”. “Parent(s)/caregiver(s)/legally authorized representative(s)” 
was added to “participants”.  
This is to clarify that 
caregiver(s)/legally authorized 
representative(s) can withdraw 
consent for children/adolescent 
patients. 
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Brief rationale 
8. Study assessments and 
procedures 
The following wording was added: “In light of the public health 
emergency related to COVID-19 (Coronavirus disease 2019) (or in 
case of any other pandemic requiring public health emergency), 
the continuity of clinical study conduct and oversight may require 
implementation of temporary or alternative mechanisms eg, phone 
contact, virtual visits, online meetings, use of local clinic or 
laboratory locations, and home visits by skilled staff. 
Implementation of such mechanisms may differ country by country, 
depending on country regulations and local business continuity 
plans.  Additionally, no waivers to deviate from protocol enrollment 
criteria due to COVID-19 (or any other pandemic) will be granted. 
All temporary mechanisms utilized, and deviations from planned 
study procedures are to be documented as being related to 
COVID-19 (or any other pandemic) and will remain in effect only for 
the duration of the public health emergency.” 
This is to describe alternative 
temporary mechanism that can 
be implemented in the study 
conduct in case of pandemic 
requiring public health emergency 
eg, COVID-19. 
8. Study assessments and 
procedures 
8.1 Efficacy assessments 
The following terms were added: “Parent(s)/caregiver(s)/ legally 
authorized representative(s) should not select any of the response 
choices on behalf of their child”. 
“Patient(s)/parent(s)/caregiver(s)/legally authorized 
representative(s)” were added to “participant(s)”. 
This is to clarify that adolescents 
as well as children may be helped 
by their parents/caregivers for the 
reading and the understanding of 
the instructions before the 
completion of questionnaires, and 
that parents/caregivers will not 
answer instead of their child. 
“The maximum amount of blood collected from each participant 
over the duration of the study, including any extra assessments 
that may be required, will not exceed 168 mL” (instead of 209 mL).  
“The maximum amount of blood collected expected as per 
schedule of activities from each adolescent over the duration of the 
study will not exceed 101 mL” (instead of 100 mL). 
The following wording was added for children aged ≥6 to 
<12 years: “The maximum amount of blood collected from each 
child will be compliant with the European guideline (27). The 
maximum amount of blood collected per each visit from each child 
aged ≥6 to <12 years will not exceed 11 mL per visit and the total 
maximum amount of blood collected expected as per schedule of 
activities for each child over the duration of the study will not 
exceed 47 mL”. 
Standard blood volumes were 
corrected for the study.  
8.5.1.2 Handling 
procedures 
Blood sample volume of 2 mL was added for children aged ≥6 to 
<12 years. 
This is to specify the volume of 
blood taken from children ≥6 to 
<12 years of age that is lower 
than that of adults and 
adolescents. 
9.1 Statistical hypotheses 
The statistical hypotheses changed from “for comparing dupilumab 
300 mg q2w against placebo” to “for comparing dupilumab”. 
The “300 mg q2w” was deleted 
here as “dupilumab” also included 
200 mg q2w dose for adolescents 
<60 kg. 
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9.4.3 Other analyses 
The following wording was added: 
“Data collected regarding the impact of the COVID-19 or other 
pandemics, on the patients will be summarized (eg, discontinuation 
due to COVID-19). Any additional analyses and methods required 
to investigate the impact of COVID-19 or other pandemics 
pandemic requiring public health emergency on the efficacy (eg, 
missing data due to COVID-19) and safety will be detailed in the 
SAP”. 
This is to describe alternative 
temporary mechanism that can 
be implemented in the study 
conduct in case of pandemic 
requiring public health emergency 
eg, COVID-19. 
10.1.3 Informed consent 
process 
The following wording was deleted: 
“A copy of the ICF(s) must be provided to the participant or the 
participant’s legally authorized representative”. 
The following wording was added: 
“• All participants should be informed to the fullest extent possible 
about the study, in language and terms they are able to 
understand. 
• It is the responsibility of the Investigator or designee (if 
acceptable by local regulations) to obtain written informed assent 
form (IAF) from each participant ≥6 years of age, and written ICF 
from each participant's parent(s)/caregiver(s)/legally authorized 
representative(s), prior to the participant's participation in the 
study, and prior to initiating any screening procedures. The 
written IAF/ICF should be signed and dated by the participant(s) 
and parent(s)/caregiver(s)/legally authorized representative(s), 
respectively.  
• The ICF and possibly the IAF used by the Investigator for 
obtaining the informed consent of the participant and parent(s) or 
the participant’s legally acceptable representative must be 
reviewed and approved by the Sponsor prior to submission to the 
appropriate IRB/IEC for approval/favorable opinion. 
• For the children/adolescents’ participation, local law must be 
observed in deciding whether one or both parents/ legally 
authorized representatives’ consent is required. If only one 
parent or legally authorized representative signs the consent 
form, the Investigator must document the reason for only one 
parent or legally authorized representative’s signature. 
• In addition, children/adolescents will assent as detailed below or 
will follow the Ethics Committee (IRB/IEC) approved standard 
practice for pediatric participants at each participating center 
(age of assent to be determined by the IRBs/IECs or be 
consistent with the local requirements): 
- Participants who can read the IAF will do so before writing their 
name and dating or signing and dating the form. 
- Participants who can write but cannot read will have the IAF 
read to them before writing their name on the form. 
• The original of each completed IAF/ICF must be retained by the 
Investigator as part of the participant’s study record and a copy 
of the signed assent/consent form must be given to the 
participant/participant’s parent(s)/caregiver(s)/legally authorized 
representative(s)”. 
Informed consent form section 
was adapted for children. 
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The wording as regards to ICF was amended as follows: 
“For adults only, adults will have the option to provide consent for 
the use of remaining mandatory samples as well as any remaining 
additional serum/plasma samples for optional exploratory 
research”.  
Wording is changed to allow 
flexibility for country specifications 
and to be aligned with global ICF. 
 
10.3 Appendix 3: 
ADVERSE EVENTS: 
DEFINITIONS AND 
PROCEDURES FOR 
RECORDING, 
EVALUATING, FOLLOW-
UP, AND REPORTING 
Recording and follow-up of 
AE and/or SAE 
“In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical 
records before submission to Sponsor.” was replaced by “In such 
case, care should be taken to ensure that the patient's identity is 
protected and the patient's identifiers in the study are properly 
mentioned on any copy of a source document provided to the 
Company”. 
The amended text was aligned 
with internal new process for the 
management of complementary 
source documents in the scope of 
the Safety Data Flow 
improvement program, in order to 
minimize the transfer of personal 
data to be compliant with the 
General Data Protection 
Regulation (GDPR), and 
harmonize processes across 
countries. 
10.13 Appendix 10: 
Protocol Amendment 
History  
The overall rationale and table with summary of changes for 
Amended protocol 01 were moved from the Cover page to Section 
10.13. 
This is aligned with Sanofi 
procedures. 
10.12 Appendix 12: 
Abbreviations 
IAF was added in the list of abbreviations. 
IAF was added as the ICF section 
was adapted for children. 
11. References 
Reference No. 1 was newly added. The following reference was 
deleted: “Saini SS, Bindslev-Jensen C, Maurer M, Grob JJ, Baskan 
EB, Bradley MS, et al. Efficacy and safety of omalizumab in 
patients with chronic idiopathic/spontaneous urticaria who remain 
symptomatic on H1 Antihistamines: A randomized, placebo-
controlled Study. J Invest Dermatol. 2015;135(1):67-75”, and the 
referencing numbering was updated accordingly. 
The list of references was 
updated to refer the maximum 
amount of blood collected from 
children per visit and as per 
schedule of activities according to 
the European guideline. 
Global 
Minor edits and typo fixes were made. 
This is to improve clarity. 
The wording “Children” was added to “adolescents”. 
This is for consistency with the 
study design. 
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10.13.3 Amended protocol 03 (09 October 2020)  
This amended protocol 03 (Amendment 03) was considered to be nonsubstantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
Overall Rationale for the Amendment  
The primary purpose of this amendment was to address requirement of the French Ethic 
Committee to clearly specify in the protocol that children aged ≥6 to <12 years would not be 
recruited in France (see Appendix 11, Section 10.11.2 for specifics).  
Protocol amendment summary of changes table 
Section # and name 
Description of change 
Brief rationale 
1.1 Synopsis 
“In some selected countries” was added next 
to inclusion of children (≥6 to <12 years) in 
the study. 
As per request from the French Ethic 
Committee, the wording is modified to 
specify that children aged ≥6 to 
<12 years will not participate in the study 
in France.  
5.1 Inclusion Criteria 
For inclusion criterion I.01, reference 
provided to Appendix 11 (Section 10.11.2) 
that describes Local French requirements 
was added. 
10.11.2 Amendment for France  
Inclusion criterion I01 is modified for French 
participants to exclude participation of 
children aged ≥6 to <12 years, and a 
blanket statement is provided which 
confirms that all references to the ≥6 to 
<12 years age group in this protocol will not 
be applicable in France.  
10.13.4 Amended protocol 04 (29 April 2021)  
This amended protocol 04 (Amendment 04) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
EFC16461 is a double-blind placebo controlled phase 3 study in patients with chronic 
spontaneous urticaria (CSU) who remain symptomatic despite the use of H1 antihistamine 
treatment, composed of Study A conducted in patients naïve to omalizumab and Study B in 
patients who are intolerant or incomplete responders to omalizumab.  
There is no change to the Study A conduct or analysis plan. 
The primary purpose of this amendment is to plan for an interim analysis for Study B when 
80 randomized participants would have completed their 24-week treatment period. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Front page 
Sponsor name and address added 
These were missing in 
amended protocol 03 
Section 1.1 Synopsis 
- Number of participants  
Added:  
An interim analysis will be performed when the first 80 randomized 
patients would have completed their 24-week treatment period, by 
the interim analysis cut-off date. 
Due to COVID impact and 
associated difficulties to enroll 
patients in Study B (intolerant or 
incomplete responders to 
omalizumab), an interim 
analysis of Study B will be 
performed to allow an earlier 
assessment of efficacy or stop 
for futility in this population. 
This protocol amendment 
describes the details of this 
interim analysis with possible 
scenarios for study 
discontinuation for considering 
efficacy, continuation or 
stopping the study. Blinding and 
integrity of the study will be 
ensured by appropriate 
measures. 
Section 1.1 Synopsis 
- Sample size 
calculations 
Added:  
Considering the reduced drop-out rate of 10% observed during the 
study, an interim analysis will be performed when the first 80 
randomized patients would have completed their Week 24 visit by 
the interim analysis cut-off date. Using the O’Brien-Fleming 
approach with information fraction 0.77 and overall type-I error 
controlled at 0.05, the alpha spending at this interim analysis will be 
0.021, and the alpha spending at the final analysis when all 
104 patients complete the study will be 0.043.  
At the Study B interim analysis, it is estimated that 40 patients per 
group will provide 74% power to detect a treatment effect of 5 or 
higher with SD 7 and minimal detectable difference (MDD) of 
approximately 3.8 for ISS7 and a treatment effect of 10 or higher 
with SD 14 and MDD of approximately 7.6 for UAS7 between the 
dupilumab arm and placebo using a 2-sided t-test with alpha = 
0.021.  
With the decision process outlined in section 9.5, the overall power 
for the study will be approximately 88%. 
Updated:  
The sample size calculations and the alpha spending by O’Brien-
Fleming approach were calculated by nQuery Advisor and nTerim 
4.0. 
Section 1.1 Synopsis 
Analysis population 
Added: 
For Study B interim analysis, the primary analysis population will be 
the intent-to-treat24 (ITT24) population, defined as all patients who 
were randomized at least 24 weeks before the interim analysis cut-
off date and would have completed the Week 24 visit by the cut-off 
date of interim analysis. 
Section 1.1 Synopsis 
Multiplicity considerations 
Updated: 
Within each study, Study A (omalizumab naïve) and Study B 
(omalizumab intolerant or incomplete responders), the multiplicity 
procedure is proposed to control the overall Type-I error rate for 
testing the primary endpoint and the key secondary endpoints. 
Detailed hierarchical testing procedure will be defined in the study 
SAP.  
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Section # and Name 
Description of Change 
Brief Rationale 
 
Added:  
Study A is considered positive when the primary endpoint achieves 
statistical significance with 2-sided significance level 0.05. 
At the interim analysis, the study B is considered positive when the 
primary endpoint achieves statistical significance using  
2-sided significance level 0.021. If Study B meets the criteria to 
continue at the interim analysis, at the final analysis of Study B, it will 
be considered positive when the primary endpoint achieves 
statistical significance using 2-sided significance level 0.043. 
Multiplicity adjustment for the other efficacy endpoints will be 
described in the study SAP. 
Section 1.1 Synopsis 
Planned database lock 
date/interim analysis 
Added in section title: /Interim analysis 
Added: In addition, an interim analysis will be performed for Study B 
when the defined ITT24 population data are available. 
Section 9.2 Sample size 
determination 
Added:  
Considering the reduced drop-out rate of 10% observed during the 
study, an interim analysis will be performed when the 
first 80 randomized patients would have completed their Week 24 
visit by the interim analysis cut-off date. Using the O’Brien-Fleming 
approach with information fraction 0.77 and overall type-I error 
controlled at 0.05, the alpha spending at this interim analysis will be 
0.021, and the alpha spending at the final analyses when all 
104 patients complete the study will be 0.043.  
At the Study B interim analysis, it is estimated that 40 patients per 
group will provide 74% power to detect a treatment effect of 5 or 
higher with SD 7 and minimal detectable difference (MDD) of 
approximately 3.8 for ISS7 and a treatment effect of 10 or higher 
with SD 14 and MDD of approximately 7.6 for UAS7 between the 
dupilumab arm and placebo using a 2-sided t-test with alpha = 
0.021.  
With the decision process outlined in section 9.5, the overall power 
for the study will be approximately 88%. 
Updated:  
The sample size calculations and the alpha spending by O’Brien-
Fleming approach were calculated by nQuery Advisor and nTerim 
4.0. 
Section 9.3 Populations 
for analyses 
 
 
 
 
 
Efficacy 
Added in Table 5: the ITT24 population (for the Study B interim 
analysis).  
All participants who were randomized at least 24 weeks before the 
interim analysis cut-off date and would have completed the Week 24 
visit by the cut-off date of interim analysis. The exact interim analysis 
cut-off date will be specified in the SAP, which will be finalized before 
the interim analysis. 
Updated in Table 5: The ITT population (ITT24 for Study B interim 
analysis). 
Section 9.4.1 Efficacy 
analysis 
Added:  
For study B, an interim analysis will be performed using the O’Brien-
Fleming approach with information fraction 0.77 and overall type-I 
error controlled at 0.05, the alpha spending at this interim analysis 
will be 0.021, and the alpha spending at the final analyses when all 
104 patients complete the study will be 0.043. The decision process 
that applies to this interim analysis is outlined in Section 9.5. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.5 Interim 
analysis 
Updated: 
No interim analysis is planned for Study A. 
For Study A, a primary database lock will be performed when all 
randomized participants have completed their treatment phase. Final 
analysis in the CSR will be based on all data collected up to this 
database lock. The database will be updated at the end of the study 
for all participants to include the post-treatment follow-up information 
and updates for the events previously ongoing at the time of the 
primary lock. Additional data between this database lock and last 
participant completing last visit will be summarized in a CSR 
addendum. 
Added:  
For Study B, an interim analysis (IA) will be performed when the first 
80 randomized participants would have completed their  
24-week treatment period by the interim analysis cut-off date. This 
interim analysis will use the O’Brien-Fleming approach with 
information fraction 0.77 and overall type-I error controlled at 0.05, 
with an alpha spending at the interim analysis of 0.021, and an alpha 
spending at the final analysis (when all 104 patients complete the 
study) of 0.043. 
The possible outcomes from this interim analysis are summarized 
below and in Table 8: 
Efficacy at IA: 
• 
In case p-value at interim analysis is ≤0.021 in ISS7 and 
UAS7, Study B is considered “Efficacy at IA for ISS7 and 
UAS7” (as shown in Table 8).  
• 
In case p-value at interim analysis is <=0.021 for ISS7 and 
>0.1 for UAS7, Study B is considered “Efficacy at IA for 
ISS7” (as shown in Table 8). 
 
In case of “Efficacy at IA”, the cut-off date for the interim analysis will 
be considered as the primary database lock, the study treatment will 
continue, and a final database lock will occur when all participants 
have completed the last visit in the study. Additional data between 
this database lock and last participant completing last visit will be 
summarized in a CSR addendum. 
Stop for futility:  
• 
In case p-value at interim analysis is >0.1 for ISS7 and 
UAS7, Study B is considered “Stop for futility” (as shown in 
Table 8).  
In case of stop for futility, enrollment of additional patients will stop 
for Study B if 104 patients have not been enrolled and the study 
treatment will be stopped for all current participants. Additional data 
between this database lock and last participant completing last visit 
will be summarized in a CSR addendum. 
 
Continue up to EOT for the primary analysis:  
• 
For all other situations the decision is to continue the study 
(as shown in Table 8) until 104 patients (52 patients per 
group) complete the study treatment and the final analysis 
will be conducted with an alpha 0.043.  
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Section # and Name 
Description of Change 
Brief Rationale 
In this case Study B will continue up to the EOT for the primary 
analysis, a second database lock will be performed when all 
randomized participants have completed their treatment phase and a 
final database lock will occur when all participants have completed 
the last visit in the study. 
Table with p values added, as Table 8 (Table 8 in amended protocol 
03 becomes Table 9) 
Table 8: Possible outcomes from the Study B interim analysis. 
 
To maintain study integrity with respect to the subsequent visits and 
analyses after the Study B interim analysis, a dissemination plan will 
be written. This plan will clearly identify two independent study teams 
and an independent committee (including a statistician). Details of 
the process will be described in the Study SAP.  
The independent committee will be in charge of analyzing and 
reviewing the interim analysis and providing guidance about the 
above described scenarios (continue, success or futility).  
Two independent study teams will be put in place. Specific steps will 
be setup to maintain the blind of the study to all individuals involved 
in the conduct of the study and/or analysis, and to protect the overall 
blinding and integrity of the study data, after the interim analysis has 
been performed. Details will be provided in the dissemination plan. 
Section 10 Supporting 
documentation and 
operational 
considerations 
Section 10.13 was added  
To include Protocol Amendment 
History for amended protocol 03 
 
 
UAS7 (treatment effect) 
ISS7 (treatment effect) 
 
≤0.021 
p>0.021 
and p≤0.1  
p>0.1 
≤0.021 
Efficacy at IA 
for ISS7 and 
UAS7  
Continue 
up to EOT 
for final 
analysis 
Continue up to 
EOT for final 
analysis 
p>0.021 and p≤0.1 
Continue up to 
EOT for final 
analysis 
Continue 
up to EOT 
for final 
analysis 
Continue up to 
EOT for final 
analysis 
p>0.1 
Efficacy at IA 
for ISS7 
Continue 
up to EOT 
for final 
analysis 
Stop for 
futility 
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11 
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