Conditions: Cold Urticaria
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 82
Healthy volunteers: no

Brief summary:
Primary Objective:

To demonstrate the efficacy of dupilumab in adult and adolescent participants with primary acquired chronic inducible cold urticaria (ColdU) who remain symptomatic despite the use of an H1-antihistamine

Secondary Objectives:

To demonstrate the efficacy of dupilumab on primary acquired chronic inducible ColdU disease control To demonstrate the efficacy of dupilumab on primary acquired chronic inducible ColdU local signs and symptoms (hives/wheals, itch, burning sensation and pain) after provocation test To demonstrate the efficacy of dupilumab on primary acquired chronic inducible ColdU disease activity To demonstrate improvement in health-related quality-of-life and overall disease status and severity To evaluate the ability of dupilumab in reducing the proportion of participants who require rescue therapy To evaluate the proportion of participants with cold exposure triggered urticaria To evaluate safety outcome measures To evaluate immunogenicity of dupilumab

Detailed description:
The duration of study for each participant included 2-4 weeks of screening period, 24 weeks of treatment period and 12 weeks of post treatment period.

Arms:
arm 1: Dose regimens, on top of regular or as needed non-sedating H1-antihistamine arm 2: Placebo, on top of regular/as needed non-sedating H1-antihistamine

Interventions: intervention 1: Dupilumab SAR231893 intervention 2: Placebo intervention 3: Non sedating H1-antihistamine
Intervention descriptions: intervention 1: Pharmaceutical form: Injection solution Route of administration: Subcutaneous intervention 2: Pharmaceutical form: Injection solution Route of administration: Subcutaneous intervention 3: Pharmaceutical form: Tablet Route of administration: Oral

Protocol document:
Prot_000.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
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 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01  
Protocol title: 
A randomized, double-blind, placebo-controlled, multi-
center, parallel-group study of dupilumab in patients with 
chronic inducible cold urticaria who remain symptomatic 
despite the use of H1-antihistamine treatment 
Protocol number: 
EFC16720 
Amendment number: 01 
Compound number 
(INN/Trademark): 
SAR231893/REGN668 
dupilumab/Dupixent® 
Study phase: 
Phase 3 
Short title: 
Dupilumab for the treatment of chronic inducible cold 
urticaria in patients who remain symptomatic despite the 
use of H1-antihistamine 
LIBERTY-CINDU CUrIADS 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address: 
1 avenue Pierre Brossolette 
91385 Chilly-Mazarin Cedex 
FRANCE 
Monitoring Team’s 
Representative Name 
and Contact 
Information 
 
Regulatory agency identifier number(s): 
IND:  
IND105379 
EudraCT: 
2020-003756-33 
NCT: 
NCT04681729 
WHO: 
U1111-1246-6913 
Other: 
Not applicable 
 
Date: 
27-Sep-2022 
Total number of pages: 137 
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Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/ 
countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 01  
All 
27 September 2022, version 1 (electronic 1.0) 
Original Protocol 
 
25 September 2020, version 1 (electronic 2.0) 
Amended protocol 01 (27 September 2022) 
This amended protocol (amendment 01) 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 redefine the Cold Urticaria Activity Score 
(ColdUAS) efficacy endpoints. It is anticipated that the newly defined ColdUAS endpoints are 
more sensitive to detect a treatment effect and will better address the objectives of the EFC16720 
study. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis -
Objectives and 
endpoints/ 
Section 3 
Objectives and 
endpoints/ 
Section 9.4.1 
efficacy analyses/ 
Section 10.13 
Appendix 13 -
Estimands for main 
endpoints 
The following ColdUAS secondary endpoints have been 
removed: 
- Proportion of participants with cold exposure triggered 
urticaria signs and symptoms at Week 12 and Week 24 as 
measured by ColdUAS compared with placebo 
- Proportion of days with cold exposure triggered urticaria 
signs and symptoms at Week 12 and Week 24 as measured 
by ColdUAS compared with placebo 
- Proportion of participants with severe cold exposure 
triggered urticaria signs and symptoms at Week 12 and 
Week 24 as measured by ColdUAS compared with placebo 
- Proportion of days with severe cold exposure triggered 
urticaria signs and symptoms at Week 12 and Week 24 as 
measured by ColdUAS compared with placebo 
 
 
 
Newly proposed secondary endpoints 
are considered sensitive to detect a 
shift in cold urticaria signs and 
symptoms severity, either via reduction 
in signs/symptoms severity score or 
change in proportion of symptom free 
days. Symptom free days are 
considered clinically meaningful for 
assessment of treatment benefit. 
 
 
 
 
 
 Of note, 
there will be no change in data 
collection for ColdUAS. The proposed 
modifications affect the ColdUAS data 
analysis. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
And replaced by the following secondary endpoints: 
• 
Change from baseline in cold urticaria signs and 
symptoms severity at Week 24 on cold exposure 
days as measured by ColdUAS, compared with 
placebo 
• 
Change from baseline in the proportion of cold 
urticaria sign and symptom free days at Week 24 
on cold exposure days as measured by ColdUAS, 
compared with placebo 
And the following tertiary/exploratory endpoint: 
• 
 
 
 
Section 1.1 
Synopsis Objectives 
and endpoints/ 
Section 3 
Objectives and 
endpoints/ 
Section 9.4.1 
efficacy analyses 
The following endpoints were no longer considered as 
secondary endpoints but were moved to exploratory 
endpoints: 
• 
Patient Global Impression of Change (PGIC) of 
primary acquired chronic inducible ColdU at 
Week 12 and Week 24 compared with placebo 
• 
Change from baseline in Patient Global Impression 
of Severity (PGIS) of primary acquired chronic 
inducible ColdU at Week 12 and Week 24 
compared with placebo 
PGIS and PGIC scales are used in the 
study as a benchmark/anchor 
instrument for the analysis of the other 
patient-reported outcomes (PROs). 
Therefore, they were considered 
exploratory endpoints rather than 
secondary ones.  
Section 1.1 
Synopsis Objectives 
and endpoints/ 
Section 3 
Objectives and 
endpoints/ 
Section 9.4.1 
efficacy analyses/ 
Section 10.13 
Appendix 13 -
Estimands for main 
endpoints 
The following secondary endpoint was removed: 
• 
Time to first rescue therapy for primary acquired 
chronic induced ColdU during the planned 
treatment period compared with placebo 
Cold urticaria signs and symptoms as 
well as need for rescue therapy occur 
episodically. Analysis of “Time to onset 
of rescue therapy” will likely be 
confounded by this factor. This 
endpoint was removed since the 
Sponsor considered the secondary 
endpoint of “proportion of participants 
receiving rescue therapy” already 
defined in the protocol as sufficient to 
evaluate the effect of the study 
intervention on rescue therapy need.  
Section 3 
Objectives and 
endpoints/ 
Section 9.4.1 
efficacy analyses 
The following tertiary/exploratory endpoints were removed: 
• 
Change from baseline in 
 at Week 12 
and at Week 24 compared with placebo 
• 
Change from baseline in 
 over time up to 
Week 24 compared to placebo 
• 
Change from baseline in HRQoL as measured by 
Cold Urticaria Quality of Life (ColdU-QoL) 
questionnaire at Week 24 compared placebo 
 scoring is not validated by 
the scale developer and therefore the 
endpoints evaluating change in 
 score were removed. 
 
 
This endpoint was removed from 
tertiary endpoints as it was already 
mentioned as a secondary endpoint 
(was duplicated by error). 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis  
Analysis of 
secondary 
endpoints/ 
Section 9.4.1 
Efficacy analyses/ 
Section 10.13 
Appendix 13 -
Estimands for main 
endpoints 
• 
Change in the imputation rule from “worst possible 
value” to “worst observation carried forward 
(WOCF) approach” for participants taking highly 
influential prohibited medications and/or highly 
influential rescue medications. 
• 
The following changes related to missing data 
handling were made: For participants who 
discontinue study intervention 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 study 
intervention 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 highly influential prohibited medications 
and/or highly influential rescue medications on or 
before Week 24 and excluding patients who 
discontinue due to lack of efficacy on or before 
Week 24. 
Handling of missing data after taking 
highly influential prohibited medications 
and/or highly influential rescue 
medications or after withdrawal of 
study intervention are modified to 
include each participant's own worst 
data in order to better reflect the clinical 
scenario of treatment failure. 
 
Section 6.3 
Measures to 
minimize bias: 
Randomization and 
blinding 
• 
Code breaking: Investigator could decide at his/her 
discretion to contact the Sponsor to discuss the 
situation prior to unblinding participant’s 
intervention assignment. 
To clarify that the responsibility to 
unblind treatment assignment in 
emergency situations resides solely 
with the investigator as per the EMA 
GCP Inspectors Working Group (GCP 
IWG) and the Clinical Trial Facilitation 
Group (CTFG). Consequently, the 
Sponsor cannot require or insist on 
being involved in the decision to 
unblind, stall or delay in any way the 
unblinding of trial participant treatment 
in emergency situations. 
Section 8.1.5 Cold 
Urticaria Activity 
Score 
• 
The following text was removed: “
 
 
. The 
 will be assessed over 
prior to baseline, Week 12, and Week 24”. 
 scoring is not validated by 
the scale developer and therefore the 
endpoints evaluating change in 
 score were removed. 
• 
Text was corrected as follows: After each week of 
completion, participants will be asked 2 additional 
questions about the overall disease activity of their 
ColdU in the past week using a 4-point Likert scale 
from “No disease activity” to “High disease activity” 
and 1 question about their current disease activity 
in the past week compared with before treatment 
using a 4-point Likert scale.  
And the following text was deleted : “After each 
2 weeks of completion, participants will be asked 
about the overall disease activity of their ColdU in 
the past 2 weeks using a 4-point Likert scale from 
“No disease activity” to “High disease activity”, and 
they should rate disease activity in the second 
Correction of error 
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Section # and 
Name 
Description of Change 
Brief Rationale 
week compared with first week from “markedly 
higher than in the first week” to “markedly lower 
than in the first week”. 
Section 10.1.6 
Dissemination of 
clinical study data 
• 
Reference to ‘clinicalstudydatarequest.com’ was 
changed to “https://vivli.org” 
Change in the Sponsor’s data sharing 
platform. 
10.15 Appendix 15: 
Protocol 
amendment history 
• 
Section updated to state that the Protocol 
Amendment Summary of Changes Table for the 
current amendment is located directly before the 
Table of Contents. 
Aligned with Sanofi procedures. 
Global 
• 
Minor editorial/formatting changes. 
Correction of minor editorial/formatting 
issues 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 01 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 6 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 11 
1 
PROTOCOL SUMMARY ............................................................................................................... 12 
1.1 
SYNOPSIS ..................................................................................................................................... 12 
1.2 
SCHEMA ........................................................................................................................................ 23 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 24 
2 
INTRODUCTION ............................................................................................................................ 28 
2.1 
STUDY RATIONALE...................................................................................................................... 29 
2.2 
BACKGROUND ............................................................................................................................. 30 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 30 
2.3.1 
Benefit assessment ........................................................................................................................ 30 
2.3.2 
Risk assessment ............................................................................................................................ 32 
2.3.3 
COVID-19 Benefit-risk assessment ............................................................................................... 33 
2.3.4 
Overall benefit: risk conclusion ...................................................................................................... 34 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 35 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 37 
4 
STUDY DESIGN ............................................................................................................................ 39 
4.1 
OVERALL DESIGN ........................................................................................................................ 39 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 40 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 42 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 43 
5 
STUDY POPULATION .................................................................................................................. 44 
5.1 
INCLUSION CRITERIA .................................................................................................................. 44 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 46 
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5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 49 
5.4 
SCREEN FAILURES...................................................................................................................... 49 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION ........................................................................................................................ 50 
6 
STUDY INTERVENTION AND CONCOMITANT THERAPY ........................................................ 51 
6.1 
STUDY INTERVENTION ADMINISTERED ................................................................................... 51 
6.1.1 
Investigational medicinal products ................................................................................................. 51 
6.1.2 
Noninvestigational medicinal product ............................................................................................ 53 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 54 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 55 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 56 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 57 
6.5.1 
Rescue medicine ............................................................................................................................ 58 
6.6 
DOSE MODIFICATION .................................................................................................................. 59 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 59 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 60 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 60 
7.1.1 
Definitive discontinuation ............................................................................................................... 60 
7.1.2 
Temporary discontinuation ............................................................................................................. 61 
7.1.2.1 
Rechallenge ................................................................................................................................... 62 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 62 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 63 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 64 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 65 
8.1.1 
Ice cube provocation test ............................................................................................................... 66 
8.1.2 
Wheal intensity Likert scale ........................................................................................................... 67 
8.1.3 
Peak pruritus numerical rating scale (NRS), peak pain NRS, and peak burning sensation 
NRS ................................................................................................................................................ 67 
8.1.4 
Urticaria control test (UCT) 4-item version..................................................................................... 67 
8.1.5 
Cold Urticaria Activity Score .......................................................................................................... 68 
8.1.6 
Dermatology Life Quality Index and Children’s Dermatology Life Quality Index ........................... 68 
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8.1.7 
Cold Urticaria Quality of Life Questionnaire ................................................................................... 69 
8.1.8 
Patient Global Impression of Change of chronic inducible ColdU disease and Patient 
Global Impression of Severity of chronic inducible ColdU disease ............................................... 69 
8.1.9 
Acquired Cold Urticaria Severity Index .......................................................................................... 69 
8.1.10 
EuroQol-5 Dimensions questionnaire ............................................................................................ 70 
8.1.11 
Health care resource utilization/productivity .................................................................................. 70 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 70 
8.2.1 
Physical examinations ................................................................................................................... 70 
8.2.2 
Vital signs ....................................................................................................................................... 71 
8.2.3 
Electrocardiograms ........................................................................................................................ 71 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 71 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 72 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 72 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 72 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 72 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 73 
8.3.5 
Pregnancy ...................................................................................................................................... 73 
8.3.6 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 74 
8.3.7 
Adverse event of special interest ................................................................................................... 74 
8.3.7.1 
Anaphylactic reactions ................................................................................................................... 75 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 75 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 75 
8.5 
PHARMACOKINETICS AND IMMUNOGENICITY ASSESSMENTS ............................................ 76 
8.5.1 
Systemic drug concentration and antidrug antibodies ................................................................... 76 
8.5.1.1 
Sampling time ................................................................................................................................ 76 
8.5.1.2 
Handling procedures ...................................................................................................................... 76 
8.5.1.3 
Bioanalytic method ......................................................................................................................... 76 
8.6 
PHARMACODYNAMICS ............................................................................................................... 77 
8.7 
GENETICS ..................................................................................................................................... 77 
8.8 
BIOMARKERS ............................................................................................................................... 77 
8.8.1 
Use of Biological Samples and Data for Future Research ............................................................ 78 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................... 79 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 80 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 80 
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9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 80 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 80 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 81 
9.4.1 
Efficacy analyses ........................................................................................................................... 81 
9.4.2 
Safety analyses .............................................................................................................................. 84 
9.4.3 
Other analyses ............................................................................................................................... 85 
9.5 
INTERIM ANALYSES .................................................................................................................... 85 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 87 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 87 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 87 
10.1.2 
Financial disclosure........................................................................................................................ 87 
10.1.3 
Informed consent process .............................................................................................................. 88 
10.1.4 
Data protection ............................................................................................................................... 88 
10.1.5 
Committees structure ..................................................................................................................... 91 
10.1.6 
Dissemination of clinical study data ............................................................................................... 91 
10.1.7 
Data quality assurance .................................................................................................................. 91 
10.1.8 
Source documents ......................................................................................................................... 92 
10.1.9 
Study and study center closure ...................................................................................................... 92 
10.1.10 Publication policy ........................................................................................................................... 93 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 94 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 96 
10.3.1 
Definition of AE .............................................................................................................................. 96 
10.3.2 
Definition of SAE ............................................................................................................................ 97 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 98 
10.3.4 
Reporting of SAEs........................................................................................................................ 100 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 101 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 104 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS .......................................................................................................................... 105 
10.7 
APPENDIX 7: CLINICAL-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES ................................................................................................................................ 106 
10.7.1 
Cold Urticaria activity score (ColdUAS) ....................................................................................... 106 
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10.7.2 
Acquired Cold Urticaria Severity Index ........................................................................................ 109 
10.7.3 
Itch numerical rating scale, pain numerical rating scale, and burning sensational numerical 
rating scale ................................................................................................................................... 110 
10.7.4 
Wheal Intensity Likert Scale ......................................................................................................... 111 
10.7.5 
ColdU-QoL ................................................................................................................................... 112 
10.7.6 
Urticaria control test (UCT) .......................................................................................................... 115 
10.7.7 
Dermatology life quality index (DLQI) .......................................................................................... 116 
10.7.8 
Children’s dermatology life quality index (CDLQI) ....................................................................... 117 
10.7.9 
Patient Global Impression of Change .......................................................................................... 118 
10.7.10 Patient Global Impression of Severity .......................................................................................... 118 
10.7.11 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L) .......................................................... 119 
10.8 
APPENDIX 8: COUNTRY SPECIFIC REQUIREMENTS ............................................................ 122 
10.8.1 
Japan ........................................................................................................................................... 122 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 124 
10.10 
APPENDIX 10: DEFINITION OF ANAPHYLAXIS ....................................................................... 126 
10.11 
APPENDIX 11: LIST OF OPPORTUNISTIC INFECTIONS......................................................... 127 
10.12 
APPENDIX 12: LIST OF PROHIBITED LIVE ATTENUATED VACCINES .................................. 128 
10.13 
APPENDIX 13: ESTIMANDS FOR MAIN ENDPOINTS .............................................................. 129 
10.14 
APPENDIX 14: ABBREVIATIONS ............................................................................................... 131 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY .............................................................. 133 
11 
REFERENCES ............................................................................................................................. 134 
 
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LIST OF TABLES  
Table 1 – Objectives and endpoints .............................................................................................................. 15 
Table 2 - Objectives and endpoints ............................................................................................................... 35 
Table 3 - Overview of study interventions administered ............................................................................... 51 
Table 4 - Summary of handling procedures .................................................................................................. 76 
Table 5 - Summary of bioanalytical methods for functional dupilumab and anti-dupilumab antibodies ....... 77 
Table 6 - Analyses population ....................................................................................................................... 81 
Table 7 - Efficacy analyses ........................................................................................................................... 82 
Table 8 - Safety analyses .............................................................................................................................. 84 
Table 9 - Protocol-required laboratory assessments .................................................................................... 94 
Table 10 - Methods of contraception ........................................................................................................... 102 
Table 11 - Summary of primary estimand for main endpoints in ColdU study ............................................ 129 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 23 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A randomized, double-blind, placebo-controlled, multi-center, parallel-group 
study of dupilumab in patients with chronic inducible cold urticaria who remain 
symptomatic despite the use of H1-antihistamine treatment 
Short title: 
Dupilumab for the treatment of chronic inducible cold urticaria in patients who 
remain symptomatic despite the use of H1-antihistamine 
Rationale: 
Chronic inducible urticaria (CIndU) is a subtype of chronic urticaria characterized by recurrent 
itchy wheals, angioedema, or both with a minimum disease duration of 6 weeks, that only occurs 
after exposure to defined external triggers and is classified according to the stimulus that provokes 
the development of signs and symptoms (1, 2). Unlike chronic spontaneous urticaria (CSU), 
symptoms in CIndU patients (itchy wheals and angioedema) develop only and reproducibly in 
response to the trigger stimulus that is specific for their condition (eg, cold exposure in cold 
urticaria [ColdU]). The triggers that lead to the urticarial signs and symptoms in CIndU patients 
are mainly physical or chemical stimuli, which results in 2 main sub-groups of CIndU: physical 
and non-physical, respectively. Physical triggers include pressure (in delayed pressure urticaria 
[DPU]), radiation (in solar urticaria), friction (in symptomatic dermographism), temperature (in 
cold and heat urticaria), and vibration (in vibratory angioedema). Chemical triggers of CIndU 
reactions include water (in aquagenic urticaria), sweat (in cholinergic urticaria [CholU]), and 
other urticariogenic chemical compounds (in contact urticaria) (3). 
Chronic inducible urticaria has an estimated prevalence of about 0.5% in the general population 
(4), and has substantial impact on quality of life (QoL) in many patients, mainly due to the need 
for trigger avoidance. Within the group of CIndU, most CIndU subtypes are rare and therefore 
very difficult to study (1). The most common are symptomatic dermographism, CholU and ColdU 
(also called chronic inducible cold urticaria), chronic inducible ColdU being the second most 
common form of physical urticaria (1). Cold urticaria is a relatively rare disorder with a reported 
prevalence of 0.05% as per one study in Europe (4), with a higher prevalence in northern climates. 
It is also self-limited, lasting 4 to 5 years on average (5). 
Chronic inducible ColdU manifests as wheals, angioedema, or both secondary to the release of 
mast cell mediators after exposure to cold or cooling and rewarming of the skin. The clinical 
symptoms occur within minutes after skin contact with cold air, cold liquids, cold solid objects, or 
evaporation-based cooling and persist in general for a few hours (4). In severe cases, patients can 
develop systemic involvement including anaphylaxis. Local angioedema affecting the lips, 
tongue, or pharyngeal tract has been associated with the ingestion of cold beverages or food, and 
shock like reactions are reported after swimming in cold water. Cold urticarias can be classified as 
those with typical responses to cold provocation tests, those with atypical responses to cold 
provocation, and those with familial forms. Primary acquired chronic inducible ColdU is the most 
common form of chronic inducible ColdU and is considered idiopathic in nature. Historically the 
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majority (96%) of patients with acquired cold-induced urticaria have been shown to have primary 
cold-induced urticaria, with only rare occurrences of secondary cold-induced urticaria (6). 
Secondary acquired chronic inducible ColdU is very rare and associated with an underlying 
disease most commonly cryoglobulinemia, but infectious causes, leukocytoclastic vasculitis, and 
some drug-induced cases have been reported. Both primary and secondary acquired chronic 
inducible ColdU have typical positive responses to cold provocation. Several other rare forms of 
atypical acquired chronic inducible ColdU exist, which have negative immediate tests to cold 
provocation and include systemic atypical acquired chronic inducible ColdU, cold-dependent 
dermographism, cold-induced CholU, delayed chronic inducible ColdU, and localized cold-reflex 
urticaria. Lastly, hereditary forms of chronic inducible ColdU have been described: 1) Familial 
cold autoinflammatory syndrome caused by mutations in NLRP3 (cryopyrin) and is inherited in 
an autosomal dominant manner, which includes cryopyrin-associated periodic syndromes, 
Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease; 2) Familial 
atypical cold urticaria inherited in an autosomal dominant fashion with having phospholipase 
C-g2-associated deficiency and immune dysregulation (PLAID) (4). 
Chronic inducible urticarias are diagnosed based on the patient history and the results of 
provocation testing (1, 2). The treatment of inducible urticaria is trigger avoidance and 
prophylaxis by H1-antihistamines that prevent the effects of the mast cell‐mediator histamine 
(4, 7) or, if antihistamines are not effective, agents that prevent the activation of mast cells (eg, 
anti-immunoglobulin E [IgE] omalizumab) (7, 8, 9). The consensus recommendations for CIndU 
management (EAACI/GA²LEN/EDF/UNEV) (1) are mainly based on treatments approved for 
CSU, and some clinical data available in patients suffering from various types of CIndUs 
(cholinergic, symptomatic dermographism, ColdU). The recommended therapies are, in general, 
not approved for CIndU by regulatory agencies, with only limited specific countries where 
antihistamines are approved under broader “urticaria” indications. All patients are advised to 
avoid prolonged skin contact with cold objects or exposure to cold air temperatures. The first-line 
symptomatic therapy for CIndU is a non-sedating second-generation H1 antihistamine at 
approved doses for CSU. In patients who do not obtain complete control, increasing the dose up to 
4 times approved doses for CSU is recommended. Steps 3 and 4of treatment options include 
omalizumab and ciclosporin A, respectively. All these treatments are used off label and lack good 
evidence of effectiveness in patients with CIndU. 
Chronic inducible urticarias last several years and often pose a great treatment challenge because 
of their resistance to first-line therapy with H1-antihistamine (1). They are debilitating, often 
causes systemic reactions including anaphylaxis in severe cases and severely affect patient QoL 
(7, 8). Avoidance of offending triggers poses massive changes to everyday life and therefore is 
typically not feasible. Thus, the need for approved treatment options for CIndU, especially for 
chronic inducible ColdU that have proven to be safe and efficacious in chronic inducible ColdU 
patients, is high. 
Chronic inducible ColdU presents as pruritic wheals with or without angioedema secondary to the 
release of mediators from mast cells after exposure of the skin to cold air, liquid, or cold objects. 
Degranulation of mast cells in CIndU is held to be mediated by Fc epsilon receptor (FcεRI) 
activation, through cell surface-bound IgE cross-linked by as of yet unidentified autoallergens. 
The subsequent release of histamine and other pro-inflammatory mediators leads to local tissue 
edema and pruritus. Many symptoms of urticaria are mediated primarily by the actions of 
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histamine (a mast cell mediator) on the H1-receptors, and treatment with H1-antihistamine is a 
mainstay of therapy (1). Approximately 50% of patients achieve symptomatic control with 
conventional H1-antihistamine therapy (2). Increasing the dose of anti-histamines in some cases 
has been demonstrated to be effective but not in all cases (10). Omalizumab anti-IgE which is 
approved for CSU may be efficacious in ColdU, however it is not approved for use in this specific 
condition. The mechanism by which omalizumab exerts its therapeutic effects is likely 
constrained to reduction in serum IgE and consequent down regulation of high affinity IgE 
receptors. Novel therapies that target signaling pathways important for mast cell survival and 
function may provide additional treatment options for patients with this disease who are not 
responsive to treatment with H1-antihistamine therapy. Interleukin-4 (IL-4)/IL-13 signaling is 
required for antibody isotype switching to IgE production in B cells and contribute to mast cell 
survival and function (4, 7). Therefore, blockade of IL-4/IL-13 by dupilumab represents a novel 
therapeutic approach for chronic inducible ColdU patients. 
Dupilumab is a human monoclonal antibody (mAb) directed against the interleukin-4 receptor 
alpha subunit (IL-4Rα), 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, which is responsible for several pathophysiological mechanisms 
including mast cell and basophil degranulation. Dupilumab has shown efficacy in multiple 
diseases with underlying type 2 inflammation such as atopic dermatitis (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 studies, a decrease in urinary leukotriene E4 (LTE4) and prostaglandin D2 
metabolite (PGDM) suggests that dupilumab has impact on mast cell function. In a proof of 
concept study in EoE dupilumab modulated type 2 inflammatory genes including genes associated 
with mast cell activation (11). 
In a small case series of patients who had concurrent AD and CSU (12) and were resistant to 
omalizumab, treatment with dupilumab improved their urticaria. The same has been observed in 
1 patient with chronic inducible ColdU (13). These data further support the rationale to target 
IL-4/IL-13 signaling with dupilumab in patients with chronic urticaria. As this is a novel therapy 
that acts further upstream than IgE-targeted therapies, the clinical study proposed here will test the 
efficacy of dupilumab in patients who have failed antihistamines alone. 
Based on available literature data for ColdU and dupilumab mechanism of action, the present 
study will be evaluating the efficacy and safety of dupilumab in patients with primary acquired 
chronic inducible ColdU. 
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Objectives and endpoints 
Table 1 – Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To demonstrate the efficacy of dupilumab in adult 
and adolescent participants with primary acquired 
chronic inducible cold urticaria (ColdU) who remain 
symptomatic despite the use of an H1-antihistamine 
• 
Proportion of participants with negative ice cube 
provocation test* at Week 24 compared with 
placebo  
*Negative ice cube provocation test is defined as 
the absence of a confluent hive/wheal at the entire 
skin site of exposure after Ice cube provocation 
testa 
Secondary 
• 
To demonstrate the efficacy of dupilumab on 
primary acquired chronic inducible ColdU disease 
control 
• 
Change from baseline in urticaria control test (UCT 
4-item) at Week 24 compared with placebo. 
• 
Proportion of well-controlled participants (UCT≥12) 
at Week 24 compared with placebo. 
• 
Proportion of participants with an improvement of 
≥3 in UCT 4- item from baseline to Week 24 
compared with placebo. 
• 
To demonstrate the efficacy of dupilumab on 
primary acquired chronic inducible ColdU local signs 
and symptoms (hives/wheals, itch, burning 
sensation, and pain) after provocation test 
• 
Change from baseline in local wheal intensity at the 
provocation site at Week 12 and Week 24 using the 
wheal intensity Likert scale ranging from 0 to 5 
(clinician evaluation) compared with placebo. 
• 
Change from baseline in local itch severity at the 
provocation site at Week 12 and Week 24 using the 
Peak Pruritus Numerical Rating Scale (NRS, score 
0 to 10) (patient reported) compared with placebo. 
• 
Change from baseline in local skin burning 
sensation at the provocation site at Week 12 and 
Week 24 using the peak burning sensation NRS 
(patient reported) compared with placebo. 
• 
Change from baseline in local pain severity at the 
provocation site at Week 12 and Week 24 using the 
peak pain sensation NRS (patient reported) 
compared with placebo. 
• 
Proportion of participants with negative ice cube 
provocation test at Week 12 compared with 
placebo. 
• 
To demonstrate the efficacy of dupilumab on 
primary acquired chronic inducible ColdU disease 
activity  
• 
Change from baseline in cold urticaria signs and 
symptoms severity at Week 24 on cold exposure 
days as measured by ColdUAS, compared with 
placebo 
• 
Change from baseline in the proportion of cold 
urticaria sign and symptom free days at Week 24 on 
cold exposure days as measured by ColdUAS, 
compared with placebo 
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Objectives 
Endpoints 
• 
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 participants ≥16 years old, and in 
Children’s Dermatology Life Quality Index (CDLQI) 
in participants ≥12 to <16 years old at Week 24 
compared with placebo  
• 
Change from baseline in Cold Urticaria Quality of 
Life (ColdU-QoL) at Week 24 compared with 
placebo. 
• 
To evaluate the ability of dupilumab in reducing the 
proportion of participants who require rescue 
therapy 
• 
Proportion of participants receiving rescue therapy 
for primary acquired chronic induced ColdU during 
the planned treatment period compared with 
placebo 
• 
To evaluate the proportion of participants with cold 
exposure triggered urticaria  
• 
Proportion of participants with cold exposure 
triggered urticaria requiring emergency medical 
care visit or treatment with epinephrine (at 
provocation test and/or at home). 
• 
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 antidrug 
antibodies (ADA) against dupilumab over time 
a Provocation test reading time for all endpoints: 15 minutes after the ice cube application start = 5 minutes ice cube application plus 
10 minutes of rewarming after removal of ice cube 
Overall design: 
The EFC16720 study is a 24-week, randomized, double-blind, placebo-controlled, parallel-group, 
multi-center study to evaluate the use of dupilumab in adults and adolescents (≥12 to <18 years 
old) with primary acquired chronic inducible ColdU who remain symptomatic despite the use of 
H1-antihistamine. Participants using H1-antihistamine regularly/daily or as needed are eligible 
since both treatment regimens are common in patients with ColdU (5). The study is designed to 
test the hypothesis that dupilumab will increase the proportion of participants with negative ice 
cube provocation test compared with placebo. Negative ice cube provocation test is defined as 
absence of a confluent hive/wheal at the entire skin site of exposure after ice cube provocation 
test. 
Chronic inducible ColdU signs and symptoms will be evaluated after a provocation test by the 
Investigator (hives/wheals intensity) and participant (itch severity, skin pain, skin burning 
sensation). In addition, chronic inducible ColdU disease activity will be assessed daily by the 
participant using the Cold Urticaria Activity Score (ColdUAS) questionnaire in an e-diary where 
the participant will report his/her skin reactions (wheals and swelling), skin sensations (itching, 
burning, pain or feeling hot), if they have been in contact with cold temperatures that usually 
cause skin reactions, if they have avoided trigger exposure, and overall symptoms severity. The 
study will also assess the effect of dupilumab on urticaria control, participants´ health-related 
quality of life (HRQoL) and overall health status, proportion of patients with cold urticaria 
requiring emergency medical care visit or treatment with epinephrine and on reduction of rescue 
therapy. 
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Disclosure Statement:  
This is a parallel, treatment study with 2 arms that is blinded/masked for participants and 
Investigators. 
Number of participants: 
The total anticipated number of participants randomized in the study is 78. This corresponds to 
approximately 39 participants who will be randomly assigned to each intervention arm: the 
dupilumab or the placebo treatment arm. At least 4 participants randomized in the study will be 
adolescents (≥12 to <18 years old) who will be recruited in a few selected countries. 
Randomization will be stratified by age (adolescent versus adult) and within adult group by 
country and background H1-antihistamine regular/daily use (Yes/No) (see Section 6.1.2 for 
additional background therapy details). 
Number of participants using H1-antihistamine as needed prior to study entry should be at least 
. 
Intervention groups and duration: 
Participants who satisfy the inclusion and exclusion criteria will be randomized (1:1) to 1 of the 
following investigational medicinal product (IMP) treatment groups: 
• Dupilumab: 300 mg every 2 weeks (q2w) for adults; 200 mg q2w for adolescents ≥30 kg 
and <60 kg at baseline or 300 mg q2w for adolescents ≥60 kg at baseline. 
• 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. 
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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. 
• 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:  
• One injection of 300 mg q2w after an initial loading dose of 600 mg (2 injections of 
300 mg) on Day 1 for all adult participants and for adolescents weighing ≥60 kg. 
• One injection of 200 mg q2w after an initial loading dose of 400 mg (2 injections of 
200 mg) in adolescent participants ≥30 kg and <60 kg. 
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:  
• One injection of placebo matching 300 mg q2w after an initial matching placebo loading 
dose of 600 mg (2 injections of placebo matching 300 mg) on Day 1 for all adult 
participants and for adolescents weighing ≥60 kg. 
• One injection of placebo matching 200 mg q2w after an initial matching placebo loading 
dose of 400 mg (2 injections of placebo matching 200 mg) in adolescent participants 
≥30 kg and <60 kg. 
Noninvestigational medicinal products 
During the study, participants should continue their established standard of care background 
therapy with a long-acting non-sedating H1-antihistamine, at up to 4-fold the approved dose for 
CSU. 
• Participants who used H1-antihistamine regularly/daily prior to study entry should 
continue to take it daily. Note: regular/daily use of H1-antihistamine prior to study entry is 
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defined as H1-antihistamine intake for at least 4 days per week for at least 1 month prior to 
screening visit (Visit 1) 
• Participants who took H1-antihistamine as needed prior to study entry should limit the use 
to short-term. 
The H1-antihistamine dose used during the study should be the same dose the participants took to 
prevent ColdU symptoms prior to study entry (“prescreening dose”). However, if participants 
experience a flare rescue therapy may be initiated. Please refer to Section 6.5.1 for rescue therapy. 
If participants are on a dose higher than 4-fold the approved CSU dose at the screening visit 
(Visit 1), the Investigator can adjust the participant’s dose within the stipulated range at the 
screening visit (Visit 1). 
The following list of H1-antihistamines is allowed as background and rescue therapy during the 
study (see Section 6.1.2 and Section 6.5.1), and noted with their recommended dose: 
• Cetirizine 10 mg once per day (qd). 
• Levocetirizine dihydrochloride 5 mg qd 
• Ebastine 10 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-antihistamines after discussion with the Sponsor 
For other information related to H1-antihistamine including safety precautions, please refer to the 
locally approved 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-study access to IMP  
The Sponsor does not plan to provide post-study access to the IMP. 
Statistical considerations: 
• Sample size calculations 
Sample size is calculated based on the following assumptions: 
1. The placebo group has 
 participants with negative ice cube provocation test at Week 
24 and the dupilumab group has 
 participants with negative ice cube provocation test 
at Week 24. 
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2. There is a drop-out rate of 10% in both groups. 
3. The statistical test is a Z test that is based on the difference of the 2 proportions with 
unpooled variance estimate and 2-sided 1% significance level. 
4. Participants are equally randomized to the dupilumab group and the placebo group. 
With these assumptions, 39 participants per group (78 participants in total) will provide 
90% power to detect the difference of 
 response rate in the dupilumab group and 
 response rate in the placebo group. The sample size calculations were performed 
using nQuery+nTerim 4.0. 
• Randomization 
Participants will be randomized in a 1:1 ratio to dupilumab or placebo. The randomization 
will be first stratified by age (adults versus adolescents) with at least 4 adolescents. Then 
in adult’s randomization will be stratified further by country and background 
H1-antihistamine regular/daily use (Yes/No). Randomization will not be stratified further 
in adolescents. 
Number of participants using H1-antihistamine as needed prior to study entry should be at 
least 
. 
• Analysis population 
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. 
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. 
• Primary analysis 
The primary efficacy endpoint is the proportion of participants with negative ice cube 
provocation test at Week 24. The statistical hypothesis for comparing dupilumab against 
placebo on the primary endpoint is: 
- 
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 the Cochran-Mantel-Haenszel test 
stratified by region and background H1-antihistamine regular/daily use (Yes/No). The 
comparison of the proportions of participants with negative ice cube provocation test at 
Week 24 between dupilumab and placebo will be derived, and the corresponding odd 
ratios and the 95% confidence interval (CI) will be reported. Participants who receive 
highly influential prohibited medications and/or highly influential rescue medications 
(details of selection will be specified in the statistical analysis plan [SAP]) will be 
considered as having positive ice cube provocation tests for time points after the 
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medication usage. For other participants, all available data including those collected 
during the off-treatment period will be used to determine the positive/negative ice cube 
provocation test outcomes. Participants with missing ice cube provocation test data at 
Week 24 will be considered as having positive ice cube provocation tests. 
• Analysis of secondary endpoints 
The continuous secondary endpoints at Week 24 will be analyzed using Analysis of 
covariance (ANCOVA) with multiple imputation. For participants taking highly influential 
prohibited medications and/or highly influential rescue medications (details of selection 
will be specified in the SAP), their data after the medication usage will be set to missing, 
and the WOCF approach (worst postbaseline observation for the participant will be carried 
forward) will be used to impute missing Week 24 value (for participants whose 
postbaseline values are all missing, the participant’s baseline value will be used to impute 
the missing endpoint value). Participants who discontinue the treatment prematurely are 
encouraged to follow the planned clinical visits. For participants who did not take the 
highly influential prohibited medications and/or highly influential 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 study intervention 
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 study intervention 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 highly 
influential prohibited medications and/or highly influential 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 endpoint, treatment group, region 
(combined countries), and background H1-antihistamine regular/daily use (Yes/No) as 
covariates. Statistical inference obtained from all imputed data will be combined using 
Rubin’s rule. Descriptive statistics including number of participants, 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% CI will be provided along with the p-values. 
The continuous endpoints at Week 12 will be analyzed in a similar way as the secondary 
endpoints at Week 24. 
The binary endpoints will be analyzed in the similar way to the primary efficacy endpoint. 
The safety variables, including adverse events (AEs), laboratory parameters, vital signs, 
electrocardiogram (ECG), and physical examinations will be summarized using 
descriptive statistics. 
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• Missing data handling 
For continuous endpoints, missing data due to lack of efficacy will be imputed using 
WOCF approach and missing data not due to lack of efficacy will be imputed using a 
multiple imputation method, which will use all participants except those who have taken 
the highly influential prohibited medications and/or highly influential rescue medications 
and excluding patients who discontinue due to lack of efficacy. 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 
A multiplicity hierarchical testing will be proposed to control the overall Type-I error rate 
for testing the primary endpoint, selected patient-reported outcome (s) (PRO) and the other 
key secondary endpoints. The study is considered positive when the primary endpoint 
achieves statistical significance. Detailed multiplicity adjustment procedure for the 
efficacy endpoints will be described in the study SAP. 
• Planned database lock date 
A primary database lock will be performed when all randomized participants have 
completed their treatment phase. Final analyses in the clinical study report (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. 
Data Monitoring Committee: No 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
Screening
Double-blind treatment period (24 weeks)
Follow-up (12 weeks)
R
Dupilumab 
Dupilumab 300 mg SC Q2W for adults 
and for adolescents ≥60 kg
Dupilumab 200 mg SC Q2W for adolescents ≥30 kg and <60 kg 
N=39
N=39
Matched placebo
Matched placebo 300 mg SC Q2W for adults 
and for adolescents ≥60 kg
Matched placebo 200 mg SC Q2W for adolescents ≥30 kg and <60 kg
Week -4 
to -2
Week 0 
(Day 1)
Week 24
(EOT)
Week 36 
(EOS)
Provocation test at Screening, Randomization, Week 12, Week 24 and Follow-up
Ice Cube Test 
Abbreviations: EOS: End of study; EOT: End of treatment; Q2W: Every 2 weeks; N: number of participants; R: Randomization; SC: Subcutaneous
Background: Participants will be on non-sedating H1-antihistamine (taken daily or as needed)
Dupilumab 300 mg Q2W, administered as 1 SC injection of dupilumab 300 mg (2 mL)
Dupilumab 200 mg Q2W, adminstered as 1 SC injection of dupilumab 200 mg (1.14 mL)
Matched placebo is prepared in the same formulation without the addition of protein (ie, the active substance)
A loading dose equivalent to treatment group assigned will be administered on Day 1
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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) 
0 (Day 1) 
12 
±3 days 
24 
±3 days 
36 
±7 days 
Visit 
1 
2a 
3 
4 (EOT) 
5 (EOS) 
Screening/baseline: 
Informed consent 
X 
 
 
 
 
Medical history including systemic 
hypersensitivity reactions and ACUSIb 
X 
 
 
 
 
Prior and concomitant medicationc 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
Patient e-diary training 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
Study intervention 
Call IVRS/IWRS 
X 
X 
X 
X 
X 
IMP administration 
 
---------------Xd-----------------→ 
 
 
Dispense/Upload electronic diarye 
X 
----------------------------------------X------------------------------------------→ 
X 
Dispense EpiPenf 
 
X 
 
 
 
Safetyg 
Physical examinationh 
X 
X 
 
X 
X 
Vital signsi 
X 
X 
X 
X 
X 
Electrocardiogram (12 lead)j  
X 
 
 
 
 
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Procedures 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period (Weeks) 
Follow-up (12 weeks) 
0 (Day 1) 
12 
±3 days 
24 
±3 days 
36 
±7 days 
Visit 
1 
2a 
3 
4 (EOT) 
5 (EOS) 
Hematology, biochemistry, urine 
analysisk 
X 
X 
X 
X 
X 
Hepatitis, HIV Serology, TB testl 
X 
 
 
 
 
Pregnancy testm 
Serum 
Ur 
Ur 
Ur 
Ur 
AE reporting, including SAEs 
X 
X 
X 
X 
X 
Pharmacokinetics and ADAg 
Serum PK samples for dupilumab 
concentrationn 
 
X 
X 
X 
X 
Anti-dupilumab antibodyn 
 
X 
X 
X 
X 
Biomarkersg 
Serum total IgE 
 
X 
X 
X 
X 
Basophil activation test at selected sites 
(optional) o  
 
X 
X 
X 
 
Archive serum and plasma samples 
(optional)p  
 
X 
X 
X 
X 
DNA  
(whole blood) samples - Optionalq 
 
X 
 
 
 
RNA  
(whole blood) samples - Optionalr 
 
X 
 
X 
 
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Procedures 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period (Weeks) 
Follow-up (12 weeks) 
0 (Day 1) 
12 
±3 days 
24 
±3 days 
36 
±7 days 
Visit 
1 
2a 
3 
4 (EOT) 
5 (EOS) 
Efficacy g 
Ice cube provocation tests 
X 
X 
X 
X 
X 
Wheal intensity Likert scale after 
provocation testt 
 
X 
X 
X 
X 
Peak pruritus NRS, peak pain NRS, and 
peak burning sensation NRS after 
provocation test 
 
X 
X 
X 
X 
ColdUAS 
X 
X 
X 
X 
 
UCT  
X 
X 
X 
X 
X 
DLQI/CDLQIu 
 
X 
 
X 
 
ColdU-QoL 
 
X 
 
X 
 
PGIC 
 
 
X 
X 
 
PGIS 
X 
X 
X 
X 
 
EQ-5D-5L 
 
X 
 
X 
 
Healthcare resource 
utilization/productivity (missed 
school/workdays)v  
 
X 
 
X 
 
Abbreviations: ACUSI = Acquired Cold Urticaria Severity Index; ADA = antidrug antibodies; AE = adverse event; AESI = adverse event of special interest; CDLQI = Children’s Dermatology Life Quality Index; 
ColdUAS= Cold Urticaria Activity Score; ColdU-QoL = Cold Urticaria Quality of Life; DLQI = dermatology life quality index; DNA = deoxyribonucleic acid; ECG = electrocardiogram; eCRF = electronic case report form; 
e-diary = electronic diary,  EOS = End of study; EOT= End of treatment; EQ-5D-5L = 5-level EuroQol 5-dimensional questionnaire; HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B surface antibody; 
HBs Ag = hepatitis B surface antigen; HBV = hepatitis B virus; HCRU = Healthcare resource utilization; HCV = hepatitis C virus; HCV Ab = hepatitis C virus antibodies; HIV = Human Immunodeficiency Virus; 
IgE = immunoglobulin E; IMP = investigational medicinal product; IVRS = interactive voice response system; IWRS = interactive web response system; NRS, Numerical Rating Scale; 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; 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 SC injections. 
b ACUSI will be captured in the eCRF. 
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c Concomitant medication, including rescue OCS taken since last visit will be collected throughout the study. 
d Loading dose at Day 1 (Visit 2): 600 mg/matched placebo (2 SC injections) for 300 mg/matched placebo q2w regimen for adults and adolescents ≥60 kg OR 400 mg/matched placebo (2 SC injections) for 200 mg/ 
matched placebo q2w regimen for adolescents ≥30 kg and <60 kg. Investigational medicinal product will be administered every other week. The planned last dose is at Week 22. Participants are allowed to self-
inject IMP at home after appropriate training of the participants (or parent/legally authorized representatives, or caregivers). 
e Electronic diary is used for daily recording of ColdUAS and antihistamine medication from screening up to Week 24. This device is dispensed at screening visit (Visit 1), including instructions for use. At the EOT, 
the e-diary is returned to the study center. For UCT, DLQI (>16 years old)/CDLQI (<16 years old), ColdQoL and EQ-5D-5L the participant will fill in the questionnaires during their study center visit in the e-diary. 
The e-diary will be also used to complete peak pruritus NRS, peak pain NRS, and peak burning sensation NRS, after the provocation test. Participants will complete the PGIS and PGIC on the e-diary after they 
have answered the peak pruritus NRS, peak pain NRS and peak burning sensation NRS. 
f 
EpiPen or equivalent to be provided locally. 
g Assessments/procedures should be conducted in the following order: patient-reported outcomes questionnaires, safety and laboratory assessments (including sample collection for ADA, PK, biomarker, and 
optional DNA and RNA), ice cube provocation test, participant´s and Investigator’s assessment of signs and symptoms after provocation test, and administration of IMP. 
h Physical examinations will include skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
i 
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate will be measured at every visit prior and after provocation test. 
Height (cm) will be measured at screening visit (Visit 1) only. Body weight (kg) will be measured at screening visit (Visit 1) and at EOT/EOS Visits. 
j 
ECG to be locally collected and read. 
k 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, nitrite, 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 examination. 
l 
Clinical laboratory testing at screening visit (Visit 1) will include hepatitis screen covering HBs Ag, HBs Ab, HBc Ab, HCV Ab, 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. 
m 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 study center 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. 
In between visit, urine pregnancy tests must be performed at home. For urine pregnancy tests performed at home, female participants will have to complete a pregnancy test diary. 
n Serum dupilumab concentration and ADA samples will be collected and archived prior to administration of IMP. 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. 
o For participants (with exception of adolescents) who decide to participate and provide a specific written informed consent for the optional basophil activation test at selected sites in US and Canada only. 
p For participants (with exception of adolescents) who decide to participate and provide a specific written informed 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. 
q For participants (with exception of adolescents) who decide to participate and provide a specific written informed 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. 
r 
For participants (with exception of adolescents) who decide to participate and provide a specific written informed consent for the optional genomics sub-study (RNA sample collection). The RNA sample must be 
collected before the administration of the first dose of IMP and at Week 24 before the administration of the IMP. 
s Positive provocation test defined as presence of at least a confluent hive/wheal at the entire skin site of exposure after ice cube provocation test. 
t 
The Wheal intensity Likert scale for wheal intensity after provocation test will be completed by the Investigator after the provocation test and entered in the eCRF. 
u Participants will complete the DLQI (≥16 years old) or CDLQI (≥12 to <16 years old). 
v HCRU (missed school/workdays) baseline version to be administered at baseline; postbaseline version to be administered at the subsequent visits. It will be entered in the eCRF. 
 
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2 
INTRODUCTION  
Chronic urticaria comprises CSU and CIndU, and both are characterized by the appearance of 
itchy wheals (hives), angioedema, or both that reoccur for more than 6 weeks. The symptoms 
occur either without a specific trigger in the case of CSU, or are induced (provoked) by a specific 
and definite trigger in the case of CIndU (1, 2). There are 9 subtypes of CIndUs depending on the 
type of trigger that provokes urticaria signs and symptoms: symptomatic dermographism, ColdU, 
DPU, solar urticaria, heat urticaria, vibratory angioedema, CholU, contact urticaria, and aquagenic 
urticaria. Most CIndU subtypes are rare and the most common are symptomatic dermographism, 
ColdU (also called chronic inducible cold urticaria) and CholU (1). 
Chronic inducible ColdU is the second most common form of physical urticaria (1, 14). Cold 
urticaria is a relatively rare disorder with a reported prevalence of 0.05% as per one study in 
Europe (4), with a higher prevalence in northern climates. It is also self-limited, lasting 4 to 
5 years on average (5). Chronic inducible ColdU often develops in young adults and is diagnosed 
based on the patient history and the results of provocation testing. Systemic symptoms of mast 
cell activation may occur, and up to 35% to 70% of patients with chronic inducible ColdU have 
experienced systemic reactions including anaphylaxis in severe cases (4). 
Therapy is focused on the avoidance of the trigger factor and symptomatic treatment. The 
consensus recommendations for CIndU management (EAACI/GA²LEN/EDF/UNEV) (1) are 
mainly based on treatments approved for CSU, and some clinical data available in patients 
suffering from various types of CIndUs (cholinergic, symptomatic dermographism, ColdU). The 
recommended therapies are, in general, not approved for CIndU by regulatory agencies, with only 
limited specific countries where antihistamines are approved under broader “urticarial” 
indications. All patients are advised to avoid prolonged skin contact with cold objects or exposure 
to cold air temperature for CIndU, a similar stepwise approach as in patients with CSU is 
recommended: second-generation H1-antihistamines are the first-line (standard doses) and second 
line (high doses) therapies, although there is a lack of good evidence in patients with CIndU for 
the latter recommendation. Approximately 50% of patients achieve symptomatic control with 
conventional H1-antihistamine therapy, defined as reduction of hives and itch (15). Step 3and 
4 of treatment options include omalizumab and ciclosporin A, respectively. Omalizumab, a 
monoclonal anti- IgE antibody, is the most used off label treatment in antihistamine-resistant 
patients with CIndU including ColdU. However, approximately a third of the patients treated with 
omalizumab are not well-controlled (16). 
Chronic inducible ColdU is debilitating and severely affects patients QoL. Avoidance of 
offending triggers poses massive changes to everyday life and therefore is typically not feasible. 
Thus, the need for treatment options is high, especially as no approved treatments are available. 
The underlying pathologic mechanism, while not well understood, is thought to be driven by mast 
cell activation and degranulation. Activation of skin mast cells with the release of histamine and 
other pro-inflammatory mediators leads to the signs and symptoms of CIndUs. Increased numbers 
of mast cells are found in both lesional and non-lesional skin in CSU and inducible urticaria. 
Interleukin-4 and IL-13, causative cytokines of type 2 inflammation, are secreted by mast cells in 
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addition to T helper 2 (Th2) lymphocytes. Mast cells express the IL-4 receptor, IL-4Rα, which is 
also stimulated by IL-13. Stimulation of mast cell IL-4Rα has been shown to also promote 
degranulation, adhesion, and chemotaxis, and to enhance FcεRI expression (4, 17). 
Dupilumab is a human mAb directed against the IL-4Rα, 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 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 mast cell and basophil degranulation. 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 studies, a decrease in urinary LTE4 and 
PGDM was reported, suggesting that dupilumab has impact on mast cell functions. 
Based on the above described dupilumab mechanism of action as well as available data with 
dupilumab, this study will evaluate dupilumab efficacy in patients with primary acquired chronic 
inducible ColdU. 
2.1 
STUDY RATIONALE  
Primary acquired chronic inducible ColdU patients with and without angioedema experience 
hives and pruritus secondary to mast cell dysregulation. Degranulation of mast cells in CIndu is 
held to be mediated by FcεRI activation, through cell surface-bound IgE cross-linked by as of yet 
unidentified autoallergens. The subsequent release of histamine and other pro-inflammatory 
mediators leads to local tissue edema and pruritus. While antihistamines are the mainstay of 
therapy, not all patients are controlled with antihistamines alone, and not all antihistamine-
refractory patients are adequately responsive to omalizumab (anti-IgE antibody) 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, 7). Therefore, blockade 
of IL-4/IL-13 by dupilumab represents a novel therapeutic approach for chronic urticaria 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 (12). The same has been observed 
in 1 patient with chronic inducible ColdU (13). These data further support the rationale to target 
IL-4/IL-13 signaling with dupilumab in patients with chronic urticaria. As this is a novel therapy 
that acts further upstream than IgE -targeted therapies, the clinical study proposed here will test 
the efficacy of dupilumab in patients who have failed antihistamines alone. 
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 at baseline OR 200 mg q2w with a loading 
dose of 400 mg for adolescents ≥30 kg and <60 kg at baseline. To achieve effective drug 
concentrations rapidly and thereby allowing a rapid clinical and pharmacodynamics (PD) 
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response, a loading dose is selected for this study as done in the dupilumab AD program. These 
are the approved dose regimens for AD, another skin disease and they are expected to achieve 
concentrations in serum that saturate the IL-4/IL-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. The same dosing regimens are currently under investigation in a 
dupilumab Phase 3 study in patients with CSU who remain symptomatic despite the use of 
H1-antihistamine treatment. 
The study is designed to test the hypothesis that dupilumab is effective in inhibiting hives/wheals 
after provocation test (ice cube provocation test), in patients suffering from primary acquired 
chronic inducible ColdU who remain symptomatic despite the use of H1-antihistamine treatment. 
2.2 
BACKGROUND  
Chronic inducible ColdU is a debilitating condition that severely affects QoL. It is normally not 
feasible to avoid the offending trigger without significant changes to everyday life. The majority 
of patients with chronic inducible ColdU may experience systemic reactions, including 
anaphylaxis in severe cases. There is no approved treatment available to date for chronic inducible 
ColdU, and EAACI/GA²LEN/EDF/WAO guidelines treatment recommendations (2) are mainly 
based on the approved treatments for CSU. Many patients however are refractory to these 
treatments; therefore, a high unmet medical need exist. 
In the EFC16720 study the target population consists of patients with primary acquired chronic 
inducible ColdU who remain symptomatic despite treatment with H1-antihistamine as these 
patients have a significant unmet medical need. The updated international guideline on the 
definition, classification, diagnosis, and management of urticaria (1, 2) provides recommendations 
and a treatment algorithm. Steps 1 and 2 of this algorithm is the use of non-sedating H1-
antihistamines at approved, or increased doses (up to 4-fold), respectively. Step 3 and 4 of 
treatment options include omalizumab and ciclosporin A, respectively. This protocol allows the 
use of H1-antihistamine at up to 4-fold the approved doses as background medication at stable 
doses. 
2.3 
BENEFIT/RISK ASSESSMENT  
The Sponsor recognizes that the “Coronavirus Disease 2019” (COVID-19) pandemic may have an 
impact on the conduct of clinical trials. The Sponsor will monitor the situation closely and ensure 
the integrity of the trial conduct and data (see Appendix 9 [Section 10.9]). 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of dupilumab are available in the Investigator’s brochure (IB). 
2.3.1 Benefit assessment  
Dupixent (dupilumab) is authorized for marketing in over 50 countries worldwide including the 
United States (US), European Union (EU) (Centralized Procedure), Japan, China, Canada, and 
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Australia for adult AD indication. Dupilumab is also authorized in the US, EU, and other 
jurisdictions for the adolescent AD indication, and in the US, EU, Japan and other jurisdictions for 
the adult and adolescent asthma indication. Dupilumab also has approval for its CRSwNP 
indication in the US, EU, and Japan. 
The target population of EFC16720 are patients with chronic inducible ColdU who remain 
symptomatic despite the use of H1-antihistamine treatment. These patients have failed 
antihistamine therapy and have active disease as indicated in Section 5. There are currently no 
therapies that are approved specifically for the treatment of cold-induced urticaria. Therefore, 
these patients have a high unmet medical need for novel effective treatment. Participation in 
EFC16720 will provide an opportunity for these patients to be treated with dupilumab that has 
proven efficacy in disease states (eg, AD, asthma, CRSwNP) where type 2 inflammation is the 
underlying driver of the disease process, and which targets signaling pathways important for mast 
cell survival and function that may provide a new treatment option for chronic inducible ColdU. 
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 (12, 18, 19, 20, 
21, 22). It is hypothesized that dupilumab will be effective in reducing itch and hives and improve 
angioedema urticaria control as well as QoL, in adults and adolescents with CSU and chronic 
inducible ColdU. Supporting the mechanistic rationale for dupilumab’s potential effectiveness in 
CSU, dupilumab improved the hives and itch severity/frequency in a case series of 6 patients with 
CSU (12). Ferrucci et al reported (13) that a patient with chronic inducible ColdU who failed to 
respond to omalizumab (anti- IgE antibody) and oral cyclosporine, healed shortly after starting 
dupilumab. Itch (Numerical Rate Scale) and QoL (Dermatology Life Quality Index [DLQI]) 
significantly improved in this patient after only 1 month of therapy with dupilumab and the ice 
cube provocation test was negative. The patient underwent cold-water exposure by rafting in a 
mountain river (water temperature 3°C), without showing any relapse of urticaria. 
The participants who will participate in this study may have the potential benefit of receiving a 
novel treatment for the underlying disease process. Based on the dupilumab mechanism of action 
in reducing IgE production and effects on mast cells mediators, it is anticipated that use of 
dupilumab will lead to reduced signs and symptoms associated with primary acquired chronic 
inducible ColdU and improved function and QoL for these participants. 
Treatments approved in CSU are antihistamines or omalizumab. In general, treatments for chronic 
inducible ColdU including omalizumab are given off label. Thirty-five percent to 70% of patients 
with chronic inducible ColdU have experienced systemic reactions including anaphylaxis in 
severe cases. Thus, the need for approved treatment options for chronic inducible ColdU is high 
(4). 
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 contribute to mast cell 
and basophil survival and function. Therefore, blockade of IL-4/IL-13 by dupilumab represents a 
novel therapeutic approach for chronic inducible ColdU patients. 
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This 24-week study allows for assessment of the effect of dupilumab on urticaria symptoms after 
the cold provocation test (hives/wheals, itch, pain, and burning sensation), and on participant’s 
HRQoL, and health status. 
2.3.2 Risk assessment  
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 March 2020 (Data Lock Point), 
10 191 subjects were enrolled into the development program for dupilumab and are included in 
the safety population: 382 as healthy volunteers, 4405 from AD studies, 3614 from asthma 
studies, 782 from CRSwNP studies, 232 from EoE studies, 248 from the grass allergy and peanut 
allergy studies, 511 from the chronic obstructive pulmonary disease (COPD) studies, 5 from 
prurigo nodularis (PN) studies, and 12 from the CSU studies. The number of subjects exposed to 
dupilumab in clinical studies was 8720 (356 in healthy volunteer studies, 4052 in AD studies, 
3263 in asthma studies, 470 in CRSwNP studies, 166 in EoE studies, 148 in the grass allergy and 
peanut allergy studies, 256 from the COPD studies, 3 from PN studies, and 6 from the CSU 
studies). 
Based on clinical studies in AD, the safety profile in adolescent patients (ie, 12–17 years of age) 
appears similar to that of adults with AD. As of 28 September 2019, 336 adolescents had been 
exposed to dupilumab in AD clinical studies, with a total of 457.7 person-years of exposure. 
Based on the sales figures 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 161 582 patient-years (01 January 2017 to 31 March 2020). 
Dupilumab has been generally well-tolerated in all populations tested in clinical development 
programs consistent with a positive benefit/risk profile. The adverse drug reactions (ADRs) 
identified to date for dupilumab include injection site reactions, conjunctivitis (including allergic 
and bacterial), oral herpes, herpes simplex, blepharitis, keratitis, dry eye, eye pruritus, 
eosinophilia, serum sickness, anaphylactic reaction, angioedema, and arthralgia. These ADRs 
were generally mild or moderate, transient, and manageable. These ADRs were not consistently 
observed in all indications (see IB for greater details). More significant serious allergic reactions 
were very rare. The ADRs reported in the post-marketing setting include events of anaphylactic 
reaction, angioedema, arthralgia, keratitis, and ulcerative keratitis. 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 mAbs are potentially immunogenic. Rare serious and systemic 
hypersensitivity reactions have been observed in the dupilumab program including serum 
sickness/serum sickness-like reaction in the adult AD program and anaphylaxis related to 
dupilumab in the adult asthma clinical studies. 
The important potential risk for dupilumab is “eosinophilia associated with clinical symptoms in 
asthma patients.” The observed increase in eosinophil count is transient, which is consistent with 
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the current understanding of the mechanism of action of dupilumab. In dupilumab asthma studies, 
a small number of patients with asthma experienced serious systemic eosinophilia presenting with 
clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic 
granulomatosis with polyangiitis, conditions which are often treated with systemic corticosteroids 
(SCS) therapy. These events have been seen in other drug development programs for severe 
asthma and usually, but not always, have been associated with the reduction of oral corticosteroid 
therapy suggesting possible unmasking of these conditions with tapering of corticosteroids during 
dupilumab therapy. The association of dupilumab treatment and these events has not been 
established. Health care providers should be alert to eosinophilia associated with vasculitis rash, 
worsening of pulmonary symptoms, pulmonary infiltrate, cardiac complications, and/or 
neuropathy presenting in their patients, especially upon reduction of SCS. 
Patients with known helminth infections were excluded from participation in clinical studies, 
therefore it is not known if dupilumab will influence the immune response against helminth 
infections. Consequently, patients with pre-existing helminth infections should be treated for their 
helminth infection before initiating therapy with dupilumab. 
The common ADR across all indications is injection site reaction. Other potential risks based on 
the safety profile in particular indications are discussed in the IB. 
To date, the safety profile has been similar among adult and adolescent patients in asthma and AD 
populations and adult patients with CRSwNP. While long-term data are still accumulating, data 
from randomized, placebo-controlled trials and open-label extension studies to date, have not 
identified any new safety concern in these populations. It is anticipated that dupilumab in patients with 
primary acquired chronic inducible ColdU will have a favorable safety profile as observed across 
other type 2-driven immunological disorders. 
2.3.3 COVID-19 Benefit-risk assessment  
Dupilumab has shown clinical benefit in several type-2 driven immunological disorders, such as 
AD, asthma, and CRSwNP. In asthma and AD, clinical benefit has also been established in certain 
pediatric patients (asthma in adolescents and AD in 6 to18 years old) and a similar benefit-risk 
profile to adults has been observed.  
To date, more than 8000 patients have been treated with dupilumab during the clinical 
development program in several indications, of which AD, asthma, and CRSwNP are licensed in 
some countries. 
Currently, as sufficient data in patients with COVID-19 who are being treated with dupilumab is 
not available. Thus, the safety and efficacy of dupilumab in COVID-19 patients are unknown. 
During the course of the clinical trial program, respiratory infections including viral infections 
were monitored and these events are not listed as ADRs with dupilumab. 
The target population of EFC16720 are participants with primary acquired chronic inducible 
ColdU have uncontrolled disease and in general, treatments for chronic inducible ColdU including 
omalizumab are given off label. Therefore, these patients have a high unmet medical need for 
novel effective treatment. Participation in EFC16720 will provide an opportunity for these 
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patients to be treated with a novel therapy that has proven efficacy in certain other disease states 
(ie, AD, asthma, CRSwNP), where type 2 inflammation is the underlying driver of the disease 
process. 
Based on the aforementioned potential benefits to patients participating in EFC16720, the 
Sponsor’s assessment is that the benefit-risk remains favorable for the participants to participate 
in this study. 
2.3.4 Overall benefit: risk conclusion  
Based on the evidence to support the potential therapeutic benefit in patients with primary 
acquired chronic inducible ColdU, a patient population with an unmet medical need, considering 
the favorable benefit/risk profile across multiple indications, and the extensive available safety 
database, the Sponsor is proposing to conduct a Phase 3 program with dupilumab for the treatment 
of patients with cold-induced urticaria. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To demonstrate the efficacy of dupilumab in adult 
and adolescent participants with primary acquired 
chronic inducible cold urticaria (ColdU) who remain 
symptomatic despite the use of an H1-antihistamine 
• 
Proportion of participants with negative ice cube 
provocation test* at Week 24 compared with 
placebo  
*Negative ice cube provocation test is defined as 
the absence of a confluent hives/wheal at the entire 
skin site of exposure after ice cube provocation 
testa. 
Secondary 
• 
To demonstrate the efficacy of dupilumab on 
primary acquired chronic inducible ColdU disease 
control 
• 
Change from baseline in urticaria control test (UCT 
4-item) at Week 24 compared with placebo 
• 
Proportion of well-controlled participants (UCT ≥12) 
at Week 24 compared with placebo 
• 
Proportion of participants with an improvement of 
≥3 in UCT 4- item from baseline to Week 24 
compared with placebo. 
• 
To demonstrate the efficacy of dupilumab on 
primary acquired chronic inducible ColdU local 
signs and symptoms (hives/wheals, itch, burning 
sensation and pain) after provocation test 
• 
Change from baseline in local wheal intensity at the 
provocation site at Week 12 and Week 24 using the 
wheal intensity Likert scale ranging from 0 to 5 
(clinician evaluation) compared with placebo 
• 
Change from baseline in local itch severity at the 
provocation site at Week 12 and Week 24 using the 
Peak Pruritus Numerical Rating Scale (NRS, score 
0 to 10) (patient reported) compared with placebo 
• 
Change from baseline in local skin burning 
sensation at the provocation site at Week 12 and 
Week 24 using the peak burning sensation NRS 
(patient reported) compared with placebo 
• 
Change from baseline in local pain severity at the 
provocation site at Week 12 and Week 24 using the 
peak pain sensation NRS (patient reported) 
compared with placebo 
• 
Proportion of participants with negative ice cube 
provocation test at Week 12 compared with placebo 
 
• 
To demonstrate the efficacy of dupilumab on 
primary acquired chronic inducible ColdU disease 
activity  
• 
Change from baseline in cold urticaria signs and 
symptoms severity at Week 24 on cold exposure 
days as measured by ColdUAS, compared with 
placebo 
• 
Change from baseline in the proportion of cold 
urticaria sign and symptom free days at Week 24 on 
cold exposure days as measured by ColdUAS, 
compared with placebo 
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Objectives 
Endpoints 
• 
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 participants ≥16 years old, 
and in Children’s Dermatology Life Quality Index 
(CDLQI) in participants ≥12 to <16 years old at 
Week 24 compared with placebo  
• 
Change from baseline in Cold Urticaria Quality of 
Life (ColdU-QoL) at Week 24 compared with 
placebo. 
• 
To evaluate the ability of dupilumab in reducing the 
proportion of participants who require rescue 
therapy 
• 
Proportion of participants receiving rescue therapy 
for primary acquired chronic inducible ColdU during 
the planned treatment period compared with 
placebo 
• 
To evaluate the proportion of participants with cold 
exposure triggered urticaria  
• 
Proportion of participants with cold exposure 
triggered urticaria requiring emergency medical 
care visit or treatment with epinephrine (at 
provocation test and/or at home) 
• 
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 antidrug 
antibodies (ADA) against dupilumab over time 
 
Tertiary/exploratory 
Pharmacokinetic (PK)/Pharmacodynamic (PD) 
 
• 
To evaluate PK of dupilumab 
• 
Functional dupilumab concentrations in serum and 
PK profile 
• 
To evaluate PD effect of dupilumab 
• 
Total immunoglobulin E over time. 
a Provocation test reading time for all endpoints: 15 minutes after the ice cube application start = 5 minutes ice cube application plus 
10 minutes after removal of ice cube 
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3.1 
APPROPRIATENESS OF MEASUREMENTS  
Primary acquired cold urticaria (ACU) is a type of physical chronic inducible urticaria that is 
characterized mainly by the appearance of wheals after contact with cold or cooling and 
rewarming of the skin (4). The assessments used in this study focus on evaluation of local 
symptoms that occur after skin contact to cold using ice cube provocation test. In addition, overall 
urticaria control, daily documentation of skin reactions to cold, participant’s QoL, reduction in 
need of rescue therapy and health status are evaluated. 
The proposed primary endpoint is proportion of participants with negative ice cube provocation 
test (absence of a confluent hive/wheal at the entire skin site of exposure) at Week 24.  Cold 
provocation tests are standard in diagnosis of cold urticaria (4). In addition, they are used for 
assessment of efficacy in clinical trials (23, 24) in patients with ColdU. Cold urticaria symptoms 
appear only after skin contact with a cold trigger (cold air, liquids, or solid objects), usually within 
minutes, and persist for up to a few hours. The use of cold provocation tests allows for the 
standardization of the cold trigger and for performing assessment in predefined time points. The 
ice cube provocation test will be standardized for the purpose of this study and an operational 
manual with instructions for ice cube preparation and cold provocation test administration will be 
provided to the study centers along with the study protocol. This will ensure that all study centers 
will apply the ice cube provocation tests consistently across this international, multi-center 
clinical study. 
Presence of a confluent hive/wheal as well as wheal intensity will be assessed by the clinicians 
10 minutes after removal of the ice cube, as recommended in the CIndU 
(EAACI/GA²LEN/EDF/UNEV) guidelines (1). Assessment will be performed at each provocation 
test, ie, at Week 0, Week 12, and Week 24. In addition, symptoms of itch severity, skin burning 
sensation, and skin pain will be assessed by the participant 10 minutes after the cold provocation 
test. 
The clinical picture of a participant at the time of study visits may not be totally representative of 
the actual current disease status due to symptom fluctuation that is dependent upon the contact 
with the triggering temperature. Therefore, the participants will rate the disease activity using the 
ColdUAS questionnaire in an e-diary. On a daily basis, participants will report their skin reactions 
(wheals and swelling), skin sensations (itching, burning, pain or feeling hot), avoidance behavior 
and trigger exposure, and overall symptoms severity. Cold Urticaria Activity Score will provide 
important supportive information on clinical improvement of the participants on a daily basis. 
Since skin reactions, skin sensations and behavioral avoidance to trigger vary from one day to 
another, ColdUAS will be assessed on a daily basis. 
Participants with primary inducible ColdU are at risk of developing systemic hypersensitivity 
reactions including anaphylaxis after exposure to cold triggers. Such systemic reactions are 
mainly described as provoked by aquatic activities (eg, swimming in cold water) when the whole 
body, or a large proportion of it, was in contact with cold. Systemic hypersensitivity events will 
be documented via adverse event of special interest (AESI)/serious adverse event (SAE) 
reporting, and information about corrective treatment will be collected. 
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To get a complete picture of the disease, it is important to assess disease control over the course of 
treatment in addition to urticaria symptom assessment. Patients are best positioned to accurately 
assess this control, as they experience and feel it. They will self-assess their ColdU control using 
the urticaria control test (UCT), a well-developed and validated instrument in chronic urticaria 
patients (25). 
Lastly, patients with primary acquired chronic inducible ColdU experience substantial HRQoL 
impairment. Therefore, the DLQI, a dermatology-specific instrument designed to assess HRQoL 
in adults ≥16 years old (26) with dermatologic conditions, and the corresponding Children’s 
Dermatology Life Quality Index (CDLQI) for adolescents aged ≥12 years to <16 years old will be 
used, in addition to the newly developed disease-specific Cold Urticaria Quality of Life (ColdU-
QoL) questionnaire.. 
The proposed primary and secondary endpoints will answer important clinical questions about the 
efficacy of dupilumab on disease symptoms, disease control and HRQoL in patients with primary 
acquired chronic inducible ColdU. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
The EFC16720 study is a 24-week, randomized, double-blind, placebo-controlled, parallel-group, 
multi-center study to evaluate the use of dupilumab in adults and adolescents (≥12 to <18 years 
old) with primary acquired chronic inducible ColdU who remain symptomatic despite the use of 
H1-antihistamine. Participants using H1-antihistamine regularly/daily or as needed are eligible 
since both treatment regimens are common in patients with ColdU (5). The study is designed to 
test the hypothesis that dupilumab will increase the proportion of participants with negative ice 
cube provocation test at Week 24 compared with placebo. Negative ice cube provocation test is 
defined as the absence of a confluent hive/wheal at the entire skin site of exposure after an ice 
cube provocation test. 
The study consists of 3 periods: 
• Screening period (2 to 4 weeks). 
• Randomized IMP treatment period (24 weeks). 
• Post IMP treatment period (12 weeks). 
Chronic inducible ColdU signs and symptoms will be evaluated after an ice cube provocation test, 
by the Investigator (hives/wheals intensity) and participant (itch severity, skin pain, skin 
sensation). In addition, chronic inducible ColdU disease activity will be assessed daily by the 
participant using ColdUAS questionnaire in an e-diary where the participant will report his/her 
skin reactions (wheals and swelling), skin sensations (itching, burning, pain or feeling hot), if they 
have been in contact with cold temperatures that usually cause skin reactions, if they have avoided 
trigger exposure, and overall symptoms severity. The study will also assess the effect of 
dupilumab on urticaria control, participants´ HRQoL and overall health status, proportion of 
patients with cold urticaria requiring emergency medical care visit or treatment with epinephrine 
and on reduction of rescue therapy. 
The total anticipated number of participants randomized in the study is 78. This corresponds to 
approximately 39 participants who will be randomly assigned to each intervention arm: 
• Dupilumab: 300 mg every q2w for adults; 200 mg q2w for adolescents ≥30 kg and <60 kg 
at baseline or 300 mg q2w for adolescents ≥60 kg at baseline. 
• Matched placebo. 
At least 4 participants randomized in the study will be adolescents (≥12 to <18 years old) who 
will be recruited in a few selected sites in selected countries. Randomization will be stratified by 
age (adolescent versus adult) and within adult group by country and background H1-antihistamine 
regular/daily use (Yes/No) (see Section 6.1.2 for additional background therapy details). 
Number of participants using H1-antihistamine as needed prior to study entry should be at 
least 
. 
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During the study, participants should continue their established standard of care background 
therapy with a long-acting non-sedating H1-antihistamine, at up to 4-fold the approved dose for 
CSU. 
• Participants who used H1-antihistamine regularly/daily prior to study entry should 
continue to take it daily. Note: regular/daily use of H1-antihistamine prior to study entry is 
defined as H1-antihistamine intake for at least 4 days per week for at least 1 month prior to 
screening visit (Visit 1) 
• Participants who took H1-antihistamine as needed prior to study entry should limit the use 
to short-term. 
The H1-antihistamine dose used during the study should be the same dose the participants took to 
prevent ColdU symptoms prior to study entry (“prescreening dose”). However, if participants 
experience a flare rescue therapy may be initiated. Please refer to Section 6.5.1 for rescue therapy. 
If participants are on a dose higher than 4-fold the approved CSU dose at the screening visit 
(Visit 1), the Investigator can adjust the participant’s dose within the stipulated range at the 
screening visit (Visit 1).  
All participants will be allowed to take study-defined H1-antihistamine as rescue therapy as long 
as they do not exceed 4-fold the approved CSU dose during screening, treatment, and follow-up 
periods. If symptoms are still uncontrolled after increase of H1-antihistamine to the maximum 
allowed dose, or if the participant is already on the 4-fold approved dose of H1-antihistamine, 
participants can switch to another antihistamine up to 4-fold (2-fold in Japan) the approved dose 
for CSU or a short course of oral corticosteroids (OCS) is allowed during the treatment and 
follow-up periods. For rescue therapy in participants in Japan, please see Appendix 8 
(Section 10.8). 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 the EFC16720 study the target population consists of patients with primary acquired chronic 
inducible ColdU who remain symptomatic despite treatment with H1-antihistamine alone as these 
patients have a significant unmet medical need. Therapy for the patients is focused on the 
avoidance of the trigger factor and symptomatic treatment. The updated international guideline on 
the definition, classification, diagnosis and management of urticaria (1, 2) provides 
recommendations and a treatment algorithm. The consensus recommendations for CIndU 
management are mainly based on treatments approved for CSU, and some clinical data available 
in patients suffering from various types of CIndUs (cholinergic, symptomatic dermographism, 
ColdU). The recommended therapies are, in general, not approved for CIndU by regulatory 
agencies, with only limited specific countries where antihistamines are approved under broader 
“urticaria” indications. A similar stepwise approach as in patients with CSU is recommended for 
CIndU, including ColdU. Steps 1 and 2 of this algorithm is the use of non-sedating 
H1-antihistamines at approved, or increased doses (up to 4-fold), respectively. Step 3and 4 of 
treatment options include omalizumab and ciclosporin A, respectively. More than 50% of 
acquired primary chronic inducible cold urticaria patients do not respond to H1-antihistamine 
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treatment (8). Omalizumab, a monoclonal anti- IgE antibody, is the most used off label treatment 
in antihistamine-resistant patients with CIndU including ColdU. However, approximately a third 
of the patients treated with omalizumab are not well-controlled (12). 
Study EFC16720 targets patients not adequately controlled with H1-antihistamine treatment and 
allows the use of H1-antihistamine at up to 4-fold the approved doses as background medication at 
stable doses. 
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. In addition, 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 pro-inflammatory cytokines, chemokines, nitric oxide, and IgE (21). 
There are a limited number of studies conducted in patients with cold urticaria. As mentioned 
above, the guideline recommendations for CSU are adopted for patients with CIndU; however, 
there are several differences between CSU and CIndU. In CIndU, the symptoms only occur after 
skin exposure to physical or chemical triggers. The duration of individual wheals is often 
relatively brief for CIndU, lasting minutes to hours. This is the reason why different assessment 
tools and endpoints are used in CIndU clinical studies compared with CSU. Cold provocation 
tests are used in clinical studies in patients with chronic urticaria to evaluate efficacy of 
treatments, mainly antihistamine treatments, but also doxepin, cyproheptadine (4), either by 
evaluating proportion of patients who after treatment did not develop signs/symptoms with the 
cold provocation test or evaluating the response to an experimental cold-simulation time test 
(CSTT) ie, minimum time threshold of cold stimulation required to induce a coalescent wheal and 
other cold urticaria signs and symptoms. This study will assess efficacy using the primary 
endpoint of the proportion of participants with negative ice cube provocation test at Week 24. The 
patients/Investigators will also score local signs and symptoms before and after provocation test 
assessing effect of the IMP on hives, itch, burning sensation, and pain. Ice cube provocation test is 
a traditional test used in common practice. For the study, the method will be standardized and 
compliant with according to the International EAACI/GA2LEN/EDF/UNEV guidelines (1). In 
addition to provocation test, cold urticaria signs and symptoms will be evaluated using ColdUAS. 
It is scored by patients daily to assess overall disease activity. 
A large portion of patients with ColdU (35% to 70%) have experienced systemic reactions 
including anaphylaxis, after extensive cold exposure and exercise, respectively (4). Avoidance of 
offending triggers poses massive changes to everyday life and therefore is typically not feasible. 
This has significant impact on patients´ QoL. The study will assess the proportion of patients with 
cold exposure triggered urticaria requiring emergency medical care visit or treatment with 
epinephrine urticaria. 
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. 
Rescue medication including epinephrine ensure that the safety or health of participants is not 
compromised. In addition to common safety measures implemented in the currently planned study 
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(per protocol Section 1.3 and Section 8.2), the Investigators will oversee efficacy via monitoring 
of ColdU symptoms collected daily in an e-diary and can continuously assess benefit and risk for 
each individual participant and decide about the need to administer rescue therapy (Section 6.5.1) 
or to discontinue the IMP. The study participants may withdraw from treatment if he or she 
decides to do so, at any time and irrespective of the reason. 
The 24-week treatment duration should be sufficient for efficacy evaluation of dupilumab. 
Dupilumab treatment has shown clinical efficacy prior to Week 24 in all Phase 3 clinical studies 
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 AD clinical studies, including the 
52-week AD 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 ColdU. 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. 
In addition to adults, the study will evaluate efficacy and safety in adolescents. It is reported that 
cold urticaria often develops in young adults (1) and therefore, it is considered important to make 
dupilumab available to adolescent without delay. It is planned to enroll at least 4 adolescent 
participants (9). Inclusion of both populations in one study is supported by the fact that ColdU is 
similar in adult and adolescent patients in terms of pathophysiology, clinical presentation and 
diagnostic procedures, and treatment guidelines (EAACI/GA2LEN/EDF/WAO) are similar for 
both adult and adolescent population. 
Assessment of dupilumab will provide efficacy data that can be used for positioning of dupilumab 
in current treatment algorithm of ColdU recommended in International Guideline (2). 
4.3 
JUSTIFICATION FOR DOSE  
Based on the known 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 ≥30 kg and <60 kg. These are the approved dose regimens for AD, another skin 
disease and they are expected to achieve concentrations in serum that saturate the IL-4/IL-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 primary acquired chronic inducible cold urticaria 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 PD response as demonstrated by improvement in 
pruritus, a hallmark of AD. Similarly, as pruritus is a core symptom of primary acquired chronic 
inducible cold urticaria, and to achieve effective drug concentrations more rapidly, a loading dose 
is selected for this study. 
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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 EOS Visit. If a participant discontinues the 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  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be ≥12 years to 80 years (or the minimum legal age for adolescents in the 
country of the investigational site) of age inclusive at the time of signing the informed 
consent. For those countries where local regulations do not permit enrollment of 
adolescents (≥12 years to <18 years of age), the recruitment will be restricted to those who 
are ≥18 years of age. 
Type of participant and disease characteristics 
I 02. Participants who have a diagnosis of primary acquired chronic inducible ColdU defined as 
recurrence of itchy wheals and/or angioedema due to cold for longer than 6 weeks prior to 
screening visit (Visit 1). 
I 03. Participants with positive ice cube provocation test, ie, presenting at least a confluent 
hive/wheal on the exposed skin area, at the screening visit (Visit 1) and randomization visit 
(Visit 2). 
I 04.  Participants meeting at least 1 of the following criteria despite regular/daily or as needed 
use of H1-antihistamine: 
- 
Urticaria Control Test (UCT) (4-item) <12 at the screening visit (Visit 1) and 
randomization visit (Visit 2) 
- 
Within 6 months prior to the screening visit, documented medical history of cold 
exposure triggered anaphylaxis or oropharyngeal edema 
- 
Within 6 months prior to the screening visit, documented medical history of cold 
exposure triggered urticaria requiring emergency medical care visit or treatment with 
epinephrine. 
I 05. Participants who are using a study-defined H1-antihistamine regularly/daily or as needed 
for primary acquired chronic inducible ColdU (see Section 6.1.2 for the list of 
antihistamines allowed for the study). Regular/daily use is defined as H1-antihistamine 
intake for at least 4 days per week for at least 1 month prior to screening visit (Visit 1). 
Note: The participants who take H1-antihistamine regularly/daily should have the dose 
stable for at least 5 consecutive days prior to screening visit (Visit 1). The participants who 
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take H1-antihistamine as needed should not take H1-antihitamine for at least 5 consecutive 
days prior to screening visit (Visit 1). 
Weight  
I 06. Body weight ≥30 kg.  
Sex 
I 07. 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 a contraceptive method that is highly effective, with 
a failure rate of <1%, as described in Appendix 4 (Section 10.4) of the protocol 
during the study (at a minimum until 12 weeks after the last dose of study 
intervention). 
- 
A WOCBP must have a negative highly sensitive 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) of the protocol. 
- 
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 
I 08. Capable of giving signed informed consent as described in Appendix 1 of the protocol 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. In countries where the legal age of majority is 
above 18 years old, a specific ICF must also be signed by the participant’s legally 
authorized representative. For adolescents, both the adolescent and the parent/legally 
authorized representative must sign the specific ICF (Section 10.1.3 of the protocol). 
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Clearly defined underlying etiology for urticaria other than primary acquired chronic 
inducible ColdU. This includes but is not limited to the following urticarias: 
- 
Acute urticaria 
- 
Chronic spontaneous urticaria  
- 
Inducible urticaria: all other forms of ColdU (acquired secondary ColdU, atypical 
acquired ColdU, hereditary ColdU syndromes), solar, cholinergic, heat, 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 02. Systemic hypersensitivity reaction including anaphylaxis related or suspected to be related 
to ice cube provocation test at the screening visit (Visit 1) and randomization visit 
(Visit 2). 
E 03. Presence of skin morbidities or associated with itch other than primary acquired chronic 
inducible ColdU that may interfere with the assessment of the study outcomes. 
E 04. Participants having active AD. 
E 05. 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. 
E 06. History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at 
the screening visit (Visit 1). 
E 07. Severe concomitant illness(es) that, in the Investigator’s judgment, would adversely affect 
the participant’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 [CRFs], etc). 
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E 08. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections (eg, tuberculosis [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 09. Participants with active TB or nontuberculous 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 10. 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 11. History of malignancy within 5 years before Visit 1, except completely treated in situ 
carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal 
cell carcinoma of the skin. 
E 12. Known or suspected alcohol and/or drug abuse. 
E 13. History of systemic hypersensitivity or anaphylaxis to any other biologic therapy or any of 
its excipients. 
E 14. Planned major surgical procedure during the participant’s participation in this study. 
E 15. Participant’s with any other medical or psychological condition including relevant 
laboratory or ECG findings 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 study, may make 
participant’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). 
Prior/concomitant therapy 
E 16. Participation in a prior dupilumab clinical study or have been treated with commercially 
available dupilumab. 
E 17. Exposure to another systemic or topical investigative drug (mAbs 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 mAbs, whichever is 
longer, and an interval of <30 days or <5 PK half-lives, whichever is longer, for 
investigative small molecules. 
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E 18. 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.  
E 19.  Treatment with biologics as follows: 
- 
Any cell-depleting agents including but not limited to rituximab: within 6 months 
before the screening visit (Visit 1). 
- 
Anti-Ig E therapy (omalizumab) within 4 months before the screening visit (Visit 1). 
- 
Other mAbs (which are biological response modifiers): within 5 half-lives (if known) 
or 16 weeks before the screening visit (Visit 1), whichever is longer. 
E 20. Treatment with a live (attenuated) vaccine (Appendix 12 [Section 10.12] of the protocol) 
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: 
- 
Participants for whom administration of live (attenuated) vaccine can be safely 
postponed would be eligible to enroll into the study. 
- 
Participants who have their vaccination preponed can enroll in the study only after a 
gap of 4 weeks following administration of the vaccine. 
E 21. Routine (daily or every other day during 5 or more consecutive days) doses of doxepin 
within 14 days prior to the screening visit (Visit 1). 
E 22. Planned or anticipated use of any prohibited medications (Section 6.5) and procedures 
during the screening and study treatment period. 
E 23. Either intravenous immunoglobulin (IVIG) therapy and/or plasmapheresis within 30 days 
prior to the screening Visit (Visit 1). 
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Diagnostic assessments 
E 24. Participants with any of the following result at the screening visit (Visit 1): 
- 
Positive (or indeterminate) hepatitis B virus surface antigen (HBs Ag)HBs Ag or, 
- 
Positive total hepatitis B core antibody (HBc Ab) confirmed by positive hepatitis B 
virus (HBV) Deoxyribonucleic acid (DNA) or, 
- 
Positive hepatitis C antibody (HCV Ab) confirmed by positive hepatitis C virus (HCV) 
ribonucleic acid (RNA). 
Noncompliance to completion of the e-diary 
E 25. Participants are not complaint with completion of e-diary by completing entries on less 
than 4 days out of the 7 days immediately preceding the baseline visit (Visit 2). 
Other exclusions 
E 26. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 27. Any country-related specific regulation that would prevent the participant from entering 
the study. 
E 28. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 29. Participants are employees of the clinical study center or other individuals directly 
involved in the conduct of the study, or immediate family members of such individuals (in 
conjunction with Section 1.61 of the International Council of Harmonisation [ICH]-Good 
Clinical Practice [GCP] Ordinance E6). 
E 30. Any specific situation during study implementation/course that may raise ethical concerns. 
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  
Participants unwilling to attempt avoidance of known cold triggers. 
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 
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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 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). 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Appendix 9 (Section 10.9) and should be considered for 
screening/enrollment/randomization/administration of study intervention. 
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6 
STUDY INTERVENTION AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION ADMINISTERED  
6.1.1 Investigational medicinal products  
Table 3 - Overview of study interventions administered  
ARM name 
Dupilumab 
Placebo 
Intervention name 
For adults and those adolescents ≥60 kg: 
Dupilumab 300 mg  
 
For adolescents ≥30 kg and <60 kg: Dupilumab 
200 mg  
For adults and those adolescents ≥60 kg: 
Placebo matching dupilumab 300 mg 
 
For adolescents ≥30 kg and <60 kg: Placebo 
matching dupilumab 200 mg 
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 
0 mg every 14 ±3 days after an initial loading 
dose of 0 mg 
Route of 
administration 
Subcutaneous 
Subcutaneous 
Use 
Experimental 
Experimental 
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 participant 
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 participant 
kit box. Both glass pre-filled syringe and box 
will be labeled as required per country 
requirement 
Abbreviations: IMP = investigational medicinal product; NIMP = noninvestigational medicinal product. 
The IMP is administered every 14 ±3 days (q2w) during the 24-week treatment period with the 
last IMP administration at Week 22. 
The first IMP administration should be performed at the study center. Subsequent IMP 
administrations can be done at home by the participant (or parent/legally authorized 
representative, or caregiver). If the participant (or parent/legally authorized representative or 
caregiver) is unable or unwilling to prepare and inject IMP, injections can be performed at the 
study center by way of unscheduled visits; or arrangements can be made for qualified study center 
personnel and/or health care professionals (eg, visiting nurse service) to administer IMP at 
participant’s home. 
For doses not given at the study center, paper diaries will be provided to record information 
related to the injections. The paper diary will be kept as source data in the participants study file. 
At Visit 2, the Investigator or delegate will prepare and inject the first dose of IMP in front of the 
participant (or parent/legally authorized representative, or caregiver). If home administration is 
planned, the participant (or parent/legally authorized representative or caregiver) will prepare and 
inject the second dose of IMP under the supervision of the Investigator or delegate. The training 
must be documented in the participant’s study file. In case of emergency (eg, natural disaster, 
pandemic etc.) different training ways (eg, virtual training via video call etc.) can be performed 
(and will be documented in the participant’s study file). 
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 the Investigator or delegate) or health care 
professional but not the participants themselves. 
Participants should be monitored for at least 30 minutes. The monitoring period may be extended 
as per country specific or local study center-specific requirements. 
The participant/parent/legally authorized representative/caregiver should be trained by the study 
center 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 study 
center-specific requirements) following injection. In case of hypersensitivity symptom/s the 
participant should contact his/her healthcare provider/emergency contact. 
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The IMP may be supplied at the study center or from the Investigator/study center/Sponsor to the 
participant via a Sponsor-approved courier company where allowed by local regulations and 
agreed upon by the participant. 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 9 (Section 10.9). 
6.1.2 Noninvestigational medicinal product  
During the study, participants should continue their established standard of care background 
therapy with a long-acting non-sedating H1-antihistamine, at up to 4-fold the approved dose for 
CSU. 
• Participants who used H1-antihistamine regularly/daily prior to study entry should 
continue to take it daily. Note: regular/daily use of H1-antihistamine prior to study entry is 
defined as H1-antihistamine intake for at least 4 days per week for at least 1 month prior to 
screening visit (Visit 1) 
• Participants who took H1-antihistamine as needed prior to study entry should limit the use 
to short-term. 
The H1-antihistamine dose used during the study should be the same dose the participants took to 
prevent ColdU symptoms prior to study entry (“prescreening dose”). However, if participants 
experience a flare rescue therapy may be initiated. Please refer to Section 6.5.1 for rescue therapy. 
If participants are on a dose higher than 4-fold the approved CSU dose at the screening visit 
(Visit 1), the Investigator can adjust the participant’s dose within the stipulated range at the 
screening visit (Visit 1). 
The following list of H1-antihistamine is allowed as background and rescue therapy during the 
study (see Section 6.5.1) and noted with their recommended dose: 
• Cetirizine 10 mg qd. 
• Levocetirizine dihydrochloride 5 mg qd 
• Ebastine 10 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-antihistamine after discussion with the Sponsor. 
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For other information related to H1-antihistamine including safety precautions, please refer to the 
locally approved product labeling. 
In each participant, all ice cube provocation tests from screening visit (Visit 1) to EOS (Visit 5) 
should be done under the same background therapy conditions. For at least 5 consecutive days 
prior to the test, participants should either be on stable H1-antihistamine prescreening dose (if 
they take H1-antihistamine regularly/daily) or be without H1-antihistamine intake (if they use 
antihistamine as needed). If needed the ice cube provocation test can be delayed in order to keep 
the conditions unchanged during the study. 
Background therapy 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 IMP received and any discrepancies are reported and resolved 
before use of the study intervention. 
2. Only participants randomized in the study may receive IMP and only authorized study center 
staff may supply or administer IMP. At study center, all IMP 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 study center 
staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
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 8.3.8). 
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 
direct-to-patient [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 study protocol, or 
dispose of IMP in any other manner. 
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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to randomized IMP using an interactive response 
technology (IRT). The Investigator will be questioned during the interactive voice response 
system (IVRS) phone call/interactive web response system (IWRS) web module if he/she wishes 
to enroll the participant in the study. 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 the screening visit (Visit 1), the Investigator or designee will contact the IRT system to receive 
the participant number. If a participant who had previously failed screening is approached for 
rescreening, a new ICF must be signed. In such case, a new participant number will be assigned 
by IRT. 
Methods of assigning participants 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 as described in the Table 3. 
Randomization will be stratified by age (adolescent versus adult) and within adult group by 
country and background H1-antihistamine regular/daily use (Yes/No) (see Section 6.1.2 for 
additional background therapy details). 
Number of participants using H1-antihistamine as needed prior to study entry should be at least 
. At screening (Visit 1), the Investigator or designee will contact the IRT system to receive 
the participant number. If a participant who had previously failed screening is approached for 
re-screening, a new ICF must be signed. In such case, a new participant number will be assigned 
by IRT. 
A randomized participant is defined as a participant who has been allocated to a randomized 
intervention regardless of whether the treatment was administered or not (ie. participant registered 
by the IRT). A participant cannot be randomized more than once in the study. 
Study intervention will be dispensed at the study visits summarized in schedule of activities (SoA) 
(Section 1.3). Returned study intervention 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 boxes will be labeled with a treatment kit number. Whilst this study is 
double-blinded in terms of treatment with either dupilumab or placebo, it is not blinded to weight-
based dose levels, due to the different volume size (2 mL versus 1.14 mL) of the dose level of 
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dupilumab (300 mg/matching placebo or 200 mg/matching placebo) that will be used for the 
different weight categories for adolescents. 
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 intervention 
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 intervention assignment unless this could delay emergency treatment of 
the participant. If a participant’s intervention assignment is unblinded, the Sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was broken 
must be recorded in the source documentation and the electronic case report form (eCRF), as 
applicable. 
If the code is broken, the participant must withdraw from IMP administration. 
6.4 
STUDY INTERVENTION COMPLIANCE  
• The Investigator or his/her delegate must ensure that IMP is administered to each 
participant according to the labeling instructions. 
• Investigational medicinal product accountability: 
- 
Investigational medicinal product units 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 Intervention Log Form. 
- 
The Investigator or his/her delegate records the dosing information on the appropriate 
pages of the 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 intervention log forms/source documents. 
- 
A paper diary will be dispensed to the participants for indicating IMP administration at 
home. 
When participants are dosed at the study center, they will receive study intervention directly from 
the Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. The 
dose of study intervention and study participant identification will be confirmed at the time of 
dosing by a member of the study center staff other than the person administering the study 
intervention. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by checking diary and 
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used/unused kits/pre-filled syringes during the study center visits and documented in the source 
documents and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in the 
eCRF. 
A record of the number of kits/pre-filled syringes dispensed to and taken by each participant must 
be maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also 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. 
Non-sedating H1-antihistamines, at up to 4-fold the approved dose for CSU, are allowed as 
background medication and on demand as recue medication. 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 ) 
• Any cell-depleting agents including but not limited to rituximab 
• Monoclonal antibodies (which are biological response modifiers) including anti-IgE 
therapy (omalizumab) 
• Treatment with a live (attenuated) vaccine 
• 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: 
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• Topical corticosteroids 
• Topical calcineurin inhibitors 
• Topical and oral antihistamines (other than those allowed as background or rescue 
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 
chronic inducible ColdU 
• Antifibrinolytic tranexamic acid and epsilon-aminocaproic acid 
• Phototherapy, including tanning beds. 
6.5.1 Rescue medicine  
All participants will be allowed to take study-defined H1-antihistamine (see Section 6.1.2) as 
rescue therapy as long as they do not exceed 4-fold the approved dose for CSU during the 
screening, treatment, and follow-up periods. If symptoms are still uncontrolled after increase of 
H1-antihistamine to the maximum allowed dose, or if the participant is already on the 4-fold 
approved H1-antihistamine, participants can switch to another antihistamine up to 4-fold the 
approved dose for CSU or a short course of OCS is allowed 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. 
Due to an episodic nature of ColdU, it is recommended to prescribe rescue therapy for a short 
period of time (not more than 7 days). 
The ice cube provocation test should be delayed if rescue therapy (H1-antihistamine or OCS) is 
taken within 5 days prior to the test. The ice cube provocation test can be done when the 
participant is back to prescreening H1-antihistamine dose or is off H1-antihistamine (or OCS) 
intake for at least 5 consecutive days to allow to have ice cube provocation test performed under 
the same background condition for each participant from screening visit (Visit 1) to EOS (Visit 5). 
In case of systemic hypersensitivity reactions due to cold, the participants may require 
epinephrine treatment. EpiPen (or a local equivalent) will be provided to the participants at the 
beginning of the study, and the participants should be appropriately trained how and when to use 
it. EpiPen use should be in accordance with the locally approved product labeling. 
For rescue medication in participants in Japan, please see Appendix 8 (Section 10.8). 
The initial background therapy should remain unchanged throughout the study. Participants 
should continue their prescreening dose of initial H1-antihistamine once rescue treatment is no 
longer required or stop H1-antihistamine intake. The use of permitted rescue medications should 
be delayed in all participants, 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. 
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For other information including safety precautions related to H1-antihistamine, OCS, and EpiPen 
(or a local equivalent), please refer to the locally approved 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 
the 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 10.9). 
• 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 10.11). 
• 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). 
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• If the participant develops a medical condition that requires use of prohibited medication 
(see Section 6.5). 
• If the participant misses more than 2 consecutive doses of the IMP (see Section 7.1.2). 
• Systemic hypersensitivity reaction including anaphylaxis related or suspected to be related 
to ice cube provocation test. In the participants who experienced such reaction no further 
ice cube provocation test should be done during the study. 
        
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. 
If a clinically significant ECG finding is identified (including, but not limited to changes from 
baseline in QT interval corrected using [Bazett’s formula {QTcB} or Fridericia’s formula 
{QTcF}]) at screening, the Investigator or qualified designee will determine if the participant is 
eligible for the study. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE. 
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 study center 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. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of eCRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to regional or national emergency declared by 
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a governmental agency (Appendix 9 [Section 10.9]). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
eCRF. 
In addition, if patients 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. 
7.1.2.1 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned adverse event 
was unlikely and if the selection criteria for the study are still met (refer to Section 5.1 and 
Section 5.2). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
A participant may withdraw from the study at any time at his/her own request 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 study center records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
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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. 
Participants who withdraw from the study intervention should be explicitly asked 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 study center 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. 
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 study center 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 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). 
• It is recommended that assessments/procedures at a study center visit are performed in the 
following order if applicable (see Section 1.3) and possible: 
- 
Patient-Reported Outcome questionnaires (ColdUAS [if not performed at home before 
the study visit], DLQI/CDLQI, UCT, ColdU-QoL, 5-level EuroQol 5-dimensional 
questionnaire [EQ-5D-5L]) 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. 
- 
ECG (at screening), physical examination including vital signs, safety and laboratory 
assessment. 
- 
Ice cube provocation test. 
- 
Investigator/participant evaluation of urticaria symptoms at the provocation test site 
will be performed 10 minutes after ice cube removal. The Investigator will do his/her 
assessment first (the presence/absence of a confluent hive/wheal at the entire skin site 
of exposure [primary endpoint] and wheal intensity Likert scale). Then the participant 
will rate peak pruritus Numerical Rating Scale (NRS), peak burning sensation NRS, 
peak pain sensation NRS and will answer the Patient Global Impression of Severity 
(PGIS) and Patient Global Impression of Change (PGIC). It is important that the 
Investigator does not give any details of the evaluation to the participant, so his/her 
scoring and answers are not influenced by the Investigator’s assessment. 
• Adolescents complete the same PRO questionnaires as adults, except for the CDLQI 
(version adapted to adolescents). They 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. However, adolescents should 
answer the question themselves; parents/caregivers should not influence nor interpret their 
child's answer; parents/caregivers should not select any of the response choices on behalf 
of their child. 
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• 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 160 mL. The 
maximum amount of blood collected from each adolescent over the duration of the study 
will not exceed 93 mL. The maximum amount of blood collected per each visit from each 
adolescent will not exceed 21 mL per visit. The maximum amount of blood collected from 
each adolescent per visit and within 4-week interval will be complaint with the European 
guideline (27). Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
In light of the public health emergency related to COVID-19 (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. For a regional or national emergency declared by a governmental 
agency, contingency measures are included in Appendix 9 (Section 10.9). 
8.1 
EFFICACY ASSESSMENTS  
The e-diary is used for: 
• Daily recording of the ColdUAS questionnaire  
• Daily recording of H1-antihistamine medication use 
• DLQI (≥16 years old)/CDLQI (≥12 to <16 years old), UCT, ColdU-QoL and EQ-5D-5L 
evaluation at the study center visit 
• Assessment of peak pruritus NRS, peak burning sensation NRS, peak pain sensation NRS 
after provocation test. 
• Assessment of PGIS and PGIC after participants have completed the NRS. 
Timing of the assessment is specified in SoA (Section 1.3). 
This device will be dispensed at the screening visit (Visit 1), including instructions for use and 
participants will be instructed on the use of the device. 
Recorded information will be downloaded from this device daily. At the EOT visit, the e-diary 
will be downloaded and returned to the study center. 
The study center staff regularly, and when alerts received, should check the status of the 
compliance to background therapy and overall e-diary compliance including ColdUAS. The study 
center should follow-up with the participant as appropriate. 
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Wheal intensity Likert scale and missed school/workday questionnaire will be filled in by the 
Investigator/study center staff in the eCRF. 
8.1.1  Ice cube provocation test  
Cold urticaria is defined by the appearance of its signs and symptoms (hives/wheals, itch, pain, 
and burning sensation) after contact cooling and rewarming of the skin. Chronic inducible 
urticarias, including primary acquired chronic inducible ColdU, are diagnosed based on the 
patient history and the results of provocation testing. Moreover, cold provocation tests are used in 
clinical studies in patients with chronic urticaria to evaluate efficacy of treatments, mainly 
antihistamine treatments, but also doxepin, cyproheptadine (7, 24), either by evaluating the 
proportion of patients who after treatment did not develop signs/symptoms with the cold 
provocation test or evaluating the response to an experimental CSTT, ie, minimum time threshold 
of cold stimulation required to induce a coalescent wheal and other ColdU signs and symptoms. 
The ice cube provocation test is the most frequently used provocation method for ColdU in 
routine clinical practice and is therefore proposed for the present clinical study. 
The consensus recommendations for CIndU (EAACI/GA²LEN/EDF/UNEV) (1) defines the 
following for provocation methods for ColdU:  
• Provocation tests should be performed by applying a cold stimulus to forearm skin. 
• Cold provocation testing should be performed for 5 minutes on volar forearm. 
• Ice cube should be melting within a thin plastic bag to avoid cold damage of the skin and 
to prevent direct water contact to avoid the confusion with aquagenic urticaria if the test is 
positive.  
• Reading time 10 minutes of rewarming after ice cube is removed. 
Emergency treatment should be available at the study center to be administered by trained study 
center staff if severe hypersensitivity reaction occurs during the ice cube provocation test. 
The ice cube provocation test procedure will be described in a separate document. 
See Section 6.1.2 and Section 6.5.1 for details regarding background therapy requirements related 
to the ice cube provocation test and instructions how to proceed when a participant is using rescue 
therapy within 5 days prior to the test. 
For each participant, it is recommended that the ice cube test results are read by the same study 
personnel during the entire study, if possible. 
The primary endpoint will be the proportion of participants with negative ice cube provocation 
test at Week 24 compared to placebo. The negative test is defined as the absence of a confluent 
hive/wheal at the entire skin site of exposure after ice cube provocation test. The assessment will 
be done by the Investigator 10 minutes after ice cube removal. The result will be recorded in 
eCRF. For each ice cube provocation test room temperature and outdoor temperature should be 
reported in eCRF. 
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8.1.2 Wheal intensity Likert scale  
The Wheal intensity Likert scale (ranging from 0 to 5) is a clinician-reported outcome measure 
comprised of a single item assessing the intensity of patients’ cutaneous reaction rated as follows: 
0=no wheals; 1=numerous small, noncoalescent wheals; 2= a large, regular, slightly edematous, 
coalescent wheal; 3=a large and moderately edematous wheal; 4=a large, regular, and 
significantly edematous wheal without pseudopodia; and 5=a large, very edematous wheal with 
pseudopodia (28, 29). 
Investigators will complete the scale at the study visit, 10 minutes after removal of the ice cube 
from the participant’s arm. Investigators will complete the wheal intensity Likert scale in eCRF as 
described in the SoA (Section 1.3). 
8.1.3 Peak pruritus numerical rating scale (NRS), peak pain NRS, and peak burning 
sensation NRS  
Participants will undergo a temperature provocation test using ice cube at study visits at study 
center. Ten minutes after the removal of the ice cube from their arm, participants will be asked to 
rate the severity of local itch, pain, and burning sensation at the provocation site skin using a 
NRS. 
The peak pruritus NRS is a PRO comprised of a single item rated on a scale from 0 (“No itch”) to 
10 (“Worst itch imaginable”). Participants will be asked to rate the intensity of their worst local 
site pruritus (itch) 10 minutes after removal of the ice cube. The 24-hour version of the scale has 
been developed, tested and validated with patients with AD; a threshold value of 4 has been 
determined as a meaningful within-person change in score in adults and adolescent patients with 
AD (30). 
The peak pain NRS is a PRO comprised of a single item rated on a scale from 0 (“No pain”) to 10 
(“Worst imaginable pain”). Participants will be asked to rate the intensity of their worst local site 
pain 10 minutes after removal of the ice cube. 
The peak burning sensation NRS is a PRO comprised of a single item rated on a scale from 
0 (“No burning sensation”) to 10 (“Worst imaginable burning sensation”). Participants will be 
asked to rate the intensity of the worst local site burning sensation of their skin 10 minutes after 
the removal of the ice cube. 
Participants will complete the NRS as described in the SoA (Section 1.3). 
8.1.4 Urticaria control test (UCT) 4-item version  
The UCT is a PRO questionnaire for assessing urticaria control. The questionnaire has been 
developed and validated with patients with CSU and CIndU (25). It is comprised of 4 items: 
severity of physical symptoms of urticaria (itch, hives and/or swelling); QoL impairment; 
frequency of treatment being not sufficient to control urticaria; overall urticarial control. Recall 
period is “last four weeks”. Each item is rated on a 5-point Likert scale (scored with 0 to 4 points). 
Low scores indicate high disease activity and low disease control. The UCT total score is 
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calculated by adding all 4 individual item scores. Accordingly, the minimum and maximum UCT 
scores are 0 and 16, with a score of 16 for complete disease control (25). 
The minimal important difference (MID) of the UCT is determined to be 3 (31). 
Participants will complete the UCT as described in the SoA (Section 1.3). 
8.1.5 Cold Urticaria Activity Score  
The ColdUAS is a disease-specific PRO questionnaire designed to determine cold urticaria 
disease activity. ColdUAS is intended for patients with cold urticaria aged 12 years old and above; 
it has been developed and comprehensively tested with adults and adolescent patients with cold 
urticaria. Disease activity assessment is based on the daily documentation of cold-induced skin 
reactions (wheals and swelling), skin sensations (itching, burning, pain or feeling hot), avoidance 
behavior and trigger exposure, and overall symptoms severity. Skin reaction, skin sensations, 
exposition to cold temperatures that usually cause ColdU symptoms and overall symptom severity 
are rated on a 4-point scale from 0 (“No”) to 4 (“Yes, severe”); avoidance of cold temperatures 
that usually lead to ColdU symptoms are answered using responses “No”, “Yes partially 
avoided”, “Yes completely avoided”. 
After each week of completion, participants will be asked 2 additional questions about the overall 
disease activity of their ColdU in the past week using a 4-point Likert scale from “No disease 
activity” to “High disease activity” and 1 question about their current disease activity in the past 
week compared with before treatment using a 4-point Likert scale. 
Participants will complete the ColdUAS as described in the SoA (Section 1.3). 
8.1.6 Dermatology Life Quality Index and Children’s Dermatology Life Quality Index  
The DLQI is a PRO developed to measure dermatology-specific HRQoL in adult participants 
(26). The instrument comprises 10 items assessing the impact of skin disease on participant’s 
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). The 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 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). So far, there is no 
MID value determined for chronic inducible ColdU patients. 
The CDLQI is a validated questionnaire designed to measure the impact of skin disease on 
children’s HRQoL (34). Participants provide responses to 10 questions (symptoms feelings 
associated with disease, the impact of the disease on leisure, school or holidays, personal 
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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 (≥12 to <16 years old) as 
described in the SoA (Section 1.3). 
8.1.7 Cold Urticaria Quality of Life Questionnaire  
The ColdU-QoL questionnaire is a newly developed disease-specific PRO questionnaire designed 
to assess the impact of cold urticaria on patients’ HRQoL. It has been developed and 
comprehensively tested with adults and adolescent patients with cold urticaria. The questionnaire 
contains 19 items, each rated using 5-point Likert scale from 0 (Not at all / Never) to 4 (Very 
much / Very often), with a “Last 2 weeks” recall period.  The total raw score of the ColdU-QoL is 
transformed to a 0-100 scale with higher scores indicating higher ColdU-related QoL impairment. 
Participants will complete the ColdU-QoL as described in the SoA (Section 1.3) 
8.1.8 Patient Global Impression of Change of chronic inducible ColdU disease and 
Patient Global Impression of Severity of chronic inducible ColdU disease  
The PGIC is a 1-item questionnaire that asks the participant to provide the overall self-assessment 
of change in their chronic inducible ColdU on a 7-point scale, compared with 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 PGIS is a 1-item questionnaire that asks participants to provide the overall self-assessment of 
their chronic inducible ColdU current severity on a 4-point scale. Response choices are: 
1=“None”, 2=“Mild”, 3=“Moderate”, 4=“Severe”. 
Participants will complete the 2 items after having answered the peak pruritus NRS, pain NRS, 
and skin burning sensation NRS as described in the SoA (Section 1.3). 
8.1.9 Acquired Cold Urticaria Severity Index  
The Acquired Cold Urticaria Severity Index (ACUSI) is a measure designed to evaluate the 
severity of the ACU signs/symptoms (35). It is composed of 4 questions regarding the severity of 
ACU: 1) worst problems ever caused by cold urticarial; 2) season during which problems with 
outdoor activities occur because it was too cold; 3) maximum treatment needed; 4) frequency of 
complains. Questions 1, 3, and 4 are attributed 1 to 4 points, and question 3 is attributed 1 to 
3 points, thus resulting in a score ranging from 4 to 15. Scores of 4 to 7, 8 to 11, and 12 to 
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15 points indicate low, middle, and high ACU severity, respectively. A fifth question assesses the 
overall severity of the disease between mild, moderate, and severe. 
The ACUSI questionnaire will be administered during the screening period and will be captured 
in the eCRF. 
8.1.10 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 EQ-5D consists of 2 parts: the descriptive system and the EuroQol 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 “extreme problems” (36). 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, 
visual analogue scale where the endpoints are labeled “best imaginable health state (100)” and 
“worst imaginable health state (0)”. This information can be used as a quantitative measure of 
health outcome as judged by the individual respondents. 
The recall period is “today”. 
Participants will complete the questionnaire as described in the SoA (Section 1.3). 
8.1.11 Health care resource utilization/productivity  
A questionnaire on health care resource utilization and productivity (missed days of school [12 to 
17 years old]/workdays [18 and above]) will be collected by the Investigator for all participants 
throughout the study through eCRF. 
Participants will complete the questionnaire as described in the SoA (Section 1.3). 
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
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. 
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• Any new finding or worsening of previous finding should be reported as a new AE. 
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  
• A single standard 12-lead ECG will be obtained at the screening visit (Visit 1) as outlined 
in the SoA (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. The ECG will be read locally and results reported 
in the eCRF. In case of a clinically significant finding the Investigator should assess if it 
impacts a participant’s eligibility and document this in the medical records. An AE should 
be reported if appropriate. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests including pregnancy 
testing 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 eCRF. 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. 
• 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. 
• 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). 
• 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 eCRF. 
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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
An AE 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 AEs or SAEs after conclusion of 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 AEs and SAEs 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.  
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 AESIs (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 provided in Appendix 3 (Section 10.3). 
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8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an 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. 
• Adverse events that are considered expected will be specified in the reference safety 
information. 
• Suspected unexpected serious adverse reactions (SUSAR) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows: 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 
7 days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days 
- 
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR, or 
any 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. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
IB is reference safety information for considering AEs as expected. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants will be collected from the signing of the 
ICF up to the EOS Visit or within 12 weeks after last study intervention, whichever was 
later. Details of all pregnancies in female partners of male participants will be collected 
after the start of study intervention 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). The IMP should be permanently discontinued in case of pregnancy of 
female participant (see Section 7.1.1). 
• 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  
An episode of ColdU 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 Adverse event of special interest  
An 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. 
• 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 participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP. 
- 
Pregnancy occurring in a female participant entered in the clinical study or in a female 
partner of a male participant entered in the clinical study. It will be qualified as an 
SAE only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
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 (See Appendix 4 
[Section 10.4]) 
• Symptomatic overdose (serious or nonserious) with IMP/Noninvestigational medicinal 
product (NIMP) 
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- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) 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 
the overdose form. An overdose (accidental or intentional) with any NIMP is an event 
suspected by the Investigator or spontaneously notified by the participant (not based on 
systematic pills count) 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. 
8.3.7.1 Anaphylactic reactions  
A serious feature of ColdU is anaphylaxis. Thirty-five percent to 70% of patients with chronic 
inducible ColdU have experienced systemic reactions including anaphylaxis in severe cases. (6, 
37, 38). 
Anaphylaxis is defined as a severe, potentially life-threatening systemic hypersensitivity reaction, 
characterized by being rapid in onset with life-threatening airway, breathing, or circulatory 
problems that is usually, though not always, associated with skin and mucosal changes. 
When the diagnosis of anaphylaxis is made, the basis for having suspected the diagnosis must be 
documented, using the criteria in Appendix 10 (Section 10.10), established by the Second 
Symposium on the Definition and Management of Anaphylaxis (37, 39). Reports of anaphylaxis 
will be collected as AESIs in the eCRF. 
All participants with ColdU and their parents/legal representative/caregiver should be cautioned 
regarding the risk of anaphylaxis and provided with an epinephrine autoinjector. 
The proportion of participants with cold exposure triggered urticaria requiring emergency medical 
care visit or treatment with epinephrine (after provocation test and/or at home) will be evaluated. 
8.3.8 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team who 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. 
8.4 
TREATMENT OF OVERDOSE  
Symptomatic overdose (serious or nonserious) with IMP/NIMP is considered as an AESI (defined 
in Section 8.3.7). No antidote is available for dupilumab. The Sponsor does not recommend 
specific treatment for an overdose. 
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In the event of an overdose, the Investigator/treating physician should: 
1. Contact the Sponsor 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 IMP if requested by the Sponsor (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 
Sponsor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS AND IMMUNOGENICITY ASSESSMENTS  
8.5.1 Systemic drug concentration and antidrug 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 the collection, 
storage, and shipping of serum are described in separate operational manuals. The date of 
collection should be recorded in the eCRF. 
8.5.1.2 Handling procedures  
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of the handling procedure for samples used in the 
determination of systemic drug concentration and antidrug antibodies (ADA) is provided in 
Table 4. 
Table 4 - Summary of handling procedures  
Sample type 
Functional dupilumab 
Anti-dupilumab antibody 
8.5.1.3 Bioanalytic method  
Serum PK and ADA samples will be assayed using validated methods as described in Table 5. 
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Table 5 - Summary of bioanalytical methods for functional dupilumab and anti-dupilumab 
antibodies  
Analyte 
Functional dupilumab 
Anti-dupilumab antibody 
Note: 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 requires 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 PK and ADA samples may be collected after the EOS 
Visit until resolution of the AE. 
8.6 
PHARMACODYNAMICS  
See Section 8.8 for IgE measurement. No other PD 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, including sequencing. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study. 
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 
the laboratory manual. 
8.8 
BIOMARKERS  
Collection of samples for biomarker research is also part of this study. 
As specified in the SoA, venous blood samples will be collected from all participants for 
measurement of total serum IgE, which will be done using a validated quantitative method. 
Optional samples for biomarker research that should be collected from participants in the study 
where possible are the following: 
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• Serum and plasma:  
- 
Samples will be collected and stored for possible future analysis of potential 
biomarkers of drug response, disease activity, safety, and type 2 inflammation. See 
Section 8.8.1 
• Basophil activation test (substudy) 
- 
Blood will be collected at selected sites for assessment of basophil activation using a 
validated assay. 
Adolescents will not participate in the optional assessments. See SoA for additional details. 
In addition, for participant(s) who have consented to it, samples that are unused or left over after 
planned testing may be used for additional research purposes, including developing assay 
methods, possible analysis of potential biomarkers of drug response, disease activity, safety, and 
type 2 inflammation, and developing companion diagnostics. 
8.8.1 Use of Biological Samples and Data for Future Research  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
and used for future research when consented to by participants (see Section 10.1.3) unless 
prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will not be 
included in the local ICF). 
For participants who consent to the storage and use of their data and remaining and/or extra 
clinical samples, data and samples may be used after the study ends for future research related 
either to the drug, the mechanism of action, and the disease or its associated conditions. Such 
research may include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites. If future research on genetic material is performed, this will also be limited to the 
purpose of addressing research questions related to the drug, the mechanism of action, the disease 
or its associated conditions. 
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. 
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research). 
All study participant data and samples will be coded such that no participant direct identifiers will 
be linked to them. Coded data and samples may be transferred to a Sponsor site (or a 
subcontractor site), which may be located outside of the country where the study is conducted. 
The Sponsor adopts safeguards for protecting participant confidentiality and personal data (see 
Section 10.1.4). 
The samples will be stored for a maximum of 15 years after the end of the study (or according to 
local regulations). Any samples remaining at the end of retention period will be destroyed. If a 
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participant requests destruction of his/her samples before the end of the retention period, the 
Investigator must notify the Sponsor (or its contract organization) in writing. In such case, 
samples will be destroyed and related coded data will be anonymized unless otherwise required by 
applicable laws. 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS  
A questionnaire on health care resource utilization and productivity will be used in this study. 
Number of missed school/workdays collection is described in Section 8.1.11 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The statistical hypothesis for comparing dupilumab against placebo for the primary endpoint of 
the proportion of participants with negative ice cube provocation test at Week 24 is: 
• 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 the secondary endpoints can be specified similarly. 
9.2 
SAMPLE SIZE DETERMINATION  
To adequately power the study for the comparison of the primary endpoint of the proportion of 
participants with negative ice cube provocation test at Week 24 between the 2 groups, the sample 
size was calculated based on the following assumptions: 
1. The placebo group has 
 of participants with negative ice cube provocation test at 
Week 24 and the dupilumab group has 
 of participants with negative ice cube 
provocation test at Week 24. 
2. There is a drop-out rate of 10% in both groups. 
3. The statistical test is a Z test that is based on the difference of the 2 proportions with 
unpooled variance estimate and 2-sided 1% significance level. 
4. Participants are equally randomized to the dupilumab group and the placebo group. 
With these assumptions, 39 participants per group (78 participants in total) will provide 
90% power to detect the difference of 
 response rate in the dupilumab group and 
 
response rate in the placebo group. The sample size calculations were performed using 
nQuery+nTerim 4.0. 
9.3 
POPULATIONS FOR ANALYSES  
The analysis populations are defined in Table 6. 
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Table 6 - Analyses population  
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. 
Efficacy 
The ITT population 
Safety 
All participants randomly assigned to IMP and who take at least 1 dose of study 
IMP. Participants will be analyzed according to the intervention they actually 
received.  
Randomized participants for whom it is unclear whether they took the study IMP 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 PD analyses will be performed on the safety population. 
Pharmacokinetic (PK) 
The PK population includes all participants in the safety population with at least 
1 non-missing result for functional dupilumab concentration in serum after first dose of 
the IMP. 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 1 non-
missing ADA result after first dose of the IMP. Participants will be analyzed according to 
the intervention actually received. 
Abbreviations: ADA = antidrug antibody; ICF = Informed consent form, IMP = investigational medicinal product; IRT = Interactive response 
technology; ITT = intent-to-treat; PD = Pharmacodynamic; PK = Pharmacokinetic.  
9.4 
STATISTICAL ANALYSES  
The SAP will be finalized prior to database lock and will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and the key 
secondary endpoints. 
9.4.1 Efficacy analyses  
Statistical analysis methods for the primary, secondary, and tertiary/exploratory endpoints are 
presented in the table below (Table 7). In addition, for the primary and secondary endpoints, the 
primary estimand and details about the intercurrent events strategy and missing data handling are 
presented in Appendix 13 (Section 10.13). 
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Table 7 - Efficacy analyses  
Endpoint 
Statistical analysis methods 
Primary 
Primary endpoint: 
Proportion of participants with negative ice cube 
provocation test at Week 24 
The primary efficacy endpoint will be analyzed using the Cochran-
Mantel-Haenszel test stratified by region and background H1-
antihistamine regular/daily use (Yes/No). The comparison of the 
proportions of participants with negative ice cube provocation test at 
Week 24 between dupilumab and placebo will be derived and the 
corresponding odd ratios and the 95% confidence interval (CI) will be 
reported. Participants who receive highly influential prohibited 
medications and/or highly influential rescue medications (details of 
selection will be specified in the statistical analysis plan [SAP]) will be 
considered as having positive ice cube provocation tests 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 positive/negative ice cube provocation test 
outcome. Participants with missing ice cube provocation test data at 
Week 24 will be considered as having positive ice cube provocation 
tests.  
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 local wheal 
intensity at the provocation site at Week 12 
and Week 24 using the wheal intensity 
Likert scale ranging from 0 to 5 (clinician 
evaluation) 
• 
Change from baseline in local itch severity 
at the provocation site at Week 12 and 
Week 24 using the Peak Pruritus Numerical 
Rating Scale (NRS, score 0 to 10) (patient 
reported)  
• 
Change from baseline in local skin burning 
sensation at the provocation site at Week 
12 and Week 24 using the peak burning 
sensation NRS (patient reported)  
• 
Change from baseline in local pain severity 
at the provocation site at Week 12 and 
Week 24 using the peak pain sensation 
NRS (patient reported)  
• 
Change from baseline in urticaria control 
test (UCT 4-item) at Week 24 
 
The secondary endpoints at Week 24 will be analyzed using analysis 
of covariance (ANCOVA) with multiple imputation. For participants 
taking highly influential prohibited medications and/or highly influential 
rescue medications (details of selection will be specified in the SAP), 
their data after the medication usage will be set to missing, and the 
WOCF approach (worst postbaseline observation for the participant 
will be carried forward) will be used to impute missing Week 24 value 
(for participants whose postbaseline values are all missing, the 
participant’s baseline value will be used to impute the missing 
endpoint value). Participants who discontinue the treatment 
prematurely are encouraged to follow the planned clinical visits. For 
participants who did not take the highly influential prohibited 
medications and/or highly influential 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 study intervention 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 study intervention 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 
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Endpoint 
Statistical analysis methods 
• 
Change from baseline in cold urticaria signs 
and symptoms severity at Week 24 on cold 
exposure days as measured by ColdUAS 
• 
Change from baseline in the proportion of 
cold urticaria sign and symptom free days 
at Week 24 on cold exposure days as 
measured by ColdUAS 
• 
Change from baseline in health-related 
quality of life (HRQoL) as measured by 
Dermatology Life Quality Index (DLQI) in 
participants ≥16 years old, and in 
Children’s Dermatology Life Quality Index 
(CDLQI) in participants ≥12 to <16 years 
old at Week 24 
• 
Change from baseline in Cold Urticaria 
Quality of Life (ColdU-QoL) at Week 24. 
participants excluding participants who have taken the highly 
influential prohibited medications and/or highly influential 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 endpoint, treatment 
group, region (combined countries), and background H1-antihistamine 
regular/daily use (Yes/No) as covariates. 
Statistical inference obtained from all imputed data will be combined 
using Rubin’s rule. Descriptive statistics including number of 
participants, 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% CI will be provided along with the 
p-values. 
The continuous endpoints at Week 12 will be analyzed in a similar way 
as the secondary endpoints at Week 24.  
Detailed analyses will be described in the SAP finalized before 
database lock. 
Secondary 
• 
Proportion of participants with negative ice 
cube provocation test at Week 12 
• 
Proportion of well-controlled participants 
(UCT ≥12) at Week 24 
• 
Proportion of participants with an 
improvement of ≥3 in UCT 4- item from 
baseline to Week 24  
 
These binary endpoints will be analyzed in a similar way as the 
primary endpoint. 
Secondary 
• 
Proportion of participants receiving rescue 
therapy for chronic induced ColdU during 
the planned treatment period 
• 
Proportion of participants with cold 
exposure triggered urticaria requiring 
emergency medical care visit or treatment 
with epinephrine (at provocation test and/or 
at home) 
 
These binary endpoints will be summarized using the count and 
percentage of participants. 
Tertiary/Exploratory 
• 
• 
• 
 
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Endpoint 
Statistical analysis methods 
• 
• 
• 
A multiplicity hierarchical testing will be proposed to control the overall Type-I error rate for 
testing the primary endpoint, selected PRO(s), and the other key secondary endpoints. The study 
is considered positive when the primary endpoint achieves statistical significance. A detailed 
multiplicity adjustment procedure for the efficacy endpoints will be described in the study SAP. 
9.4.2 Safety analyses  
All safety analyses will be performed on the safety population (Table 8). The summary of safety 
results will be presented by treatment group. The baseline value is defined generally as the last 
available value before randomization. 
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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 IMP. Serious AEs and AEs leading to study discontinuation that occur outside the 
treatment-emergent period will be summarized separately. 
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 to 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 during the 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 postbaseline time point, endpoint, and 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.  
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Endpoint 
Statistical Analysis Methods 
The proportion of participants who had at least 1 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. 
Abbreviations: AE = adverse event; AESI = adverse events of special interest; eCRF = electronic case report form; IMP = investigational 
medicinal product; SAE = serious adverse event; SAP = statistical analysis plan. 
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 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 that 
might be required to investigate the impact of COVID-19, or other pandemics declared as a public 
health emergency on the efficacy (eg; missing data due to COVID-19) and safety will be detailed 
in the SAP. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
9.5 
INTERIM ANALYSES  
No interim analysis is planned for this study.  
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. 
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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 (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
• 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 study center and adherence to 
requirements of 21 Code of Federal Regulations (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) or his/her legally authorized representative and 
answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants (and 
parents of adolescents) 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 will sign 
simplified informed consent. If during the study the adolescent reaches the age of majority 
he/she needs to re-consent. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was randomized 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. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future 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. Please note that adolescents will not 
participate to optional exploratory research. 
For adults only, the ICF will also contain a separate section concerning the other optional tests 
(genetic testing [DNA/RNA sampling], and basophil activation test). A separate signature for each 
optional test will be required to document a participant's agreement to this. Participants who 
decline to participate in this optional test will not provide this separate signature. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9) 
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 
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applicable laws and regulations including the GDPR. The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
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)”. They will 
not be collected in the countries where this is prohibited by local regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor. 
• 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 as described in the informed consent. 
• 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. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
• 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. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation[s] details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
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• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients: 
- 
Personnel within Sanofi or partners or service providers involved in the study 
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably: 
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers. 
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to 30 years, unless further 
retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project. 
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
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10.1.5 Committees structure  
There will be no study committees. 
10.1.6 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical studies and results on publicly 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 clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical studies 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 https://vivli.org. 
Individual participant data and supporting clinical documents are available for request at 
https://vivli.org. While making information available we continue to protect the privacy of 
participants in our clinical studies. Details on data sharing criteria and process for requesting 
access can be found at this web address: https://vivli.org. 
Professionals involved in the study or in the drug development program 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “European 
Federation of Pharmaceutical Industries and Associations (EFPIA) Code on Disclosure of 
Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and Healthcare 
Organizations”. 
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. 
• Guidance on completion of CRFs will be provided in the CRF completion instructions.  
• 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. 
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• 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 study center 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. 
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. 
10.1.9 Study and study center closure  
The Sponsor or designee reserves the right to close the study center or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study centers will be closed upon study 
completion. A study center is considered closed when all required documents and study supplies 
have been collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
center 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 study center 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 study center 
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 9 will be performed by the central laboratory. The participants do not 
need to be fasting for blood sampling. 
• 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 9 - 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 
 
Lactate dehydrogenase 
 
Uric acid 
 
Total cholesterol 
 
Albumin 
 
Potassium 
 
Sodium 
 
Chloride 
 
Bicarbonate 
 
Creatine Phosphokinase 
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase  
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase  
 
Alkaline phosphatase 
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Laboratory assessments 
Parameters 
 
Total bilirubin 
 
Total protein 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, leukocyte 
esterase) by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other screening tests 
• 
For women of childbearing potential: serum pregnancy test at screening visit 
(Visit 1) and urine pregnancy tests at baseline visit (Visit 2) and every 4 weeks 
during the study. A negative result must be obtained at Visit 1 and at Visit 2 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 study center 
visits planned. For the urine pregnancy tests performed at home female 
participants will have to complete a pregnancy test diary. 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. 
• 
Human Immunodeficiency Virus (HIV) serologic testing at screening visit (Visit 1): 
HIV screen (Anti-HIV-1 and HIV-2 antibodies). 
• 
Tuberculosis test (to be performed locally if required). 
The results of each test must be entered into the eCRF. 
Abbreviations: DNA = deoxyribonucleic acid; eCRF = electronic case report form; HBV = hepatitis B virus, IEC = Institutional Ethics 
Committee; IRB = Institutional Review Board; RNA = ribonucleic acid; SAE = serious adverse event; ULN = Upper Limit of Normal. 
NOTES : 
a Details of liver chemistry stopping criteria with suggested actions and follow-up assessments related to liver monitoring are given in 
Section 7.1 and Section 10.6.  All events which may indicate severe liver injury (possible Hy’s Law, ALT or AST >3 × ULN and total 
bilirubin >2 × ULN) must be reported as an SAE. 
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  
10.3.1 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. 
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• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 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. 
10.3.2 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 
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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 1 of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
- 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase 
>10 × ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of 
blood sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study 
- 
Chronic neurodegenerative diseases diagnosed during the study. 
10.3.3 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 eCRF. 
• 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 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 the Sponsor. 
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• 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. 
• 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 1 of the criteria used when determining regulatory reporting 
requirements. 
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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. 
10.3.4 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 study center will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• The study center will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given study center, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a study center 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 study center 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. 
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. 
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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 postmenopausal 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 study center’s personnel: 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 hormone replacement therapy (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. 
Table 10 - Methods of contraception  
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• 
Intrauterine device  
• 
Intrauterine hormone-releasing system  
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
• 
Highly Effective Methodsb That Are User Dependent 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 
- 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation 
- 
oral 
- 
injectable 
• 
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.) 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently 
and correctly. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male condom and female condom should not be used 
together (due to risk of failure with friction) 
 
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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 study intervention. 
• 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. 
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial 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 for medical reasons 
will be reported as an AE or SAE. 
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) 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. 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 the study intervention. 
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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, blood samples will be collected for DNA and RNA analysis from consenting 
participants. 
• Deoxyribonucleic acid (DNA) and RNA samples will be used for research related to 
dupilumab or CIndU 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: ACTIONS AND FOLLOW-UP 
ASSESSMENTS  
 
*If unable to retest in 72 hours, use original lab 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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10.7 
APPENDIX 7: CLINICAL-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES  
10.7.1 Cold Urticaria activity score (ColdUAS)  
 
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10.7.2 Acquired Cold Urticaria Severity Index  
 
 
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10.7.3 Itch numerical rating scale, pain numerical rating scale, and burning sensational 
numerical rating scale  
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10.7.4 Wheal Intensity Likert Scale  
 
 
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10.7.5 ColdU-QoL  
 
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10.7.6 Urticaria control test (UCT)  
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10.7.7 Dermatology life quality index (DLQI)  
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10.7.8 Children’s dermatology life quality index (CDLQI)  
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10.7.9 Patient Global Impression of Change  
 
10.7.10 
Patient Global Impression of Severity  
 
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10.7.11 
5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L)  
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10.8 
APPENDIX 8: COUNTRY SPECIFIC REQUIREMENTS  
10.8.1 Japan  
Section 6.5.1 Rescue medicine (see Section 6.5.1) 
Use of H1-antihistamines for chronic inducible cold urticarial treatment 
In Japan, patients with chronic inducible ColdU who are not well-controlled on approved 
H1-antihistamine dose may escalate the H1-antihistamine dose only up to 2-fold the approved 
dose. 
During the study, participants should continue their established standard of care background 
therapy with a long-acting non-sedating H1-antihistamine, at up to 2-fold the approved dose for 
CSU. 
• Participants who used H1-antihistamine regularly/daily prior to study entry should 
continue to take it daily. Note: regular/daily use of H1-antihistamine prior to study entry is 
defined as H1-antihistamine intake for at least 4 days per week for at least 1 month prior to 
screening visit (Visit 1) 
• Participants who took H1-antihistamine as needed prior to study entry should limit the use 
to short-term. 
Rescue therapy  
All participants will be allowed to take additional doses of their H1-antihistamine 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-antihistamine to the maximum allowed dose, or if the participant is already on the 2-fold 
approved H1-antihistamine, the participants can switch to another antihistamine up to 2-fold 
approved dose for CSU or a short course of OCS is allowed as rescue therapy during the treatment 
and follow-up periods. 
Due to an episodic nature of ColdU, it is recommended to prescribe rescue therapy for a short 
period of time (not more than 7 days).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 ice cube provocation test should be delayed if rescue therapy (H1-antihistamine or OCS) is 
taken within 5 days prior to the test. The ice cube provocation test can be done when the 
participant is back to prescreening H1-antihistamine dose or is off H1-antihistamine (or OCS) 
intake for at least 5 consecutive days to allow to have ice cube provocation test performed under 
the same background condition for each participant from screening visit (Visit 1) to EOS (Visit 5). 
The initial background therapy should remain unchanged throughout the study. Participants 
should continue their prescreening dose of initial H1-antihistamine once rescue treatment is no 
longer required or stop H1-antihistamine intake. 
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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-antihistamine and OCS including safety precautions please 
refer to the locally approved product labeling. 
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10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency declared by a 
governmental agency: 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested for an emergency that prevents access to the study site, to 
ensure the safety of the participants, to consider continuity of the clinical study conduct, protect 
trial integrity, and assist in maintaining compliance with GCP in Conduct of Clinical Trials 
Guidance. Sponsor agreement MUST be obtained prior to the implementation of these procedures 
for the duration of the emergency. 
Study Intervention Administration  
The following contingencies may be implemented for the duration of the emergency (after 
Sponsor agreement is obtained) to make clinical supplies available to the participant for the 
duration of the emergency:  
• In case of emergency (eg, natural disaster, pandemic, etc.), IMP may be supplied from the 
site to the participant via a Sponsor-approved courier company where allowed by local 
regulations and approved by the participant (or parent/legally authorized representative). 
• 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 study 
center-specific requirements. 
Temporary discontinuation/rechallenge  
In addition, for a regional or national emergency declared by a governmental agency, the 
temporary discontinuation will be allowed as defined in Section 7.1.2. 
During a regional or national emergency declared by a governmental agency, reinitiation of IMP 
can only occur once the Investigator has determined, according to his/her best judgment, that the 
contribution of the IMP(s) to the occurrence of the epidemic event (eg. COVID-19) was unlikely. 
Study Assessments and Procedures 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study. During the emergency, if 
the site will be unable to adequately follow protocol mandated procedures, alternative treatment 
outside the clinical trial should be proposed, and 
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screening/enrollment/randomization/administration of study intervention may be temporarily 
delayed (see also Section 5.5). 
In the event of a regional or national emergency declared by a governmental agency, the 
continuity of clinical study conduct and oversight may require implementation of temporary or 
alternative mechanisms, such as phone contact, virtual visits, online meetings, extension of visit 
windows for on-site visits, use of local clinic or laboratory locations, and home visits by skilled 
staff. The primary focus should be collection of safety information and provision of daily e-diary 
data collection for key efficacy assessments. 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 public health 
emergency) and will remain in effect only for the duration of the public health emergency. 
Contingencies implemented due to emergency will be documented. 
Statistical Consideration 
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). 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 
events requiring public health emergency on the efficacy (eg, missing data due to COVID-19) and 
safety will be detailed in the SAP. 
Informed Consent Process 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local laboratories). 
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10.10 APPENDIX 10: DEFINITION OF ANAPHYLAXIS  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death (39)”. 
Clinical criteria for diagnosing anaphylaxis 
 
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10.11 APPENDIX 11: 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 
• Non-TB mycobacteria 
• Pneumocystis pneumonia 
This list is indicative and not exhaustive. 
 
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10.12 APPENDIX 12: LIST OF PROHIBITED LIVE ATTENUATED VACCINES  
• Bacillus Calmette-Guérin (BCG) anti-TB 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. 
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10.13 APPENDIX 13: ESTIMANDS FOR MAIN ENDPOINTS  
Table 11 - Summary of primary estimand for main endpoints in ColdU study  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) strategy and missing data handling 
Population-level summary 
 
Primary objective: To demonstrate the efficacy of dupilumab in adult and adolescent participants with primary acquired chronic inducible ColdU who remain symptomatic despite the use of an 
H1-antihistamine 
Primary endpoint  
(treatment 
policy/composite 
estimand) 
Proportion of participants 
with negative ice cube 
provocation test at 
Week 24 
ITT 
Discontinuation of the study intervention before Week 24 (but not taking 
highly influential prohibited medications and/or highly influential rescue 
medications prior to Week 24): Off-study intervention data up to Week 24 
will be included in the analysis (treatment policy strategy). 
Taking highly influential prohibited medications and/or highly influential 
rescue medications prior to Week 24: Participants will be considered as 
having positive ice cube provocation tests at Week 24 (composite 
strategy). 
Having missing data at Week 24:  Participants will be considered as having 
positive ice cube provocation tests at Week 24. 
CMH test stratified by region (combined 
countries) and background H1-
antihistamine regular/daily use 
(Yes/No). The comparison of the 
proportions of treatment response 
between dupilumab and placebo will be 
derived, and the corresponding odd 
ratios and the 95% CI will be reported. 
Secondary objective: To demonstrate the efficacy of dupilumab on primary acquired chronic inducible ColdU local signs and symptoms 
Secondary endpoint 
(treatment 
policy/composite 
estimand) 
Change from baseline in 
local wheal intensity at 
the provocation site at 
Week 24 using the wheal 
intensity Likert scale 
ranging from 0 to 5 
(clinician evaluation) 
ITT 
The intercurrent events will be handled as below: 
• 
Discontinuation of the study intervention before Week 24 (but not 
taking highly influential prohibited medications and/or highly influential 
rescue medications prior to Week 24): Off-study intervention data up 
to Week 24 will be included in the analysis (treatment policy strategy)  
ANCOVA model with treatment group, 
baseline value, region, and background 
H1-antihistamine regular/daily use 
(Yes/No) as covariates will be used. 
Statistical inference obtained from all 
imputed data by ANCOVA model will be 
combined using Rubin’s rule.  
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Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) strategy and missing data handling 
Population-level summary 
 
 
Change from baseline in 
the proportion of cold 
urticaria sign and 
symptom free days at 
Week 24 on cold 
exposure days as 
measured by ColdUAS 
ITT 
• 
Taking highly influential prohibited medications and/or highly 
influential rescue medications prior to Week 24: data will be set to 
missing values after the medication usage, and the WOCF approach 
(worst postbaseline observation for the participant will be carried 
forward) will be used to impute missing endpoint value (for 
participants whose postbaseline values are all missing, the 
participant’s baseline value will be used to impute the missing 
endpoint value) (composite strategy) 
Missing data handling:  
• 
For participants who discontinue study intervention 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 study 
intervention 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 highly influential prohibited medications and/or highly 
influential rescue medications on or before Week 24 and excluding 
patients who discontinue due to lack of efficacy on or before Week 24. 
Descriptive statistics including number 
of participants, 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% CI 
will be provided along with the p-values. 
Abbreviations: ANCOVA = Analysis of covariance, CI = confidence interval, CMH = Cochran-Mantel-Haenszel, ColdU = cold urticaria, ITT= Intent-to-treat. 
Additional secondary objectives/endpoints are not included in this table but would be handled with a similar strategy as the endpoint type (ie, continuous, proportion) at other weeks. 
 
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10.14 APPENDIX 14: ABBREVIATIONS  
 
ACU: 
acquired cold urticaria 
ACUSI: 
Acquired Cold Urticaria Severity Index 
AD: 
atopic dermatitis  
ADA: 
antidrug antibody 
ADR: 
adverse drug reaction 
AEs: 
adverse event(s) 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
Analysis of covariance 
CDLQI: 
Children’s Dermatology Life Quality Index 
CFR: 
Code of Federal Regulations 
CholU: 
cholinergic urticaria 
CI: 
confidence interval 
CIndU: 
Chronic Inducible Urticaria  
ColdU: 
cold urticaria 
ColdUAS: 
Cold Urticaria Activity Score 
ColdU-QoL: 
Cold Urticaria Quality of Life 
COPD: 
chronic obstructive pulmonary disease  
COVID-19: 
Coronavirus Disease 2019 
CRF: 
case report form 
CRSwNP: 
chronic rhinosinusitis with nasal polyposis  
CSICF: 
Core Study Informed Consent Form 
CSR: 
clinical study report  
CSTT: 
cold-simulation time test 
CSU: 
Chronic Spontaneous Urticaria  
DLQI: 
Dermatology Life Quality Index 
DNA: 
Deoxyribonucleic acid  
DPU: 
delayed pressure urticaria  
DTP: 
direct to patient  
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
ELISA: 
enzyme-linked immunosorbent assay 
EoE: 
eosinophilic esophagitis  
EOT: 
end of treatment 
EQ-5D: 
EuroQol-5 dimensions  
EQ-5D-5L: 
5-level EuroQol 5 dimensional questionnaire 
EQ-VAS: 
EuroQol visual analogue scale  
EU: 
European Union 
FcεRI: 
Fc epsilon receptor 
GCP: 
Good Clinical Practice 
GDPR: 
General Data Protection Regulation 
HBc Ab: 
hepatitis B core antibody  
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HBs Ag: 
hepatitis B virus surface antigen  
HBV: 
hepatitis B virus 
HCV: 
hepatitis C virus 
HCV Ab: 
Hepatitis C antibody 
HIV: 
human immunodeficiency virus  
HRQoL: 
health-related quality of life  
HRT: 
hormone replacement therapy 
IB: 
Investigator's brochure 
ICF: 
informed consent form 
ICH: 
International Council of Harmonisation 
IEC: 
Institutional Ethics Committee 
IgE: 
immunoglobulin E 
IL: 
Interleukin 
IL-4Rα: 
interleukin-4 receptor alpha subunit 
IMP: 
investigational medicinal product  
IRB: 
Institutional Review Boards 
IRT: 
interactive response technology  
ITT: 
Intent-to-treat  
IVIG: 
intravenous immunoglobulin  
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LS: 
least squares  
LTE4: 
leukotriene E4 
LTRAs: 
Leukotriene receptor antagonists  
mAb: 
monoclonal antibody 
MID: 
minimal important difference 
NIMP: 
noninvestigational medicinal product  
NRS: 
Numerical Rating Scale 
OCS: 
oral corticosteroids 
PD: 
pharmacodynamics 
PGDM: 
prostaglandin D2 metabolite  
PGIC: 
Patient Global Impression of Change 
PGIS: 
Patient Global Impression of Severity  
PK: 
pharmacokinetics 
PN: 
prurigo nodularis  
PRO: 
patient‑reported outcome 
q2w: 
every 2 weeks  
qd: 
once per day  
QoL: 
Quality of Life 
RNA: 
ribonucleic acid  
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SCS: 
systemic corticosteroids 
SoA: 
schedule of activities 
SUSAR: 
suspected unexpected serious adverse reactions  
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TB: 
tuberculosis 
TEAE: 
treatment‑emergent adverse event 
Th2: 
T helper 2 
UCT: 
urticaria control test 
ULN: 
upper limit of normal 
US: 
United States 
WOCBP: 
woman of childbearing potential  
WOCF: 
worst observation carried forward 
 
10.15 APPENDIX 15: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). 
 
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11 
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this complication and a proposal for a diagnostic classification of cold urticaria. J Allergy Clin 
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According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
pro o 
STATISTICAL ANALYSIS PLAN      
Protocol title: 
A randomized, double-blind, placebo-controlled, multi-
center, parallel-group study of dupilumab in patients 
with chronic inducible cold urticaria who remain 
symptomatic despite the use of H1-antihistamine 
treatment 
Protocol number: 
EFC16720 
Compound number 
(INN/Trademark): 
SAR231893/REGN668 
dupilumab/Dupixent 
Study phase: 
Phase 3  
Short title: 
Dupilumab for the treatment of chronic inducible cold 
urticaria in patients who remain symptomatic despite 
the use of H1-antihistamine  
LIBERTY-CINDU CUrIADS 
Statistician: 
Statistical project leader: 
Date of issue: 
03-Oct-2022 
Regulatory agency identifier number(s): 
IND: 
105379 
EudraCT: 
2020-003756-33 
NCT: 
NCT04681729 
WHO: 
U1111-1246-6913 
Other: 
Not yet available 
 
 
 
Total number of pages: 48 
 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 7 
1.2.1 
Estimands ........................................................................................................................................ 9 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 12 
3 
ANALYSIS POPULATIONS .......................................................................................................... 13 
4 
STATISTICAL ANALYSES ........................................................................................................... 15 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 15 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 15 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 16 
4.3.1 
Definition of endpoint(s) ................................................................................................................. 16 
4.3.2 
Main analytical approach ............................................................................................................... 16 
4.3.3 
Sensitivity analysis ......................................................................................................................... 18 
4.3.4 
Supplementary analyses ................................................................................................................ 19 
4.3.5 
Subgroup analyses ........................................................................................................................ 19 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 20 
4.4.1 
Key/Confirmatory secondary endpoint(s) ...................................................................................... 20 
4.4.1.1 
Definition of endpoint(s) ................................................................................................................. 20 
4.4.1.2 
Main analytical approach ............................................................................................................... 21 
4.4.2 
Supportive secondary endpoint(s) ................................................................................................. 21 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 22 
4.5.1 
Definition of endpoint(s) ................................................................................................................. 22 
4.5.2 
Main analytical approach ............................................................................................................... 23 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 23 
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4.7 
SAFETY ANALYSES ..................................................................................................................... 23 
4.7.1 
Extent of exposure ......................................................................................................................... 23 
4.7.2 
Adverse events .............................................................................................................................. 25 
4.7.3 
Additional safety assessments ....................................................................................................... 29 
4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 29 
4.8 
OTHER ANALYSES....................................................................................................................... 31 
4.8.1 
PK analyses ................................................................................................................................... 31 
4.8.2 
Immunogenicity analyses ............................................................................................................... 32 
4.8.2.1 
Association of Immunogenicity with Exposure, Safety and Efficacy .............................................. 33 
4.8.3 
Pharmacodynamic/genomics endpoints ........................................................................................ 34 
4.9 
INTERIM ANALYSES .................................................................................................................... 35 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 36 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 36 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 37 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 37 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 40 
5.5 
APPENDIX 5 SELECTION CRITERIA FOR AE/MEDICATION GROUPINGS ............................. 46 
6 
REFERENCES ............................................................................................................................... 48 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ................................................................................................................. 7 
Table 2 - Summary of primary estimand for main endpoints ........................................................................ 10 
Table 3 - Populations for analyses ................................................................................................................ 13 
Table 4 - Highly influential prohibited medications and/or highly influential rescue medications impact on 
efficacy .......................................................................................................................................................... 17 
Table 5 - Sorting of AE tables ....................................................................................................................... 25 
Table 6 - Analyses of adverse events ........................................................................................................... 26 
Table 7 - Selections for AESIs and other AEs of interest .............................................................................. 27 
Table 8 - Weekly efficacy assessments from daily e-diary ........................................................................... 43 
Table 9 - Time window for safety endpoints .................................................................................................. 44 
Table 10 - Time window for efficacy variables .............................................................................................. 45 
Table 11 - Time window for pharmacokinetics/pharmacodynamics variables .............................................. 45 
Table 12 - List of PTs or Medications for CMQs/CDGs ................................................................................ 46 
 
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VERSION HISTORY  
This Statistical Analysis Plan (SAP) is based on the protocol amendment 01 dated 
27 September 2022.  
The first participant was randomized on 04 January 2021.  
 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
The EFC16720 study is a 24-week, randomized, double-blind, placebo-controlled, parallel-group, 
multi-center study to evaluate the use of dupilumab in adults and adolescents (≥12 to <18 years 
old) with primary acquired chronic inducible cold urticaria (ColdU) who remain symptomatic 
despite the use of H1-antihistamine treatment. The study is designed to test the hypothesis that 
dupilumab will increase the proportion of participants with a negative ice cube provocation test at 
Week 24 compared with placebo. A negative ice cube provocation test is defined as the absence 
of a confluent hive/wheal at the entire skin site of exposure after an ice cube provocation test. 
The study consists of 3 periods: 
• Screening period (2 to 4 weeks). 
• Randomized IMP treatment period (24 weeks). 
• Post IMP treatment period (12 weeks). 
Chronic inducible ColdU signs and symptoms will be evaluated after the ice cube provocation 
test, by the Investigator (hives/wheals intensity) and participant (itch severity, skin pain, skin 
sensation). In addition, chronic inducible ColdU disease activity will be assessed daily by the 
participant using ColdUAS questionnaire in an e-diary where the participant will report his/her 
skin reactions (wheals and swelling), skin sensations (itching, burning, pain or feeling hot), if they 
have been in contact with cold temperatures that usually cause skin reactions, if they have avoided 
trigger exposure, and overall symptoms severity. The study will also assess the effect of 
dupilumab on urticaria control, participants’ HRQoL and overall health status, proportion of 
patients with cold urticaria requiring emergency medical care visit or treatment with epinephrine 
and on reduction of rescue therapy. 
The total anticipated number of participants randomized in the study is 78. This corresponds to 
approximately 39 participants who will be randomly assigned to each intervention arm: 
• Dupilumab: 300 mg every q2w for adults; 200 mg q2w for adolescents ≥30 kg and <60 kg 
at baseline or 300 mg q2w for adolescents ≥60 kg at baseline. 
• Matched placebo. 
At least 4 participants randomized in the study will be adolescents (≥12 to <18 years old) who 
will be recruited in a few selected sites in selected countries. Randomization will be stratified by 
age (adolescent versus adult) and within adult group by country and background H1-antihistamine 
regular/daily use (Yes/No).  
The number of participants using H1-antihistamine as needed prior to study entry should be at 
least 
 
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During the study, participants should continue their established standard of care background 
therapy with a long acting non-sedating H1-antihistamine, at up to 4-fold (2-fold in Japan) the 
approved dose for Chronic Spontaneous Urticaria (CSU). 
• Participants who used H1-antihistamine regularly/daily prior to study entry should 
continue to take it daily. Note: regular/daily use of H1-antihistamine prior to study entry is 
defined as H1-antihistamine intake for at least 4 days per week for at least 1 month prior to 
screening visit (Visit 1). 
• Participants who took H1-antihistamine as needed prior to study entry should limit the use 
to short-term. 
The H1-antihistamine dose used during the study should be the same dose the participants took to 
prevent ColdU symptoms prior to study entry (“prescreening dose”). However, if participants 
experience a flare rescue therapy may be initiated. 
If participants are on a dose higher than 4-fold (2-fold in Japan) the approved CSU dose at the 
screening visit (Visit 1), the investigator can adjust the participant’s dose within the stipulated 
range at the screening visit (Visit 1). 
All participants will be allowed to take study-defined H1-antihistamine as rescue therapy as long 
as they do not exceed 4-fold (2-fold in Japan) the approved CSU dose during screening, treatment, 
and follow-up periods. If symptoms are still uncontrolled after increase of H1-antihistamine to the 
maximum allowed dose, or if the participant is already on the 4-fold (2-fold in Japan) approved 
dose of H1-antihistamine, participants can switch to another antihistamine up to 4-fold (2-fold in 
Japan) the approved dose for CSU or a short course of oral corticosteroids (OCS) is allowed 
during the treatment and follow-up periods. However, for the purpose of the primary analysis, 
data collected after OCS use will be set to missing and the worst post-baseline value before OCS 
will be used to impute the data. 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
• 
To demonstrate the efficacy of dupilumab in adult 
and adolescent participants with primary acquired 
chronic inducible cold urticaria (ColdU) who remain 
symptomatic despite the use of an H1-antihistamine 
• 
Proportion of participants with negative ice cube 
provocation test* at Week 24 compared with placebo  
*Negative ice cube provocation test is defined as the 
absence of a confluent hives/wheal at the entire skin 
site of exposure after ice cube provocation test a 
Secondary 
• 
To demonstrate the efficacy of dupilumab on 
primary acquired chronic inducible ColdU disease 
control 
• 
Change from baseline in urticaria control test (UCT 
4-item) at Week 24 compared with placebo 
• 
Proportion of well-controlled participants (UCT ≥12) 
at Week 24 compared with placebo 
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Objectives 
Endpoints 
• 
Proportion of participants with an improvement of ≥3 
in UCT 4-item from baseline to Week 24 compared 
with placebo. 
• 
To demonstrate the efficacy of dupilumab on 
primary acquired chronic inducible ColdU local 
signs and symptoms (hives/wheals, itch, burning 
sensation and pain) after provocation test 
• 
Change from baseline in local wheal intensity at the 
provocation site at Week 12 and Week 24 using the 
wheal intensity Likert scale ranging from 0 to 5 
(clinician evaluation) compared with placebo 
• 
Change from baseline in local itch severity at the 
provocation site at Week 12 and Week 24 using the 
Peak Pruritus Numerical Rating Scale (NRS, score 
0 to 10) (patient reported) compared with placebo 
• 
Change from baseline in local skin burning sensation 
at the provocation site at Week 12 and Week 24 
using the peak burning sensation NRS (patient 
reported) compared with placebo 
• 
Change from baseline in local pain severity at the 
provocation site at Week 12 and Week 24 using the 
peak pain sensation NRS (patient reported) 
compared with placebo 
• 
Proportion of participants with negative ice cube 
provocation test at Week 12 compared with placebo 
• 
To demonstrate the efficacy of dupilumab on 
primary acquired chronic inducible ColdU disease 
activity  
• 
Change from baseline in cold urticaria signs and 
symptoms severity at Week 24 on cold exposure 
days as measured by ColdUAS, compared with 
placebo 
• 
Change from baseline in the proportion of cold 
urticaria sign and symptom free days at Week 24 on 
cold exposure days as measured by ColdUAS, 
compared with placebo  
• 
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 participants ≥16 years old, and in 
Children’s Dermatology Life Quality Index (CDLQI) in 
participants ≥12 to <16 years old at Week 24 
compared with placebo  
• 
Change from baseline in Cold Urticaria Quality of 
Life (ColdU-QoL) at Week 24 compared with 
placebo. 
• 
To evaluate the ability of dupilumab in reducing the 
proportion of participants who require rescue 
therapy 
• 
Proportion of participants receiving rescue therapy 
for primary acquired chronic inducible ColdU during 
the planned treatment period compared with placebo 
• 
To evaluate the proportion of participants with cold 
exposure triggered urticaria  
• 
Proportion of participants with cold exposure 
triggered urticaria requiring emergency medical care 
visit or treatment with epinephrine (at provocation 
test and/or at home) 
• 
To evaluate safety outcome measures 
• 
Percentages of participants experiencing 
treatment-emergent adverse events (TEAEs) or 
serious adverse events (SAEs)  
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Objectives 
Endpoints 
• 
To evaluate immunogenicity of dupilumab 
• 
Incidence of treatment-emergent antidrug antibodies 
(ADA) against dupilumab over time 
Tertiary/exploratory 
Pharmacokinetic (PK)/Pharmacodynamic (PD) 
• 
To evaluate PK of dupilumab 
• 
Functional dupilumab concentrations in serum and 
PK profile 
• 
To evaluate PD effect of dupilumab 
• 
Total immunoglobulin E over time. 
a Provocation test reading time for all endpoints: 15 minutes after the ice cube application start = 5 minutes ice cube application plus 
10 minutes after removal of ice cube 
1.2.1 Estimands  
Primary estimand defined for main endpoints are summarized in below Table 2. More details are 
provided in Section 4. 
 
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Table 2 - Summary of primary estimand for main endpoints 
Endpoint 
Category 
 
Estimands 
Endpoint a 
Population 
Intercurrent event(s) strategy and missing data handling 
Population-level summary 
 
Primary objective: To demonstrate the efficacy of dupilumab in adult and adolescent participants with primary acquired chronic inducible ColdU who remain symptomatic despite the use of an 
H1-antihistamine 
Primary endpoint  
Proportion of participants 
with negative ice cube 
provocation test at 
Week 24 
ITT 
The intercurrent events will be handled as follows: 
• 
Discontinuation of study intervention before Week 24 (but not taking 
highly influential prohibited medications and/or highly influential rescue 
medications b prior to Week 24): Off-study intervention data up to Week 
24 will be included in the analysis (treatment policy strategy). 
• 
Taking highly influential prohibited medications and/or highly influential 
rescue medications b prior to Week 24: Participants will be considered as 
having positive ice cube provocation tests at Week 24 (composite 
strategy). 
In addition, the missing data imputation rules are as follows: 
• 
Having missing data at Week 24: Participants will be considered as 
having positive ice cube provocation tests at Week 24. 
CMH test stratified by region 
(combined countries) and 
background H1-antihistamine 
regular/daily use (Yes/No). The 
comparison of the proportions of 
treatment response between 
dupilumab and placebo will be 
derived, and the corresponding odd 
ratios and the 95% CI will be 
reported. 
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Endpoint 
Category 
 
Estimands 
Endpoint a 
Population 
Intercurrent event(s) strategy and missing data handling 
Population-level summary 
 
Secondary objective: To demonstrate the efficacy of dupilumab on primary acquired chronic inducible ColdU local signs and symptoms 
Secondary endpoint  
Change from baseline in 
local wheal intensity at 
the provocation site at 
Week 24 using the wheal 
intensity Likert scale 
ranging from 0 to 5 
(clinician evaluation) 
 
Change from baseline in 
the proportion of cold 
urticaria sign and 
symptom free days at 
Week 24 on cold 
exposure days as 
measured by ColdUAS 
ITT 
The intercurrent events will be handled as follows: 
• 
Discontinuation of study intervention before Week 24 (but not taking 
highly influential prohibited medications and/or highly influential rescue 
medications b prior to Week 24): Off-study intervention data up to Week 
24 will be included in the analysis (treatment policy strategy) 
• 
Taking highly influential prohibited medications and/or highly influential 
rescue medications b prior to Week 24: data will be set to missing values 
after the medication usage, and WOCF approach (worst post-baseline 
observation for the participant will be carried forward) will be used to 
impute missing endpoint value (for participants whose post-baseline 
values are all missing, the participant’s baseline value will be used to 
impute the missing endpoint value) ( composite strategy) 
 
In addition, the missing data imputation rules are as follows:  
• 
For participants who discontinue study intervention 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 study intervention 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 highly influential prohibited 
medications and/or highly influential rescue medications b on or before 
Week 24 and excluding patients who discontinue due to lack of efficacy 
on or before Week 24. 
ANCOVA model with treatment 
group, baseline value, region 
(combined countries), and 
background H1-antihistamine 
regular/daily use (Yes/No) as 
covariates will be used. Statistical 
inference obtained from all imputed 
data by ANCOVA model will be 
combined using Rubin’s rule. 
Descriptive statistics including 
number of participants, 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% CI will 
be provided along with the p-values. 
a  Additional secondary objectives/endpoints are not included in this table but would be handled with a similar strategy as the endpoint type (i.e., Continuous, proportion) at other weeks  
b  Highly influential prohibited medications and/or highly influential rescue medications are listed in Table 4.  
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2 
SAMPLE SIZE DETERMINATION  
Sample size is calculated based on the following assumptions: 
1. The placebo group has 
 participants with negative ice cube provocation test at Week 
24 and the dupilumab group has 
 participants with negative ice cube provocation test 
at Week 24. 
2. There is a drop-out rate of 10% in both groups. 
3. The statistical test is a Z test that is based on the difference of the 2 proportions with 
unpooled variance estimate and 2-sided 1% significance level. 
4. Participants are equally randomized to the dupilumab group and the placebo group. 
With these assumptions, 39 participants per group (78 participants in total) will provide 90% 
power to detect the difference of 
 response rate in the dupilumab group and 
 response 
rate in the placebo group. The sample size calculations were performed using nQuery+nTerim 4.0. 
 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 3 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF 
Randomized 
All participants from the screened population who have been allocated to a randomized 
intervention by IRT 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 intervention group allocated by 
randomization. 
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 a different intervention from that which was 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 intervention. 
Participants will be analyzed according to the intervention actually received. 
Anti-drug 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 intervention. Participants will be analyzed 
according to the intervention actually received. 
Abbreviations: ITT = intent-to-treat, ADA = antidrug antibody; ICF = Informed consent form, IRT = Interactive response technology; PD = 
Pharmacodynamic, PK = Pharmacokinetic 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population.  The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization will be used in any analysis population.  The safety experience associated with any 
later randomization will be reported separately. 
For participants receiving more than one study intervention (placebo and dupilumab) during the 
study, the intervention group for as-treated analysis will be the dupilumab group. 
If >10% participants are impacted by the COVID-19 pandemic, additional summaries by 
COVID-19 subgroups will be provided. Participants impacted by the COVID-19 pandemic are 
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defined as randomized participants with any critical or major deviation related to COVID-19 or 
who permanently discontinued study intervention or study due to COVID-19. 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
This SAP provides a comprehensive and detailed description of strategy and statistical techniques 
for the summary and analysis of EFC16720. 
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, minimum, and maximum. Categorical and ordinal data will be 
summarized using the count and percentage of participants. 
The baseline value of efficacy parameters is defined as the last available value up to 
randomization date and prior to the first dose of study intervention unless otherwise specified. The 
baseline value of the other parameters is defined as the last available value prior to the first dose 
of investigational medicinal product (IMP) if the participant is treated, or the last available value 
up to randomization date if the participant is not exposed to IMP. 
Observation period 
The observation period will be divided into 4 segments: 
• The pre-treatment period is defined as the period up to first IMP administration. 
• The treatment-emergent (TE) period is defined as the period from the first IMP 
administration to the last IMP administration + 98 days. The treatment-emergent period 
includes the following 2 periods: 
- 
The on-treatment period is defined as the period from the first IMP administration to 
the last administration of the IMP + 14 days 
- 
The residual treatment period is defined as the period from the end of the on-
treatment period to the end of the treatment-emergent period. 
• The post-treatment period is defined as the period from the end of the treatment-
emergent period. 
The on-study period is defined as the time from start of intervention until the end of the study 
defined as the status date collected on e-CRF page “Completion of End of Study”. 
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 3 will 
be summarized. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized. The number (%) of screen failures and reasons for screen failures will 
be provided in the screened population. 
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The number (%) of participants in the following categories will be provided: 
• Randomized participants 
• Randomized but not exposed participants 
• Randomized and exposed participants 
• Participants who completed the study intervention period as per protocol 
• Participants who did not complete the study intervention period as per protocol and main 
reason for permanent intervention discontinuation including due to COVID-19 pandemic. 
• Participants who completed the study period as per protocol 
• Participants who did not complete the study period as per protocol and main reason for 
study discontinuation including due to COVID-19 pandemic. 
• Vital status at last study contact 
The number of exposed and not randomized participants will also be summarized. 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the 
randomized population and according to COVID-19 impact (i.e., deviations related to COVID-19 
pandemic and deviations not related to COVID-19 pandemic). In addition, deviations potentially 
impacting the primary endpoint analysis may be summarized. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
4.3.1 Definition of endpoint(s)  
The primary endpoint is the proportion of participants with negative ice cube provocation test 
(absence of a confluent hive/wheal at the entire skin site of exposure) at Week 24. 
4.3.2 Main analytical approach  
The primary analysis population for the efficacy endpoints will be the ITT population. The 
statistical hypotheses for comparing dupilumab against placebo on the primary endpoint of 
proportion of participants with negative ice cube provocation test at Week 24: 
• Null hypothesis H0: No treatment difference between dupilumab and placebo. 
• Alternative hypothesis H1: There is a treatment difference between dupilumab and placebo. 
For efficacy analysis, Table 4 presents the highly influential prohibited medications and highly 
influential rescue medications which will be considered as intercurrent events if the last column 
indicates as “Yes” and confirmed through blinded medical review and therefore will be handled in 
the estimands for endpoints defined in Table 2. Blinded medical review of participants who 
received the medications listed in Table 4 will be implemented before database lock to ensure the 
medication use was due to treatment failure instead of an unrelated condition. 
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Table 4 - Highly influential prohibited medications and/or highly influential rescue medications 
impact on efficacy  
Medication 
Comment 
Highly influential (Yes/No) a / 
Selection criteria 
Systemic immunosuppressants 
(immunosuppressive/immunomodulating drugs) 
e.g., systemic corticosteroids (oral or parenteral 
[intravenous, intramuscular, SC]), cyclosporine, 
mycophenolate-mofetil, interferon gamma, Janus 
kinase inhibitors, azathioprine, methotrexate, 
hydroxychloroquine, dapsone, sulfasalazine, 
colchicine, etc. 
IMP to be discontinued 
Yes (Standardized drug groupings (SDGs) 
Other immunosuppressants, tumour 
necrosis factor (TNF) alpha inhibitors, 
Calcineurin inhibitors, Interleukin inhibitors, 
Selective immunosuppressants – all 
Narrow) 
Any cell-depleting agents including but not limited to 
rituximab 
Yes (CDG10236 Cell depletion agents) 
Other monoclonal antibodies (which are biological 
response modifiers) including anti-IgE therapy 
(omalizumab). 
Yes (SDG Monoclonal antibodies Narrow) 
IVIG 
Yes (CDG00488 Intravenous 
immunoglobulin therapy - See Section 5.5) 
Plasmapheresis 
Yes (CMQ00079 based on the following 
PTs: Plasmapheresis, Apheresis) 
Other investigational drugs. 
No, except ones with mechanism of action 
that may impact efficacy 
Topical corticosteroids.  
No IMP discontinuation 
No 
Topical calcineurin inhibitors.  
No 
Topical and oral antihistamines (other than those 
allowed as background therapy).  
No 
Routine doses of doxepin (daily or every other day 
during 5 or more consecutive days).  
No 
LTRAs and H2 receptor antagonists, unless stable 
and taken for diseases other than chronic inducible 
ColdU. 
Yes for LTRAs; No for H2 receptor 
antagonists (SDG Leukotriene receptor 
antagonists for obstructive airway diseases 
Narrow) 
Antifibrinolytic tranexamic acid and epsilon-
aminocaproic acid 
 
No 
Phototherapy, including tanning beds. 
 
No 
Additional H1-AH up to 4-fold (2-fold in Japan) 
No IMP discontinuation 
No 
Corticosteroids 
Yes (SDG Corticosteroids Narrow 
excluding where Route is Topical, Nasal, 
Respiratory (Inhalation) or Ophthalmic) 
a When yes, if confirmed through blinded medical review that the medication use was due to treatment failure instead of an unrelated 
condition, the estimand for the intercurrent event handling strategy will be as follows: composite for continuous and responder endpoints.  
Otherwise, a treatment policy strategy will be applied.  
The intercurrent event handling strategy for the primary estimand is the treatment 
policy/composite approach. 
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The primary efficacy endpoint will be analyzed using the Cochran-Mantel-Haenszel test stratified 
by region (combined countries) and background H1-antihistamine regular/daily use (Yes/No). The 
comparison of the proportions of participants with negative ice cube provocation test at Week 24 
between dupilumab and placebo will be derived, and the corresponding odd ratios and the 95% 
confidence interval (CI) will be reported. Participants who receive highly influential prohibited 
medications and/or highly influential rescue medications (see Table 4) will be considered as 
having positive ice cube provocation tests 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 positive/negative ice cube provocation test outcome. Participants with 
missing ice cube provocation test data at Week 24 will be considered as having positive ice cube 
provocation tests. 
The following is a sample code for the primary analysis. 
proc freq data=dataice; 
   tables region*background*trtgrp*response/relrisk cmh; 
   weight Count; 
run; 
4.3.3 Sensitivity analysis  
The following sensitivity analyses will be performed targeting the same estimand as in the 
primary analysis to assess the impact of other missing data handling strategies. In the primary 
analysis, participants with missing ice cube provocation test data at Week 24 will be considered as 
having positive ice cube provocation tests. 
Tipping point analysis 
A tipping point analysis will be performed for the primary endpoint with imputed missing Week 
24 values as follows: 
• Step 1. With the complete data, fit a logistic regression model with the ice cube 
provocation test result (1: negative, 0: positive) at Week 24 as outcome and treatment 
group, region (combined countries), and background H1-antihistamine regular/daily use 
(Yes/No) as covariates. 
• Step 2. Compute the probability of having negative ice cube provocation test for the 
participant with missing Week 24 value in placebo group from the fitted model but with 
the coefficient of the treatment group being added by a constant d. At the same time, 
compute the probability of having negative ice cube provocation test for the participant 
with missing Week 24 value in dupilumab group from the fitted model but with the 
coefficient of the treatment group being subtracted by a constant p.  
• Step 3. With the probabilities computed in Step 2, impute the missing ice cube 
provocation results at Week 24 by generating binary random variables with the 
corresponding probabilities. Repeat this process to generate 40 imputed datasets.   
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• Step 4. Apply the Cochran-Mantel-Haenszel test stratified by region and background 
H1-antihistamine regular/daily use (Yes/No) for each imputed dataset. The results 
obtained from multiple imputed datasets will be combined to generate statistical inference, 
i.e. p-value and treatment difference between 2 treatment groups. Then use the SAS 
MIANALYZE procedure to generate statistical inferences of the odds ratios by combining 
results from the 40 analyses using Rubin’s formula. 
Step 2 to Step 4 will be repeated iteratively until the p-value for treatment effect of dupilumab 
compared to placebo estimated is >0.01. 
4.3.4 Supplementary analyses  
The following supplementary analysis will be performed: 
As-observed analysis (Including all data after taking highly influential prohibited medications 
and/or highly influential rescue medications) 
The data collected after taking the highly influential prohibited medications and/or highly 
influential rescue medications will be included in the supplementary analysis to evaluate the 
robustness of the primary analysis results with respect to the intercurrent event handling strategy. 
Missing ice cube provocation test result at Week 24 will be considered as positive. 
4.3.5 Subgroup analyses  
To assess the homogeneity of the treatment effect across various subgroups, analyses will be 
performed on the primary endpoint across the following subgroups: 
• Age group (< median, ≥ median; adult, adolescent) 
• Gender (Male, Female) 
• Baseline weight (< median, ≥ median, <60, ≥60 kg) 
• Baseline BMI (<25, ≥25- <30, ≥30 kg/m2)  
• Region (see Section 5.3) 
• Race (White, all the Others) 
• Ethnicity (Hispanic, non-Hispanic) 
• Baseline H1-AH use (regular vs per-need) 
• Baseline serum Total IgE (<100 IU/mL, ≥100 IU/mL) 
• Duration of cold urticaria before screening visit (<5, ≥ 5 years) 
• History of allergy (Allergic, non-Allergic) 
• History of angioedema 
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To assess the consistency of the treatment effects across the subgroup levels, subgroup analyses 
will be conducted for the primary endpoint at Week 24. The analysis will be performed based on 
imputed datasets from the primary analysis. 
To test the interaction between intervention and subgroup factor, a logistic regression model 
incorporating subgroup-by-treatment interaction will be built for each subgroup factor. The model 
will include all the covariates in the main statistical model plus the subgroup variable (if not one 
of the covariates adjusted in the main model already) and the subgroup-by-treatment interaction. 
In each subgroup, the primary endpoint will be analyzed using the primary approach for the 
primary endpoint, but on the specific subgroup. Forest plots will be provided. 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
4.4.1 Key/Confirmatory secondary endpoint(s)  
4.4.1.1 Definition of endpoint(s)  
Key secondary endpoints are listed below. 
• Change from baseline in local wheal intensity at the provocation site at Week 24 using the 
wheal intensity Likert scale ranging from 0 to 5 (clinician evaluation) 
• Change from baseline in the proportion of cold urticaria sign and symptom free days at 
Week 24 on cold exposure days as measured by ColdUAS 
Wheal intensity Likert scale 
The Wheal intensity Likert scale (ranging from 0 to 5) is a clinician-reported outcome measure 
completed at the study visit, 10 minutes after removal of the ice cube from the participant’s arm. 
This scale is comprised of a single item assessing the intensity of patients’ cutaneous reaction 
rated as follows: 0=no wheals; 1=numerous small, non-coalescent wheals; 2=a large, regular, 
slightly edematous, coalescent wheal; 3=a large and moderately edematous wheal; 4=a large, 
regular, and significantly edematous wheal without pseudopodia; and 5=a large, very edematous 
wheal with pseudopodia 
Proportion of cold urticaria sign and symptom free days on cold exposure days as measured by 
ColdUAS 
The ColdUAS is a disease-specific PRO questionnaire designed to determine cold urticaria 
disease activity which is administered daily via e-diary (the details can be found in the protocol).  
The proportion of cold urticaria sign and symptom free days is defined in two steps: (1) take a 
window of 14 days before each visit date (i.e., Baseline, Week 12 and Week 24), count the 
number of days when the patient reports “exposed” to cold (i.e., ColdUAS Q3>0); (2) within the 
“exposed” days, count the number of days when the patient reports no ColdU related sign and 
symptom (i.e., ColdUAS Q1=0 and Q2=0). If the number of exposure days is zero, then the 
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proportion is set to missing, otherwise, it is the ratio of the sign and symptom free days over the 
exposure days in the 14-day window. 
The e-diary completion days should be no less than 6 and exposure days should be no less than 1 
in the 14-day window, otherwise the proportion of sign and symptom free days is considered as 
missing. Additionally, analyses based on exposure days no less than 3 will be conducted. 
4.4.1.2 Main analytical approach  
The intercurrent event handing strategy for the key secondary endpoints is the treatment 
policy/composite approach. 
This key secondary endpoints will be analyzed using an analysis of covariance (ANCOVA) model 
with baseline value of the endpoint, treatment group, region (combined countries), and 
background H1-antihistamine regular/daily use (Yes/No) as covariates, with intercurrent events 
and missing data being handled by a hybrid method of the worst-observation carried forward 
(WOCF) and multiple imputation. For participants who took highly influential prohibited 
medications and/or highly influential rescue medications (see Table 4), their data after the 
medication usage will be set to missing, and worst post-baseline value on or before the time of the 
medication usage will be used to impute missing Week 24 value (for participants whose post-
baseline 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. For participants 
who did not take the highly influential prohibited medications and/or highly influential rescue 
medications, all data collected after treatment discontinuation will be used in the analysis. For 
participants who discontinue study intervention 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 (i.e., due to study discontinuation). For participants who discontinue 
study intervention not due to lack of efficacy, all data collected after discontinuation will be used 
in the analysis, and a multiple imputation approach will be used to impute missing Week 24 value 
if needed (i.e., due to study discontinuation). This multiple imputation will use all participants 
excluding participants who have taken the highly influential prohibited medications and/or highly 
influential 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 as described above. Statistical inference obtained from 
all imputed data will be combined using Rubin’s rule. Descriptive statistics including number of 
participants, 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. 
4.4.2 Supportive secondary endpoint(s)  
The change from baseline endpoints: 
• Change from baseline in urticaria control test (UCT 4-item) at Week 24 
• Change from baseline in local wheal intensity at the provocation site at Week 12 using the 
wheal intensity Likert scale ranging from 0 to 5 (clinician evaluation) 
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• Change from baseline in local itch severity at the provocation site at Week 12 and Week 
24 using the Peak Pruritus Numerical Rating Scale (NRS, score 0 to 10) (patient reported) 
• Change from baseline in local skin burning sensation at the provocation site at Week 12 
and Week 24 using the peak burning sensation NRS (patient reported) 
• Change from baseline in local pain severity at the provocation site at Week 12 and Week 
24 using the peak pain sensation NRS (patient reported)  
• Change from baseline in cold urticaria signs and symptoms severity at Week 24 on cold 
exposure days as measured by ColdUAS 
• Change from baseline in health-related quality of life (HRQoL) as measured by 
Dermatology Life Quality Index (DLQI) in participants ≥16 years old, and in Children’s 
Dermatology Life Quality Index (CDLQI) in participants ≥12 to <16 years old at Week 24 
• Change from baseline in Cold Urticaria Quality of Life (ColdU-QoL) at Week 24 
The Week 12 and Week 24 values will be analyzed separately and use the same procedure as the 
key secondary endpoint. The endpoint change from baseline in DLQI will be summarized and 
analyzed in participants ≥ 16 years old who completed the DLQI at baseline. The endpoint change 
from baseline in CDLQI will be summarized separately in participants ≥12 to <16 years old using 
descriptive analysis only. 
The proportion endpoints below will be analyzed like the primary endpoint. 
• Proportion of well-controlled participants (UCT ≥12) at Week 24 
• Proportion of participants with an improvement of ≥3 in UCT 4-item from baseline to 
Week 24 
• Proportion of participants with negative ice cube provocation test at Week 12 
The two endpoints below will be summarized using the count and percentage of participants. 
• Proportion of participants receiving rescue therapy for primary acquired chronic induced 
ColdU during the planned treatment period 
• Proportion of participants with cold exposure triggered urticaria requiring emergency 
medical care visit or treatment with epinephrine (at provocation test and/or at home) 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
4.5.1 Definition of endpoint(s)  
Additional details are provided below for specific exploratory efficacy endpoints. 
• Patient Global Impression of Change (PGIC) of primary acquired chronic inducible ColdU 
at Week 12 and Week 24 
• Change from baseline in Patient Global Impression of Severity (PGIS) of primary acquired 
chronic inducible ColdU at Week 12 and Week 24 
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4.5.2 Main analytical approach  
Exploratory efficacy endpoints will be analyzed using the same methodology as above for similar 
data (continuous, proportion). 
4.6 
MULTIPLICITY ISSUES  
To strongly control the family-wise type-I error rate for testing the primary and selected 
secondary endpoints, hierarchical testing procedure is used. The overall two-sided alpha is 0.01. 
The comparisons with placebo will be tested based on the hierarchical order below at 2-sided α = 
0.01. 
Order of the testing hierarchy: 
1. Proportion of participants with negative ice cube provocation test at Week 24. 
2. Change from baseline in local wheal intensity at the provocation site at Week 24 using the 
wheal intensity Likert scale ranging from 0 to 5 (clinician evaluation). 
3. Change from baseline in proportion of cold urticaria symptom free days at Week 24 
(exposure-adjusted and measured by ColdUAS). 
4. Change from baseline in local itch severity at the provocation site at Week 24 using the 
Peak Pruritus Numerical Rating Scale (NRS, score 0 to 10) (patient reported). 
5. Change from baseline in health-related quality-of-life (HRQoL) as measured by 
Dermatology Life Quality Index (DLQI) in participants ≥16 years old. 
4.7 
SAFETY ANALYSES  
All safety analyses will be performed on the safety population as defined in Section 3, unless 
otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned. 
• Safety data in participants who do not belong to the safety population (e.g., exposed but 
not randomized) will be provided separately. 
4.7.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and compliance and 
summarized within the safety population. 
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Duration of IMP exposure 
Duration of IMP exposure is defined as last dose date – first dose date + 15 days, regardless of 
unplanned intermittent discontinuations. If the date of the last dose of IMP is missing, the duration 
of IMP will be left as missing. 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum).  In addition, duration of IMP exposure will also be 
summarized categorically by numbers and percentages for each of the following categories and 
cumulatively according to these categories: 
• >0 and ≤2 weeks 
• >2 and ≤4 weeks 
• >4 and ≤8 weeks 
• >8 and ≤12 weeks 
• >12 and ≤16 weeks 
• >16 and ≤20 weeks 
• >20 and ≤24 weeks 
• >24 weeks and ≤24 weeks + 3 days 
• >24 weeks + 3 days 
Additionally, the cumulative duration of IMP exposure will be provided, defined as the sum of the 
duration of treatment exposure for all participants, and will be expressed in participant years. 
Treatment compliance 
A given administration will be considered noncompliant if the participant did not take the planned 
dose as required by the protocol. No imputation will be made for participants with missing or 
incomplete data. 
Percentage of treatment compliance for a participant will be defined as the number of 
administrations that the participant was compliant divided by the total number of administrations 
that the participant was planned to take from the first administration of IMP up to the actual last 
administration of IMP. 
Treatment compliance will be summarized quantitatively and categorically: <80%, ≥80%. 
Cases of overdose (defined as at least twice the intended dose during an interval of less than 
11 days) are considered an AESI and will be listed as such. 
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4.7.2 Adverse events  
General common rules for adverse events 
All adverse events (AEs) will be coded to a lower-level term (LLT), preferred term (PT), high-
level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock.  
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the 
pre-treatment period. 
• Treatment-emergent adverse events (TEAEs): AEs that developed, worsened or became 
serious during the treatment-emergent period. 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period. 
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods. 
The primary focus of AE reporting will be on TEAEs.  Pre-treatment and post-treatment AEs will 
be described separately. 
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE. 
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If the severity is missing for 1 of the treatment-emergent occurrences of an AE, 
the severity will be imputed with the maximal severity of the other occurrences. If the severity is 
missing for all the occurrences, the severity will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase. 
The AE tables will be sorted as indicated in Table 5. 
Table 5 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs.  
SOC, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLTs and PTs. 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTs a, b 
SMQ/CMQ and PT 
By decreasing frequency of SMQs/CMQs and PTs a 
PT 
By decreasing frequency of PTs a 
a Sorting will be based on the SAR231893 dupilumab group 
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (e.g., treatment-emergent SAE) 
presented by SOC and PT, unless otherwise specified.   
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Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE 
• Any severe TEAE 
• Any treatment emergent SAE 
• TEAE leading to death 
• Any TEAE leading to permanent intervention discontinuation 
• Any treatment emergent AESI 
• Any treatment emergent other AE of interest grouping 
• Any TEAE related to IMP  
The AE summaries of Table 6 will be generated with number (%) of participants experiencing at 
least one event. 
Table 6 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
 
PT 
 
Primary and secondary SOC, HLGT, HLT and PT 
Common TEAE ≥5% in any group) 
Primary SOC and PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
TEAE by maximal intensity 
Primary SOC and PT  
Treatment emergent SAE 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
Treatment emergent SAE related to IMP as per Investigator’s judgment 
Primary SOC, HLGT, HLT and PT 
TEAE leading to permanent intervention discontinuation 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported by 
the Investigator in the AE page) 
Primary SOC, HLGT, HLT and PT 
Pretreatment AE 
Overview a 
 
Primary SOC and PT 
a Will include the following AE categories: any AEs, any serious AEs, any AEs leading to death, any AEs leading to permanent intervention 
discontinuation 
In addition, the exposure adjusted incidence rate of TEAEs by primary SOC and PT will be 
generated, showing the number of participants with at least one TEAE per 100 patient-years. For 
participants with an event, patient-years will be calculated up to the first event, and for 
participants without an event, patient-years will correspond to the length of the TE period. 
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Risk differences (constructed using the Miettinen and Nurminen method) and hazard ratios (Cox 
proportional hazards model) for dupilumab versus placebo with corresponding 95% CIs will be 
provided for the common TEAEs (PT ≥ 5% in any intervention group). Participants without an 
event will be censored at the end of the treatment-emergent period in the Cox model. Forest plots 
will also be presented. 
Analysis of deaths 
In addition to the analyses of deaths included in Table 5 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods 
• Deaths in non-randomized or randomized but not treated participants 
Analysis of adverse events of special interest (AESIs) and other AEs of interest 
Adverse events of special interest (AESIs) and other AEs of interest will be selected for analyses 
as indicated in Table 7. Number (%) of participants experiencing at least one event will be 
provided for each event of interest. Tables will be sorted as indicated in Table 5.  
Table 7 - Selections for AESIs and other AEs of interest  
AE Grouping 
Criteria 
AESI 
 
Anaphylactic reaction 
Anaphylactic reaction algorithmic approach (Introductory Guide for 
Standardised MedDRA Queries (SMQs) Version 18.1): includes 
anaphylactic reaction narrow SMQ (20000021) terms and 
programmatic identification of cases based on occurrence of at least 
two preferred terms meeting the algorithm criteria occurring within 24 
hours of each other. The latter cases identified using the algorithm will 
undergo blinded medical review taking into account the timing of 
events relative to each other and to IMP administration for final 
determination of an anaphylactic reaction or not. 
Systemic hypersensitivity reactions 
SMQ [20000214] hypersensitivity narrow search and [AE corrective 
treatment/therapy = ’Y’ or Action taken with IMP = ’Drug withdrawn’ or 
Action taken with IMP = ’Drug interrupted’] followed by blinded medical 
review (documented process) for selection of relevant systemic 
hypersensitivity events  
Helminthic infections 
CMQ10544 based on HLGT as “Helminthic disorder” 
Any severe type of conjunctivitis  
CMQ10498 based on PTs (See Section 5.5) a and “Severe” ticked in 
Adverse Events eCRF page  
Any severe type of blepharitis  
CMQ10497 based on HLT as “Lid, lash and lacrimal infections, 
irritations and inflammations” and “Severe” ticked in Adverse Events 
eCRF page 
Keratitis 
CMQ10642 based on the following PTs [keratitis, allergic keratitis, 
ulcerative keratitis, atopic keratoconjunctivitis, herpes ophthalmic, 
ophthalmic herpes simplex, corneal infection] a 
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AE Grouping 
Criteria 
Clinically symptomatic eosinophilia (or eosinophilia 
associated with clinical symptoms) b  
CMQ10641 based on HLT = Eosinophilic disorders or PT = Eosinophil 
count increased  
Pregnancy of a female patients entered in a study as 
well as pregnancy occurring in a female partner of a 
male patient entered in a study with IMP/NIMP 
“Pregnancy” or “Partner Pregnancy” checked on the Pregnancy eCRF 
page as reported by the investigator 
Significant ALT elevation 
ALT >5 x ULN in participants with baseline ALT ≤2 x ULN;  
OR ALT >8 x ULN if baseline ALT >2 x ULN 
Symptomatic overdose with IMP 
Symptomatic Overdose is answered Yes, with Overdose of IMP 
answered Yes on AE eCRF.  
Symptomatic overdose with NIMP 
Symptomatic Overdose is answered Yes, with Overdose of NIMP 
answered Yes on AE eCRF.  
Other selected AE Grouping 
 
Serious injection site reactions or severe injection site 
reactions that last longer than 24 hours  
HLT = ‘Injection site reactions’ and either with serious status, or with 
severe status and (AE end date/time - AE start date/time) ≥24 hours 
or ongoing 
Severe or serious infection 
Primary SOC = ‘Infections and infestations’ and with severe or 
serious status 
Drug-related hepatic disorder 
SMQ [20000006] Drug-related hepatic disorders- narrow  
Injection site reaction  
HLT = ‘Injection site reactions’  
Malignancy 
SMQ [20000091]– Malignant or unspecified tumors narrow 
Conjunctivitis (narrow) 
CMQ10644 based on the following PTs [Conjunctivitis, Conjunctivitis 
allergic, Conjunctivitis bacterial, Conjunctivitis viral, Atopic 
keratoconjunctivitis] a 
Conjunctivitis (broad) 
CMQ10645 based on the following PTs [Conjunctivitis, Conjunctivitis 
allergic, Conjunctivitis bacterial, Conjunctivitis viral, Atopic 
keratoconjunctivitis, Blepharitis, Dry eye, Eye irritation, Eye pruritus, 
Lacrimation increased, Eye discharge, Foreign body sensation in 
eyes, Photophobia, Xerophthalmia, Ocular hyperaemia, Conjunctival 
hyperaemia] a 
Conjunctivitis (FDA) 
CMQ10643 based on the following PTs [Conjunctivitis, Conjunctivitis 
allergic, Conjunctivitis bacterial, Conjunctivitis viral, Eye irritation, Eye 
inflammation, Giant papillary conjunctivitis] a 
Keratitis (FDA) 
CMQ30102 based on the following PTs [keratitis, allergic keratitis, 
ulcerative keratitis, atopic keratoconjunctivitis, ophthalmic herpes 
simplex,] a 
a The list of terms may be adjusted according to MedDRA version changes 
b All cases of Eosinophilia will be included in the analysis, where cases associated with clinical symptoms will be further described in the 
CSR 
The following summaries will be provided: 
• All TEAEs, by selected standardized MedDRA query (SMQ)/Customized MedDRA query 
(CMQ) and PT or by laboratory values (as in alanine aminotransferase (ALT) elevation), 
showing the number (%) of participants with at least 1 PT, 
• The exposure adjusted incidence rate by selected SMQ/CMQ and PT showing the number 
of participants with at least one TEAE per 100 patient-years. 
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• All TEAEs, by selected SMQ/CMQ including risk differences and hazard ratios with 
corresponding 95% CIs. 
• For each AESI and other selected AE groupings, 
- 
Number (%) of participants with any specific TEAE 
- 
Number (%) of participants with any specific serious AE (regardless of treatment 
emergent status) 
- 
Number (%) of participants with any specific treatment emergent serious AE 
- 
Number (%) of participants with any specific AE leading to death 
- 
Number (%) of participants with any specific TEAE leading to permanent study drug 
discontinuation 
- 
Number (%) of participants with any specific TEAE related to IMP reported by 
investigator 
- 
Number (%) of participants with any specific TEAE by maximum intensity, corrective 
treatment, and final outcome 
- 
Number (%) of participants with any specific TEAE adjusted by the exposure duration 
- 
Time to onset of first TEAE and cumulative incidence at specified time points (K-M 
estimates at Week 12 and 24) and K-M plot may be provided to depict the course of 
onset over time if the number of events is large enough. 
- 
Number (%) of participants with injection site reactions by the related injection. 
- 
Number (%) of participants with different number of injection site reactions. 
• In addition, AESIs reported by the investigator in eCRF will be summarized separately. 
4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units. 
• Hematology: 
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, red blood cell 
count, platelet count 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• Clinical chemistry: 
- 
Metabolism:  glucose, total cholesterol, total protein, creatine phosphokinase 
- 
Electrolytes:  sodium, potassium, chloride, bicarbonate  
- 
Renal function:  creatinine, blood urea nitrogen, uric acid 
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- 
Liver function:  alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin, albumin 
- 
Pregnancy test:  Serum β-human chorionic gonadotropin (all female participants) will 
be performed at screening (V1) in women of childbearing potential, and a urine 
pregnancy test will be performed at V2 and every 4 weeks thereafter. 
- 
Hepatitis screen:  hepatitis B surface antigen (HBs Ag), hepatitis B surface antibody 
(HBs Ab), hepatitis B core antibody (HBc Ab), hepatitis C virus antibodies (HCV Ab) 
will be tested at screening (V1). In case of results showing HBs Ag (negative) and 
HBc Ab (positive), an hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing 
will be performed and should be confirmed negative prior to randomization. In case of 
results showing HCV Ab (positive), an HCV ribonucleic acid (RNA) testing will be 
performed and should be confirmed negative prior to randomization. 
- 
HIV screen: Anti-HIV-1 and HIV-2 antibodies will be tested at Visit 1 
• Urinalysis: 
- 
Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrite, 
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. 
• Vital signs: heart rate (beats per minute), systolic and diastolic blood pressure (mmHg) in 
a semi-supine or sitting position after 5 minutes rest, weight, respiratory rate (breaths per 
minute), temperature (degrees Celsius) and height (screening only) 
• ECG variables:  ECG assessments will be described as normal or abnormal 
Data below the lower limit of quantitation/detection limit (LLOQ) will be replaced by half of the 
LLOQ, data above the upper limit of quantification will be replaced by ULOQ value. 
Quantitative analyses 
For all laboratory variables and vital signs variables above, descriptive statistics for results and 
changes from baseline will be provided for each analysis window, the last value and the worst 
value during the on-treatment period. These analyses will be performed using central 
measurements only (when available) for laboratory variables. 
For all parameters, mean changes from baseline with the corresponding standard error will be 
plotted over time. 
Analyses according to PCSA  
Potentially clinically significant abnormality (PCSA) analyses will be performed based on the 
PCSA list currently in effect at Sanofi at the time of the database lock. For parameters for which 
no PCSA criteria are defined, similar analyses will be done using the normal range, if applicable. 
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Analyses according to PCSA will be performed based on the worst value during the treatment-
emergent period, using all measurements (either local or central, either scheduled, nonscheduled 
or repeated). 
For laboratory variables and vital signs variables above, the incidence of participants with at least 
one PCSA during the treatment-emergent period will be summarized regardless of the baseline 
level and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
Additional analyses for suspect drug-induced liver injury 
The following additional analyses will be performed for drug-induced liver injury: 
• Time to onset of the initial ALT or aspartate aminotransferase (AST) elevation  
(>3 x ULN) and total bilirubin elevation (>2 x ULN) during the treatment-emergent period 
will be analyzed using Kaplan-Meier method.  
• A graph of the distribution of peak values of ALT versus peak values of total bilirubin 
during the treatment-emergent period will be provided.   
• For each liver function test (e.g., ALT), participants having a PCSA (e.g., ALT >5 ULN) 
will be summarized using the following categories: Returned to baseline PCSA status (or 
returned to value ≤ ULN in case of missing baseline) before last IMP dose, Returned to 
baseline PCSA status after last IMP dose, Never returned to baseline PCSA status, No 
assessment after elevation. This summary will be performed by categories of elevation 
(ALT >3, >5, >10, >20 ULN). 
4.8 
OTHER ANALYSES  
4.8.1  PK analyses   
Predose serum dupilumab concentrations at Visit 2 (Day 1), dupilumab trough levels at Week 12, 
Week 24/EOT and posttreatment serum dupilumab at Week 36 will be provided. 
Serum concentrations of SAR231893 (REGN668) will be summarized in the PK population using 
arithmetic and geometric means, SD, standard error of the mean (SEM), coefficient of variation 
(CV), minimum, median and maximum per sampling time. If date and/or time of the drug 
injection and/or sampling is missing, then the concentration will not be taken into account. For 
drug-treated participants, where concentration values are below the lower limit of quantification 
(LLOQ), the baseline concentration will be considered equal to 0, and one-half of the LLOQ will 
be used for post-baseline concentrations. Values will be expressed in the tables with no more than 
three significant figures. For participants in the placebo group, concentration values are below the 
LLOQ will be taken into account with a plasma concentration considered equal to 0. 
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4.8.2  Immunogenicity analyses   
Dupilumab anti-drug antibody (ADA) status (negative or titer value, if positive in the ADA assay) 
at Visit 2 (Day 1), Week 12, Week 24/EOT and follow up at Week 36 will be provided. The 
neutralizing antibody status for ADA positive samples will be provided. 
Incidence will be provided for the following ADA response categories: 
Pre-existing immunoreactivity is defined as:  
An ADA positive response in the assay at baseline with all post first dose ADA results negative, 
OR an ADA positive response at baseline with all post first dose ADA responses less than 4-fold 
over baseline titer levels. 
Treatment-emergent ADA responses are defined as: 
A positive response in the ADA assay post first dose, when baseline results are negative or 
missing. 
Treatment-emergent ADA responses are further classified as Persistent, Indeterminate or 
Transient 
a) Persistent Response- defined as a treatment-emergent ADA response with two or more 
consecutive ADA positive sampling time points, separated by greater than (>) 12-week 
period (84 days), with no ADA negative samples in between. 
b) Indeterminate Response- defined as a treatment-emergent response with only the last 
collected sample positive in the ADA assay 
c) Transient Response - defined as a treatment-emergent response that is not considered 
persistent OR indeterminate 
Treatment-boosted response is defined as: 
An ADA positive response in the assay post first dose that is greater-than or equal to 4-fold over 
baseline titer levels, when baseline results are positive. 
Titer values (Titer value category) 
• Low (Titer <1000) 
• Moderate (1,000 ≤ Titer ≤10,000) 
• High (Titer >10,000) 
The following summary will be provided based on ADA population: 
• Number (%) of participants with pre-existing immunoreactivity 
• Number (%) of participants with treatment-emergent ADA 
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• The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for participants with treatment-emergent ADA, and 
participants with persistent, indeterminate and transient ADA response 
• Number (%) of participant with transient treatment-emergent ADA 
• Number (%) of participants with persistent treatment-emergent ADA 
• Number (%) of participants with indeterminate treatment-emergent ADA 
• Number (%) of participants with treatment-boosted ADA 
• The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for participants with treatment-boosted ADA 
• The summary statistics (including number, mean, SD, median, Q1, Q3, minimum and 
maximum) of the ratio of peak post-baseline titer to baseline titer for participants with 
treatment-boosted ADA 
• Listing of ADA peak titer levels and neutralizing antibody status 
• Number (%) of participants with neutralizing antibody status 
Kinetics of treatment-emergent ADA response 
Number (%) of participants with treatment-emergent ADA positive response at each visit will be 
summarized by each intervention group. 
Plot of percentage of participants with treatment-emergent ADA positive response at each visit 
will be provided by each intervention group. 
4.8.2.1 Association of Immunogenicity with Exposure, Safety and Efficacy  
The safety and efficacy analysis mentioned below will be conducted using the following 
categories: 
ADA positive participants: Participants with treatment-emergent or treatment-boosted response. 
ADA negative participants: Participants with pre-existing immunoreactivity or negative in the 
ADA assay at all time points. 
Impact of ADA on PK profile  
Potential associations between ADA variables (e.g., ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, indeterminate and transient response, treatment-boosted) and 
impact on serum concentration profile of dupilumab may be explored. Plot of serum concentration 
of functional dupilumab versus visit will be provided by ADA variables for dupilumab group. 
Individual participant plots of dupilumab concentration according to ADA status will be provided. 
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Impact of ADA on clinical efficacy endpoints 
Associations between the ADA variables (e.g., ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, treatment-boosted) and the primary efficacy endpoint may be 
explored for the dupilumab dosed group. 
Association of ADA with clinical safety endpoints 
Association of safety versus ADA status may be analyzed in the ADA population. The safety 
assessment may focus on the following events: 
• Severe injection site reactions last longer than 24 hours or serious injection site reactions 
• Hypersensitivity reactions (SMQ (20000214) hypersensitivity narrow search confirmed by 
medical review) 
• Anaphylactic reactions (SMQ (20000021) anaphylactic reaction narrow search) 
Associations between ADA variables (e.g., ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent and treatment-boosted) and safety may be explored. 
4.8.3  Pharmacodynamic/genomics endpoints   
Venous blood samples will be collected at Visit 2 (Week 0), Visit 3 (Week 12), Visit 4 
(Week 24/EOT), and Visit 5 (Week 36), for measurement of total serum IgE. Total IgE will be 
measured using validated quantitative methods. 
For those participants (with exception of adolescent) who consent to the optional 
pharmacogenetic/pharmacogenomic sample collection section of the ICF, serum/plasma for 
archival samples for possible future analysis of potential biomarkers of drug response, disease 
activity, safety, and the Type 2 inflammation pathway, and 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. 
For those participants (with exception of adolescent) who consent to the optional basophil 
activation (substudy), samples will be taken at Visit 2, Visit 3 (Week 12) and Visit 4 
(Week 24/EOT).  
Total IgE will be summarized in the safety population defined as participants who actually 
received at least 1 dose or part of a dose of the IMP.  Baseline values will be the last value 
collected prior to the first IMP. Descriptive statistics (including number, mean, SD, median, Q1, 
Q3, min, max) of biomarkers at baseline will be summarized. 
Summary plots (median+/- standard error of the mean) on values at each visit, absolute changes 
from baseline and percent changes from baseline will be provided for the total IgE by intervention 
group and visit. 
Exploratory analysis of DNA/RNA will be addressed in a separate document. 
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The analyses of the basophil activation substudy will be addressed in a separate document. 
4.9 
INTERIM ANALYSES  
No interim analysis is planned. 
A primary database lock will be performed when all randomized participants in this study have 
completed their 24-week treatment phase. Analysis will be based on all data collected up to the 
database cut-off date and will be considered as the final analyses in the CSR. 
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. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
ATC: 
anatomic category 
CDG: 
customized drug grouping 
CDLQI: 
Children's Dermatology Life Qualtiy Index 
CI: 
confidence interval 
CLcr: 
Creatinine clearance 
CSU: 
Chronic Spontaneous Urticaria 
DLQI: 
Dermatology Life Quality Index 
DNA: 
deoxyribonucleic acid 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EOT: 
end of treatment 
HBc Ab: 
hepatitis B core antibody 
HBs Ab: 
hepatitis B surface antibody 
HBs Ag: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HCV Ab: 
hepatitis C virus antibodies 
HLGT: 
high level group term 
HLT: 
high level term 
HRQoL: 
health-related quality of life 
IMP: 
investigational medicinal product 
ITT: 
intent-to-treat 
LLT: 
lower-level term 
LS: 
least squares 
MedDRA: 
medical dictionary for regulatory activities 
OCS: 
oral corticosteroids 
PCSA: 
potentially clinically significant abnormality 
PGIS: 
Patient Global Impression of Severity 
PT: 
preferred term 
RNA: 
ribonucleic acid 
SAP: 
statistical analysis plan 
SDG: 
standardized drug grouping 
SDGs: 
Standardized drug groupings 
SMQ: 
standardized MedDRA query 
SOC: 
system organ class 
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TEAE: 
treatment-emergent adverse event 
UCT: 
urticaria control test 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
This Statistical Analysis Plan (SAP) for study EFC16720 is based on the protocol amendment 01 
dated 27 September 2022.  For the details of major statistical changes, see protocol amendment 
summary of changes table in study protocol. 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the randomized 
population. 
Demographic variables are 
• Age in years (quantitative and qualitative variable: 12-<18, 18-<40, 40-<65, 65-<75 and 
≥75 years), 
• Gender (Male, Female),  
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Island, unknown),  
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
• Region (Asia: Japan; Latin America: Argentina; Western Countries: Canada, USA, 
Germany) 
• Weight in kg (quantitative and qualitative variable: <60, ≥60 kg) 
• BMI in kg/m2 (quantitative and qualitative variable: <30, ≥30 kg/m2) 
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries. 
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the participant. 
This information will be coded using the version of MedDRA currently in effect at Sanofi at the 
time of database lock. 
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Comorbidity will be summarized separately.  The following comorbid diseases will be 
summarized from electronic case report form (eCRF) pages which were filled in by investigators 
based on participant reporting. Angioedema history will be further summarized under disease 
characteristics at baseline. 
CSU (Yes, Ongoing condition) 
Atopic Dermatitis (Yes, Ongoing condition) 
Allergic rhinitis (Yes, Ongoing condition) 
Allergic Conjunctivitis (Yes, Ongoing condition) 
Asthma (Yes, Ongoing condition) 
Food allergy (Yes, Ongoing condition) 
Chronic Rhinosinusitis (Yes, Ongoing condition) 
Nasal Polyps (Yes, Ongoing condition) 
Eosinophilic Esophagitis (Yes, Ongoing condition) 
Disease characteristics at baseline   
The following baseline disease characteristics will be summarized by intervention group: 
• Age at onset of cold urticaria (years) 
• Duration of cold urticaria before screening visit (years) to be derived as 
• (Year of screening visit – Year of first diagnosis of cold urticaria) + (month of screening 
visit-month of first diagnosis of cold urticaria)/12 
• Number of patients who had cold urticaria events within 12 months before screening visit 
requiring Hospitalization/emergency care [n (%)], Epinephrine [n (%)] and OCS [n (%)], 
resulting in anaphylactic reaction [n (%)] and oropharyngeal edema [n (%)] 
• Number of patients who experienced cold urticaria symptoms including Skin (e.g. 
Localized Urticaria) [n (%)], Angioedema (e.g. Oropharyngeal angioedema) [n (%)], Skin 
(e.g. Generalized Urticaria) [n (%)], Skin (e.g. Generalized Urticaria) [n (%)], Generalized 
Angioedema [n (%)], Respiratory distress (e.g. Wheezing or shortness of breath) [n (%)], 
Hypotension (e.g. Dizziness, sensation of fainting, disorientation, or shock) [n (%)], 
Gastrointestinal discomfort (e.g. Diarrhea or vomiting) [n (%)], Other symptoms [n (%)] 
• Baseline urticaria control test (UCT) 
• Baseline Wheal intensity Likert scale 
• Baseline peak pruritus NRS 
• Baseline peak pain NRS 
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• Baseline peak burning sensation NRS 
• Baseline number of cold urticaria sign and symptom free days, Baseline number of cold 
exposure days, Baseline number of days of avoidance to cold (all measured by ColdUAS) 
• Baseline proportion of cold urticaria sign and symptom free days (measured by ColdUAS) 
• Baseline cold urticaria signs and symptoms severity on cold exposure (measured by 
ColdUAS) 
• Baseline Dermatology Life Quality Index (DLQI)/Children’s Dermatology Life Quality 
Index (CDLQI) 
• Baseline ColdU-QoL 
• Baseline Patient Global Impression of Severity (PGIS) 
• Screening ACUSI 
• Baseline EQ-5D-5L and EQ-VAS 
• Baseline IgE (quantitative and qualitative variable : <100 vs ≥100) 
• Baseline H1-AH use (regular vs per-need) and dose (<1-fold, 1-fold, 2-3-fold, 4-fold) 
• Prior cold urticaria medication use (LTRAs, H2-blockers, Omalizumab) 
Prior or concomitant medications   
All medications taken within 1 month before screening and until the end of the study, including 
all prior medications taken for ColdU are to be reported in the case report form pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the participant used prior to first investigational medicinal 
product (IMP) injection.  Prior medications can be discontinued before first administration 
or can be ongoing during treatment phase. 
• Concomitant medications are any interventions received by the participant concomitantly 
to the IMP, from first administration of IMP to last IMP intake + 98 days. 
• Post-treatment medications are those the participant took in the period running from the 
end of the concomitant medications period up to the end of the study. 
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as post-treatment medication. If it cannot be determined whether a 
given medication was taken prior or concomitantly or post, it will be considered as prior, 
concomitant, and post-treatment medication. 
The prior and concomitant medications will be summarized for the randomized population 
Medications will be summarized by intervention group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the 
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first 3 digits of the ATC class (therapeutic category).  All ATC codes corresponding to a 
medication will be summarized, and participants will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication. Therefore, participants may be counted several 
times for the same medication. 
Prior medications will be summarized separating for those taken for ColdU versus other reasons. 
The tables for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across intervention groups.  In case of 
equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be 
used. 
Concomitant medication received during first IMP to last IMP +14 days and concomitant 
medication received during first IMP to last IMP +98 days will be summarized separately. The 
tables for concomitant medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the incidence in the dupilumab group. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
Medications will also be summarized by generic name sorted by decreasing frequency based on 
the incidence in the dupilumab group. 
Rescue medications  
The following rescue medications may be used: 
• Additional doses of H1-AH up to 4-fold the recommended dose (2-fold in Japan) 
• Short course of OCS 
The use of rescue medications should be delayed, if possible, for at least 8 weeks following the 
initiation of IMP. The following specific medications will be summarized: 
• Rescue medications taken during the study will be summarized separately overall and by 
type (additional doses of H1-AH medications, OCS therapy).   
• The total number of days rescue medication was taken by type will be summarized. 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Demographic formulas 
 
Age of onset of cold urticaria is calculated as: 
Year of cold urticaria diagnosis – Year of birth 
BMI is calculated as: 
Weight in kg / (height2 in meters) 
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Renal function formulas  
For adults, creatinine clearance (CLcr) value will be derived using the equation of Cockroft and 
Gault: 
CLcr (ml/min) = (140 - age) × weight (kg) × (1 - 0.15 × sex (0-M, 1-F)) / (0.814 × creatinine 
(μmol/L)) 
For participants <18 years old, CLcr value will be derived using the equation of GFR Bedside 
Schwartz 
GFR (mL/min/1.73 m²) = k × height (cm) / sCr (mg/dL), 
where the coefficient k = 0.55 for children <12; k = 0.65 for male adolescent participants or 
k = 0.55 for female adolescent participants 
CLcr will be calculated using the last weight measurement on or before the visit of the creatinine 
measurement and age at the lab sampling day. Here age is calculated as following: 
Age = age collected at screening + integer part of (lab sampling analysis day / 365.25) 
Data handling conventions for other secondary endpoints 
For the UCT, in case of missing items the score for that participant will be left missing. 
For the DLQI, handing of missing items is as follows:  
a) If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. 
b) If two or more questions are left unanswered the questionnaire is not scored. 
c) If question 7 is answered ‘yes’, this is scored 3 even if in the same question one of the 
other boxes is ticked. 
d) If question 7 is answered ‘no’ or ‘not relevant’ but either ‘a lot’ or ‘a little’ is ticked, 
this is then scored 2 or 1. 
e) If two or more response options are ticked for one question, the response option with 
the highest score should be recorded. 
For the CDLQI, handling of missing items is as follows: 
a) If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. 
b) If two or more questions are left unanswered the questionnaire is not scored. 
c) If two or more response options are ticked for one question, the response option with 
the highest score should be recorded. 
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For the ColdU-QoL total score, the raw total score will be converted to a 0 to 100 score for 
analysis using the following formula: 
ColdU-QoL total score = Sum of the score of all completed items/Maximum possible sum of the 
score of all completed items*100. 
For the ColdUAS, there are two endpoints: 
1. (E1) Proportion of sign and symptom free days over the exposure days in the 14-day 
window 
2. (E2) MEAN SCORE of Q1+Q2 adjusted for exposure in the 14-day window 
To define E1, first take all the days in the 14-day window with Q3>0 (called A1). For those days, 
look at how many days when the patient answers Q1=0 and Q2=0 (A2). The proportion is defined 
as A2/A1. It will be set to missing if A1=0. 
To define E2, first take all the days in the 14-day window with Q3>0 (called A1). For those days, 
calculate the total score Q1+Q2 for each day and then sum the total scores together (called B2). 
The MEAN SCORE of Q1+Q2 adjusted for exposure in the 14-day window is defined as B2/A1. 
It will be set to missing if A1=0. 
Example: 
Day 
ColdUAS 
Completed 
Q3 
Note for programming 
Q1 
Q2 
Q1+Q2 
1 
Y 
0 
Not exposed, not counted in A1 
1 
1 
2* 
2 
N 
NA 
Missing ediary, not counted in A1 
NA 
NA 
NA 
3 
Y 
1 
counted in A1 
0 
0 
0 
4 
Y 
2 
counted in A1 
2 
1 
3 
5 
Y 
2 
counted in A1 
2 
3 
5 
6 
Y 
1 
counted in A1 
0 
1 
1 
7 
N 
NA 
Missing ediary, not counted in A1 
NA 
NA 
NA 
8 
N 
NA 
Missing ediary, not counted in A1 
NA 
NA 
NA 
9 
Y 
1 
counted in A1 
1 
0 
1 
10 
Y 
1 
counted in A1 
0 
0 
0 
11 
Y 
0 
Not exposed, not counted in A1 
1 
2 
3* 
12 
Y 
2 
counted in A1 
2 
1 
3 
13 
N 
NA 
Missing ediary, not counted in A1 
NA 
NA 
NA 
14 
Y 
1 
counted in A1 
1 
0 
1 
A1=8 
A2=2 (within the 8 days of exposure, only 2 days with Q1+Q2=0) 
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B2=(0+3+5+1+1+0+3+1)=14 (the values 2 and 3 with superscript “*” are not counted as they 
belong to days without exposure) 
E1=A2/A1=2/8=0.25 
E2=B2/A1=14/8=1.75 
Note: The e-diary completion days should be no less than 6 and exposure days should be no less 
than 1 in the 14-day window, otherwise the proportion of sign and symptom free days and mean 
score will be considered as missing. Additionally, analyses based on exposure days no less than 3 
will be conducted. 
For the EQ-5D-5L health status, it will be converted into a single index value according to the 
new crosswalk algorithm developed by Hernandez Alava et al (1) and using the UK value set. 
Daily e-diary weekly scores 
For the daily efficacy endpoints (ColdUAS), the time period used to calculate the bi-weekly score 
at each designated study day is summarized in Table 8. Randomization day is used as the 
reference day (Day 1). 
Table 8 - Weekly efficacy assessments from daily e-diary  
Analysis visit 
Day range for calculating 
weekly score 
Target day 
Baseline (Week 0) 
-14- -1 
-1 
Week 2 
2-15 
15 
Week 4 
16-29 
29 
Week 6 
30-43 
43 
Week 8 
44-57 
57 
Week 10 
58-71 
71 
Week 12 
72-85 
85 
Week 14 
86-99 
99 
Week 16 
100-113 
113 
Week 18 
114-127 
127 
Week 20 
128-141 
141 
Week 22 
142-155 
155 
Week 24 
156-169 
169 
Week 26 
170-183 
183 
Week 28 
181-197 
197 
Week 30 
198-211 
211 
Week 32 
212-225 
225 
Week 34 
226-239 
239 
Week 36 
240-253 
253 
 
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Analysis windows for time points 
For the safety assessment, the reference date for the derivation of relative days of events or 
findings will be the date of first IMP administration. Selected safety variables will be summarized 
by the analysis window defined in Table 9 for the by visit descriptive analysis. All available 
values from central lab will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same number of days away from the target 
day, the latest one will be used. For procedures planned on Visit 2, if it is done on the same date 
as the first IMP injection but the performance time is missing, it will belong to Visit 2 time 
window. 
Table 9 - Time window for safety endpoints  
 
 
Time windows for 
Visit 
Target 
Day 
Vital 
signs 
Hematology, 
biochemistry, 
urinalysis 
Hepatitis, 
HIV 
serology 
Serum 
pregnancy 
Urine 
pregnancy 
Physical 
exam 
ECG 
Visit 1  
-28 to -14 
<-14 
<-14 
1- 
<-14 
 
<-14 
1- 
Visit 2 
(Week 0) 
1 
-14-1- 
-14-1- 
 
 
-14-1- 
-14-1- 
 
Week 4 
29 
 
 
 
 
1+-42 
 
 
Week 8 
57 
 
 
 
 
43-70 
 
 
Visit 3 
(Week 12) 
85 
1+-126 
1+-126 
 
 
71-98 
 
 
Week 16 
113 
 
 
 
 
99-126 
 
 
Week 20 
141 
 
 
 
 
127-154 
 
 
Visit 4 
(Week 24) 
169 
127-
210 
127-210 
 
 
155-182 
1+ -210 
 
Week 28 
197 
 
 
 
 
183-210 
 
 
Week 32 
225 
 
 
 
 
211-238 
 
 
Visit 5 
(Week 36) 
253 
>210 
>210 
 
 
>238 
>210 
 
1-: up to 1st dose date/time; 1+: after 1st dose date/time; 
For the efficacy assessment, the reference date for the derivation of relative days of events or 
findings will be the randomization day. If a participant receives IMP prior to the randomization by 
mistake, the reference date of efficacy assessment will be the date of the first IMP administration 
for that participant. For the primary analyses, all available values of scheduled measurements will 
be assigned to the appropriate visit window according to Table 10. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same number of days away from the target 
day, the latest one will be used. 
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Table 10 - Time window for efficacy variables 
 
 
Time windows for 
Visit 
Target 
Day 
Ice cube, 
UCT 
Likert, 
NRS 
ColdUAS, 
PGIS 
PGIC 
DLQI/CDLQI, ColdU-QoL, 
EQ-5D-5L, 
 
 
Visit 1  
-28 to -14 
<-14 
 
<-14 
 
 
Visit 2  
(Week 0) 
1 
-14-1- 
<1- 
-14-1- 
 
<1- 
Visit 3  
(Week 12) 
85 
1+-126 
1+-126 
1+-126 
1+-126 
 
Visit 4  
(Week 24) 
169 
127-210 
127-210 
>126 
>126 
≥1+ 
Visit 5  
(Week 36) 
253 
>210 
>210 
 
 
 
1-: up to randomization and before 1st dose date/time; 1+: after randomization or 1st dose date/time   
For the pharmacokinetics/pharmacodynamics variables summary, the reference date for the 
derivation of relative days of measurements will be the date of first IMP administration if the 
participant is treated with study intervention, or the randomization date if the participant is not 
treated. Pharmacokinetics/pharmacodynamics variables will be summarized by the analysis 
window defined in Table 11 for the by visit descriptive analyses. All available values of 
measurements will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same number of days away from the target 
day, the latest one will be used. For procedures planned on Visit 2, if it is done on the same date 
as the first IMP injection but the performance time is missing, it will belong to Visit 2 time 
window. 
Table 11 - Time window for pharmacokinetics/pharmacodynamics variables  
Visit 
Target Day 
Serum dupilumab, ADA, 
Total IgE 
Basophil activation (optional) 
Visit 1  
-28 to -14 
 
 
Visit 2 (Week 0) 
1 
<1- 
<1- 
Visit 3 (Week 12) 
85 
1+-126 
1+-126 
Visit 4 (Week 24) 
169 
127-210 
>126  
Visit 5 (Week 36) 
253 
>210 
 
1-: up to 1st dose date/time or randomization if participant is not treated; 1+: after 1st dose date/time or randomization date if 
participant is not treated; 
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Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs and ECG will be used for 
computation of baseline, the last on-treatment value, analysis according to PCSAs, and the shift 
summaries for safety. They will also be included in the by-visit summaries if they are re-allocated 
to scheduled visits. Unscheduled visit measurements for efficacy data will be included in the by-
visit summaries if they are re-allocated to scheduled visits. 
5.5 
APPENDIX 5 SELECTION CRITERIA FOR AE/MEDICATION GROUPINGS  
Table 12 - List of PTs or Medications for CMQs/CDGs  
Grouping 
Preferred Term/ 
Medication Code 
Preferred Term/ 
Medication 
Conjunctivitis 
10001257 
Adenoviral conjunctivitis 
Conjunctivitis 
10010725 
Conjunctival irritation 
Conjunctivitis 
10010726 
Conjunctival oedema 
Conjunctivitis 
10010736 
Conjunctival ulcer 
Conjunctivitis 
10010741 
Conjunctivitis 
Conjunctivitis 
10010744 
Conjunctivitis allergic 
Conjunctivitis 
10010745 
Conjunctivitis chlamydial 
Conjunctivitis 
10010749 
Conjunctivitis gonococcal neonatal 
Conjunctivitis 
10010754 
Conjunctivitis tuberculous 
Conjunctivitis 
10010755 
Conjunctivitis viral 
Conjunctivitis 
10018258 
Giant papillary conjunctivitis 
Conjunctivitis 
10021629 
Inclusion conjunctivitis 
Conjunctivitis 
10030861 
Ophthalmia neonatorum 
Conjunctivitis 
10048908 
Seasonal allergy 
Conjunctivitis 
10049458 
Herpes simplex virus conjunctivitis neonatal 
Conjunctivitis 
10051625 
Conjunctival hyperaemia 
Conjunctivitis 
10053991 
Inclusion conjunctivitis neonatal 
Conjunctivitis 
10061784 
Conjunctivitis bacterial 
Conjunctivitis 
10062889 
Pingueculitis 
Conjunctivitis 
10063669 
Photoelectric conjunctivitis 
Conjunctivitis 
10067317 
Oculorespiratory syndrome 
Conjunctivitis 
10067817 
Acute haemorrhagic conjunctivitis 
Conjunctivitis 
10069166 
Blebitis 
Conjunctivitis 
10071570 
Ligneous conjunctivitis 
Conjunctivitis 
10074701 
Noninfective conjunctivitis 
Conjunctivitis 
10075264 
Oculoglandular syndrome 
Conjunctivitis 
10080825 
Conjunctivitis fungal 
Conjunctivitis 
10084034 
Conjunctival suffusion 
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Statistical Analysis Plan  
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Property of the Sanofi group - strictly confidential 
Page 47 
Grouping 
Preferred Term/ 
Medication Code 
Preferred Term/ 
Medication 
Intravenous immunoglobulin therapy 
CAS 8000012671 
IMMUNOGLOBULIN HUMAN NORMAL 
Intravenous immunoglobulin therapy 
CAS 8000050682 
IMMUNOGLOBULIN, PORCINE 
Intravenous immunoglobulin therapy 
CAS 8000056919 
IMMUNOGLOBULIN G HUMAN 
Intravenous immunoglobulin therapy 
CAS 8600000563 
IMMUNOGLOBULINS NOS 
Intravenous immunoglobulin therapy 
CAS 8600001670 
IMMUNOGLOBULIN HUMAN NORMAL SLRA 
Intravenous immunoglobulin therapy 
CAS 8600001671 
IMMUNOGLOBULIN HUMAN NORMAL IFAS 
Intravenous immunoglobulin therapy 
RECNO 900708 
OTHER IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 900722 
IMMUNE SERA AND IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 900728 
IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 900914 
SPECIFIC IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 901112 
IMMUNOGLOBULINS, NORMAL HUMAN 
Abbreviations: CAS: Chemical Abstract Service Registry Number RECNO: Drug Record Number 
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Statistical Analysis Plan  
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6 
REFERENCES  
1. Hernández Alava, M., Pudney, S. and Wailoo, A. (2020) Estimating the relationship between 
EQ-5D-5L and EQ-5D-3L: results from an English population study. Policy Research Unit in 
Economic Evaluation of Health and Care Interventions. Universities of Sheffield and York. 
Report 063. 
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