A Randomized, Double-blind, Head-to-head Comparison of Dupilumab Versus Omalizumab in Severe Chronic Rhinosinusitis With Nasal Polyps (CRSwNP) and Comorbid Asthma Patients
Phase: PHASE4
Conditions: Chronic Rhinosinusitis With Nasal Polyps, Asthma
Sponsor: Sanofi

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 03 
Protocol title: 
A randomized, double-blind, head-to-head comparison 
of dupilumab versus omalizumab in severe Chronic 
Rhinosinusitis with Nasal Polyps (CRSwNP) and 
comorbid asthma patients 
Protocol number: 
LPS16747 
Amendment number: 
03 
Compound number 
(INN/Trademark): 
SAR231893 
dupilumab/Dupixent®
Study phase: 
Phase 4 
Short title: 
EVEREST: EValuating trEatment RESponses of 
dupilumab versus omalizumab in Type 2 patients 
EVEREST 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address: 
82 Avenue Raspail, 94250 Gentilly, France 
Monitoring Team’s 
Representative Name 
and Contact Information 
Regulatory agency identifier number(s): 
IND: 
105379 
EudraCT: 
2021-000829-27 
NCT: 
Not applicable 
WHO: 
U1111-1255-4713 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
Approval Date: 14-May-2024 
Total number of pages: 117 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 
All 
14 May 2024, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
13 December 2022, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01  
All 
10 June 2021, version 1 (electronic 1.0) 
Original Protocol 
 
15 March 2021, version 1 (electronic 1.0) 
Amended protocol 03 (14 May 2024) 
This amended protocol (amendment 03) is considered to be substantial based on the criteria set 
forth in Article 2(2)(13) of the Regulation No 536/2014 of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main objective of this amendment is to reduce the sample size due to enrollment challenges 
and optimization of the targeted patient population to focus on Nasal Function endpoints while 
maintaining the favorable benefit-risk of the study. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Title page, header, protocol amendment 
summary of changes section and Table of 
Content, etc is updated. 
Updated to reflect the current 
amendment, ie, amended protocol 03. 
Title page 
Changed Sponsor’s registered address 
Updated as per new address 
Section 1.1 Synopsis 
Section 3.0 Objectives and 
Endpoints 
Section 9.4.3 Secondary 
Endpoints 
Secondary objective and corresponding endpoint 
downgraded to exploratory:  
Objective: “To evaluate the efficacy of dupilumab 
in improving lung function at Week 24 compared 
to omalizumab”  
Endpoint: “Change from baseline to Week 24 
in pre bronchodilator forced expiratory volume in 
1 second (FEV1)” 
The study is powered on primary 
endpoints, hence the FEV1 
assessment was downgraded to 
exploratory endpoint 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 3.0 Objectives and 
Endpoints 
Section 9.4.3 Secondary 
Endpoints 
Secondary objective and corresponding endpoint 
downgraded to exploratory:  
Objective: “To evaluate the effect of dupilumab 
on asthma control at Week 24 compared to 
omalizumab”  
Endpoint: “Change from baseline to Week 24 in 
7 item Asthma Control Questionnaire (ACQ-7)” 
The study is powered on primary 
endpoints, hence the ACQ-7 
assessment was downgraded to 
exploratory endpoint.  
Section 1.1 Synopsis 
Section 4.1 Overall Design 
Sample size reduced from 422 participants 
(211 participants per group) to a minimum of 
320 participants (160 participants per group) 
based on enrollment projections at the moment of 
sample size reduction 
Sample size was reduced due to low 
recruitment rate  
Section 1.1 Synopsis 
Section 9.2 Sample Size 
Determination 
Deleted text describing sample size rationale 
Text removed as FEV1 is downgraded 
to exploratory endpoint 
Appendix 1 (Section 10.1.4): 
Data Protection 
Added statements regarding Sanofi Data 
Protection Officer: “Personal data of 
professionals will be retained by Sanofi for up to 
twenty-five (25) years, unless further retention is 
required by applicable regulations. 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 
- 46 avenue de la Grande Armee-75017-PARIS 
- France (to contact Sanofi by email, visit 
https://www.sanofi.com/en/our-
responsibility/sanofi-global-privacy-
policy/contact).”  
To align with OneDoc template V10 
Section 11.0 references 
References number 65 through 67 were deleted 
References were used only once in the 
sample size section for FEV1, which 
was downgraded to exploratory 
endpoint. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 17 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 18 
2 
INTRODUCTION ............................................................................................................................ 27 
2.1 
STUDY RATIONALE...................................................................................................................... 27 
2.2 
BACKGROUND ............................................................................................................................. 28 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 30 
2.3.1 
Risk assessment ............................................................................................................................ 30 
2.3.2 
Benefit assessment ........................................................................................................................ 32 
2.3.3 
Benefit/risk assessment related to Coronavirus Disease 2019 (COVID-19) ................................. 33 
2.3.4 
Overall benefit: risk conclusion ...................................................................................................... 33 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 34 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 36 
4 
STUDY DESIGN ............................................................................................................................ 38 
4.1 
OVERALL DESIGN ........................................................................................................................ 38 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 39 
4.2.1 
Participant input into design ........................................................................................................... 40 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 40 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 40 
5 
STUDY POPULATION .................................................................................................................. 41 
5.1 
INCLUSION CRITERIA .................................................................................................................. 41 
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5.2 
EXCLUSION CRITERIA ................................................................................................................ 43 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 46 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 46 
5.3.2 
Activity ............................................................................................................................................ 46 
5.4 
SCREEN FAILURES...................................................................................................................... 46 
5.5 
CRITERIA FOR TEMPORARY DELAYING SCREENING/RANDOMIZATION ............................. 47 
6 
STUDY INTERVENTION ............................................................................................................... 48 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 48 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 51 
6.2.1 
Storage and handling ..................................................................................................................... 51 
6.2.2 
Responsibilities .............................................................................................................................. 51 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 51 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 53 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 54 
6.5.1 
Prohibited medications ................................................................................................................... 54 
6.5.2 
Permitted concomitant medication ................................................................................................. 55 
6.5.3 
Rescue medicine for CRSwNP ...................................................................................................... 56 
6.5.3.1 
Rescue medications for asthma ..................................................................................................... 56 
6.6 
DOSE MODIFICATION .................................................................................................................. 56 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 56 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 57 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 57 
7.1.1 
Definitive discontinuation ............................................................................................................... 57 
7.1.2 
Temporary discontinuation ............................................................................................................. 59 
7.1.2.1 
Rechallenge ................................................................................................................................... 59 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 59 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 60 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 61 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 61 
8.1.1 
Nasal polyp score ........................................................................................................................... 61 
8.1.2 
University of Pennsylvania Smell Identification Test (UPSIT) ....................................................... 62 
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8.1.3 
Nasal Peak Inspiratory Flow (NPIF) ............................................................................................... 63 
8.1.4 
Spirometry ...................................................................................................................................... 64 
8.1.5 
Severe asthma exacerbation ......................................................................................................... 65 
8.1.6 
Patient-reported outcome (PRO) questionnaires ........................................................................... 65 
8.1.6.1 
CRSwNP nasal symptom diary including nasal congestion/obstruction, loss of smell, and 
total symptom score ....................................................................................................................... 65 
8.1.6.2 
Sino-Nasal Outcome Test-22-Items (SNOT-22) ............................................................................ 66 
8.1.6.3 
Rhinosinusitis Severity Visual Analogue Scale (rhinosinusitis VAS) ............................................. 66 
8.1.6.4 
Asthma Daytime Symptom Diary (ADSD) ..................................................................................... 67 
8.1.6.5 
Work Productivity and Activity Impairment Questionnaire: Chronic Rhinosinusitis Version 
2.0 .................................................................................................................................................. 67 
8.1.6.6 
Asthma Control Questionnaire 7-item version (ACQ-7) ................................................................. 68 
8.1.6.7 
Asthma quality of life questionnaire with standardized activities (self-administered) .................... 68 
8.1.6.8 
Cumulative number of health-care resource utilization (HCRU) .................................................... 69 
8.1.6.9 
EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire (EQ-5D) .......................................... 69 
8.1.6.10 Patient Global Impression of Control and Change in CRSwNP .................................................... 69 
8.1.6.11 Investigator Global Assessment (Severity, Control, Change) in CRSwNP ................................... 70 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 70 
8.2.1 
Physical examinations ................................................................................................................... 70 
8.2.2 
Vital signs ....................................................................................................................................... 70 
8.2.3 
Electrocardiograms ........................................................................................................................ 71 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 71 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 71 
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 ................................................................................. 72 
8.3.5 
Pregnancy ...................................................................................................................................... 73 
8.3.6 
Adverse event of special interest ................................................................................................... 74 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 75 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 75 
8.5 
PHARMACOKINETICS .................................................................................................................. 75 
8.6 
PHARMACODYNAMICS ............................................................................................................... 75 
8.7 
GENETICS ..................................................................................................................................... 76 
8.8 
BIOMARKERS ............................................................................................................................... 76 
8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 76 
8.10 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................... 76 
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9 
STATISTICAL CONSIDERATIONS .............................................................................................. 77 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 77 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 77 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 78 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 78 
9.4.1 
General considerations .................................................................................................................. 78 
9.4.2 
Primary endpoints .......................................................................................................................... 79 
9.4.3 
Secondary endpoints ..................................................................................................................... 81 
9.4.4 
Tertiary/exploratory endpoints ....................................................................................................... 82 
9.4.5 
Other safety analyses .................................................................................................................... 82 
9.4.6 
Other analyses ............................................................................................................................... 82 
9.5 
INTERIM ANALYSES .................................................................................................................... 83 
9.6 
DATA MONITORING COMMITTEE (DMC) ................................................................................... 83 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 84 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 84 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 84 
10.1.2 
Financial disclosure........................................................................................................................ 85 
10.1.3 
Informed consent process .............................................................................................................. 85 
10.1.4 
Data protection ............................................................................................................................... 86 
10.1.5 
Committees structure ..................................................................................................................... 87 
10.1.6 
Dissemination of clinical study data and results ............................................................................ 87 
10.1.7 
Data quality assurance .................................................................................................................. 87 
10.1.8 
Source documents ......................................................................................................................... 88 
10.1.9 
Study and site start and closure ..................................................................................................... 88 
10.1.10 Publication policy ........................................................................................................................... 89 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 89 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 91 
10.3.1 
Definition of AE .............................................................................................................................. 91 
10.3.2 
Definition of SAE ............................................................................................................................ 92 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 93 
10.3.4 
Reporting of SAEs.......................................................................................................................... 95 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY .............. 96 
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10.5 
APPENDIX 5: GENETICS ............................................................................................................. 98 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 99 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 100 
10.8 
APPENDIX 8: OMALIZUMAB DOSING TABLE .......................................................................... 100 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 101 
10.10 
APPENDIX 10: DEFINITION OF ANAPHYLAXIS ....................................................................... 103 
10.11 
APPENDIX 11: LIST OF OPPORTUNISTIC INFECTION ........................................................... 103 
10.12 
APPENDIX 12: DIAGNOSISOF NERD IN CRSWNP PATIENTS (± DIAGNOSED 
ASTHMA) ..................................................................................................................................... 104 
10.13 
APPENDIX 13: ABBREVIATIONS ............................................................................................... 104 
10.14 
APPENDIX 14: PROTOCOL AMENDMENT HISTORY .............................................................. 107 
11 
REFERENCES ............................................................................................................................. 112 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 34 
Table 2 - Overview of study interventions administered ............................................................................... 48 
Table 3 - Endoscopic nasal polyp score ........................................................................................................ 62 
Table 4 - Washout period of asthma controllers and rescue medication before lung function 
assessments .................................................................................................................................................. 64 
Table 5 - Nasal symptom score ..................................................................................................................... 65 
Table 6 - Populations for analyses ................................................................................................................ 78 
Table 7 - Summary of primary estimand for the primary endpoints .............................................................. 80 
Table 8 - Protocol-required laboratory assessments .................................................................................... 90 
Table 9 - Highly effective contraceptive methods ......................................................................................... 97 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 17 
Figure 2 - Omalizumab dosing table ........................................................................................................... 100 
 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A randomized, double-blind, head-to-head comparison of dupilumab versus 
omalizumab in severe Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and 
comorbid asthma patients 
Short title: 
EVEREST: EValuating trEatment RESponses of dupilumab versus omalizumab 
in Type 2 patients 
Rationale: 
Severe Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) is a serious, chronic inflammatory 
disease, predominantly driven by type 2 inflammation in at least 80% of patients (in western 
countries) and 50% (in Asian countries) (1). Chronic Rhinosinusitis with Nasal Polyps is 
characterized by bilateral nasal polyps and rhinosinusitis, which cause a range of persistent 
debilitating symptoms, including loss of smell, nasal obstruction/congestion, and nasal discharge 
(2, 3, 4). Chronic Rhinosinusitis with Nasal Polyps has an estimated prevalence of 2% to 4% 
in Europe and the United States (US) (4, 5) and is frequently associated with multiple type-2 
coexisting diseases such as asthma, allergic rhinitis, and/or Non-Steroidal Anti-Inflammatory 
Drug Exacerbated Respiratory Disease (NSAID-ERD, which further contribute to greater disease 
severity and overall disease burden (6). In CRSwNP the type 2 inflammatory signature is 
characterized by the involvement of type 2 cytokines interleukin(IL)-4 (IL-4)/IL-13 and IL-5 in its 
pathophysiology, and high levels of tissue Immunoglobulin E (IgE) (7, 8, 9, 10, 11) or presence of 
coexisting diseases such as asthma, NSAID-ERD, allergic rhinitis, or atopic dermatitis (AD) 
(4, 12, 13, 14). 
Approximately 50% to 70% of patients with asthma (15, 16, 17, 18, 19, 20), have evidence of 
type 2 airway inflammation (10, 11, 12, 21), and up to 65% of CRSwNP patients have comorbid 
asthma.  
• In patients with asthma, type 2 inflammation is associated with poor asthma control, 
increased bronchial hyperresponsiveness, greater lung function impairment, and more 
frequent severe exacerbations compared with patients with a lower type 2 inflammatory 
signature.  
• In patients with CRSwNP, the presence of type 2 inflammation is associated with more 
severe disease, a greater risk for post-surgical recurrence, and a higher frequency of 
comorbid asthma. 
As stated above, a high proportion of patients with CRSwNP have comorbid asthma, which adds 
substantially to the overall disease burden, including greater disease severity of both CRSwNP 
and asthma leading to more frequent asthma exacerbations, higher rates of postsurgical polyp 
recurrence, greater cumulative systemic corticosteroids (SCS) use, and an impaired health related 
quality of life (HRQoL) (22, 23, 24). As a result of the shared inflammatory pathway 
underpinning their pathophysiology, type 2 inflammatory airway diseases share several common 
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clinical features, notably airway obstruction and/or congestion, and excessive mucus production. 
Increased nasal sinus opacification (reduced upper airway volume) has been associated with 
evidence of type 2 inflammation (blood/tissue eosinophilia) in patients with CRSwNP 
(25, 26, 27, 28). 
First-line treatment options for CRSwNP comprises intranasal corticosteroid sprays (INCS) and 
saline nasal irrigations to improve the symptoms of disease such as nasal obstruction (29) but 
INCS show little effect in reducing nasal polyp size and improving sense of smell, the most 
important symptoms reported by CRSwNP patients (30, 31). In addition, SCS is prescribed to 
decrease polyp size and symptom burden, but continuous treatment with SCS is not recommended 
and should be avoided due to the known serious systemic side effects - both short and long term 
(32). In some patients, medical management fails and therefore, functional endoscopic sinus 
surgery (FESS) is indicated to improve sino-nasal symptoms (33). Surgical removal of nasal 
polyps does not specifically target the underlying type 2 inflammation (mediated by key type 2 
cytokines IL-4, IL-13, and IL-5) in the sinuses, leading to high rates of recurrence and revision 
surgery, and may not restore the sense of smell in many patients (22, 34, 35, 36). 
Recent therapeutic approaches have been focused on the use of biologics in order to control the 
T-helper Type 2 cell (Th2) pathway with subsequent improvement of clinical signs in CRSwNP 
and associated comorbidities. Some biologics are currently approved for the treatment of this 
disease (dupilumab, omalizumab, and recently mepolizumab), while other biologics are 
in development (eg, benralizumab).  
Dupilumab is a human monoclonal antibody (mAb) that binds specifically to the shared receptor 
component for IL-4 and IL-13, thus inhibiting the dual signaling pathways of IL-4 and IL-13, key 
and central drivers of type 2 inflammation in CRSwNP and other type 2 inflammatory diseases. 
Dupilumab’s blockade of IL-4 and IL-13 signaling has demonstrated a favorable efficacy and 
safety profile and is approved for the treatment of a variety of type 2 disease states, including 
AD (37), asthma (38), and CRSwNP (39) where type 2 inflammation is a key driver of 
the underlying disease process. 
Omalizumab is approved in the European Union (EU) and the US for the treatment of allergic 
asthma and chronic spontaneous urticaria (CSU). In the US, omalizumab is approved for 
the treatment of nasal polyps, and in EU is approved for the treatment of CRSwNP. 
In CRSwNP, the results from both dupilumab and omalizumab pivotal studies suggest that 
a head-to-head (H2H) comparison of dupilumab versus omalizumab has the potential to 
demonstrate the superiority of dupilumab in reducing the bilateral endoscopic nasal polyp score 
(NPS) and improving the sense of smell in patients with severe CRSwNP and comorbid asthma. 
Therefore, the purpose of this study is to evaluate whether the efficacy profile of dupilumab is 
superior compared to omalizumab in treating participants with severe CRSwNP and comorbid 
asthma. 
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Objectives and endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of dupilumab compared to 
omalizumab in reducing the polyp size and 
improving sense of smell 
• 
Change from baseline to Week 24 in Nasal Polyp 
Score (NPS) 
• 
Change from baseline to Week 24 in University of 
Pennsylvania Smell Identification Test (UPSIT) 
Secondary 
Key secondary objectives: 
• 
To evaluate the efficacy of dupilumab in improving 
chronic rhinosinusitis with nasal polyps (CRSwNP) 
symptoms at Week 24 compared to omalizumab 
Key secondary endpoints: 
• 
Change from baseline to Week 24 in the loss of 
smell score of the CRSwNP Nasal Symptom Diary 
• 
Change from baseline to Week 24 in the nasal 
congestion (NC) score of the CRSwNP Nasal 
Symptom Diary 
Secondary objectives: 
• 
To evaluate the efficacy of dupilumab in improving 
CRSwNP total symptom score (TSS) at Week 24 
compared to omalizumab 
Secondary endpoints:  
• 
Change from baseline to Week 24 in TSS derived 
from the CRSwNP Nasal Symptom Diary 
• 
To evaluate the effect of dupilumab on health 
related quality of life (HRQoL) at Week 24 
compared to omalizumab 
• 
Change from baseline to Week 24 in 22-Item 
Sino-nasal Outcome Test (SNOT-22) total score 
• 
Change from baseline to Week 24 in SNOT-22 
nasal domains score 
• 
To evaluate the efficacy of dupilumab in improving 
nasal peak inspiratory flow at Week 24 compared to 
omalizumab 
• 
Change from baseline to Week 24 in Nasal Peak 
Inspiratory Flow (NPIF) 
• 
To evaluate the effect of dupilumab on CRSwNP 
overall disease severity at Week 24 compared to 
omalizumab 
• 
Change from baseline to Week 24 in rhinosinusitis 
visual analogue (VAS) 
• 
To evaluate the safety of dupilumab and 
omalizumab 
• 
Incidence of treatment-emergent adverse events 
(TEAEs) and serious adverse events (SAEs)  
• 
Incidence of adverse events of special interest 
(AESIs) 
Overall design: 
This is a Phase 4, multicenter, parallel group, randomized (1:1), double-blind, active-controlled 
study to compare the efficacy of dupilumab with omalizumab over 24 weeks of treatment in 
adult participants with severe CRSwNP and comorbid asthma.  
A minimum of 320 participants (160 per group) will be randomized in a 1:1 ratio to receive either 
dupilumab or omalizumab. Randomization will be stratified by prior surgery, inhaled 
corticosteroids (ICS) doses (low versus medium/ high dose ICS), presence of Aspirin-exacerbated 
respiratory disease (AERD) and region (Eastern European [EE] versus Rest of the World [ROW]). 
Based on the subgroup analysis from prior SINUS clinical trials, different treatment effects over 
placebo were observed in the EE countries versus ROW, across a few endpoints of interest. 
Therefore, the stratification factor by region (EE versus ROW) is included. 
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Disclosure Statement: 
This is an interventional, parallel group, study with 2 groups that are participant and Investigator 
blinded. 
Number of participants: 
Based on enrollment projections at the moment of sample size reduction, a minimum of 
320 participants will be randomized in the study with approximately 160 participants per group. 
Intervention groups and duration: 
Participants who satisfy the inclusion and exclusion criteria will be randomized (1:1) to one of 
the following investigational medicinal product (IMP) treatment groups:  
• Dupilumab: 300 mg every 2 weeks (Q2W) 
• Omalizumab: 75 to 600 mg Q2W or every 4 weeks (Q4W). Participant’s dosing and 
frequency will be based on pretreatment serum total IgE levels and body weight 
(see Figure 2 [Section 10.8])  
Duration of study period (per participant) 
Study duration per participant will be 38 weeks. The study will comprise 3 periods: 
• Screening and run-in period (28±3 days). 
• Randomized IMP intervention period (24 weeks). 
• Follow-up period (up to 12 weeks after the last IMP dose [Week 22] or until the 
participant switches to commercialized dupilumab/omalizumab [or other biologic 
product], whichever comes first). For the participants who switch to commercialized 
dupilumab/omalizumab (or other biologic product), the follow-up phone call visit should 
be performed prior to the first injection with commercialized dupilumab/omalizumab 
(or other biologic product). 
Study intervention(s) 
Investigational medicinal products 
• Dupilumab 300 mg. 
• Omalizumab 150 mg and 75 mg. 
• Placebo (to blind the number of active dupilumab and omalizumab injections): dupilumab 
placebo 2 mL. 
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Dupilumab 
• Formulation: dupilumab 300 mg: a 150 mg/mL dupilumab solution in a prefilled syringe 
to deliver 300 mg in a 2 mL injection. 
• Route of administration: subcutaneous (SC) injection. 
• Dose regimen: 1 injection of 300 mg Q2W. 
Omalizumab 
• Formulation: omalizumab 150 mg: a 150 mg/mL omalizumab solution in a prefilled 
syringe to deliver 150 mg in a 1 mL injection. Omalizumab 75 mg: a 150 mg/mL 
omalizumab solution in a prefilled syringe to deliver 75 mg in a 0.5 mL injection. 
• Route of administration: SC injection. 
• Dose regimen: 75 to 600 mg Q2W/Q4W according to the dosing table (see Figure 2). 
Placebo 
• Formulation:  
- 
Dupilumab placebo: identical formulation to the active formulation without 
dupilumab, in a prefilled syringe to deliver placebo 2 mL. 
• Route of administration: SC injection. 
• Dose regimen: as needed to blind number of active dupilumab and omalizumab injections. 
The IMP will be prepared and administered by the unblinded study site personnel. All participants 
will wear an eye sleep mask to minimize the risk of unblinding. When operationally feasible and 
if treating physician determines that is appropriate and safe, administration of IMP at study 
participant’s home by qualified and trained healthcare professionals as well as direct to participant 
shipment may be arranged. These approaches will only be implemented if allowed by local 
regulations, approved labelling and agreed by the treating physician, while ensuring blinding 
measures are maintained. 
Noninvestigational medicinal products 
Background therapies and rescue therapies will be supplied by the Sponsor’s local affiliate as 
locally required or by the sites. Reimbursement will be provided when deemed necessary and as 
per country regulation. 
Intranasal corticosteroid background therapy 
Throughout the study, the participants will use a diary to record daily use of mometasone furoate 
nasal spray (MFNS) 50 μg/actuation Nasal Spray, suspension. 
Before study entry, treatment with intranasal mometasone ≥200 μg once daily (QD) or equivalent 
of another INCS is required for 1 month prior to Visit 1. After Visit 1 only MFNS is allowed for 
a better standardization of background medication. 
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Screening/Run-in period 
After Visit 1 (screening visit), once the eligibility for study entry has been confirmed, 
all participants will enter a run-in period of 28 days where they will receive MFNS: 
• Two actuations (50 μg/actuation) in each nostril twice a day (BID) (total daily dose of 
400 μg) starting at Visit 1. If the participants are unable to tolerate the BID regimen or this 
dose is not approved in specific countries, they will follow a QD regimen (total daily dose 
of 200 μg). 
• Participant’s MFNS dose will be stabilized during the run-in period. 
Mometasone furoate nasal spray will be self-administered by the participant, and at each visit 
the Investigator must ensure that the participant has the necessary doses up to the next visit, 
knowing that one MFNS device (1 bottle) contains sufficient doses for either 2 weeks of BID 
treatment/regimen or 4 weeks of QD treatment/regimen. 
Participants who receive rescue medication including INCS drops or systemic (oral, intravenous 
[IV], intramuscular [IM]) steroids between Visit 1 and Visit 2 will not be randomized, but they 
can be rescreened. 
Randomized IMP intervention period 
During the randomized intervention period, all participants will continue on the stable dose of 
MFNS. 
Post-treatment period (ie, follow-up period) 
Upon completing the randomized intervention period (or following early discontinuation of 
the IMP), participants can continue treatment with the stable dose of MFNS maintained over 
the randomized intervention period until the end of study (EOS), or modify the treatment based 
on medical judgment. 
Asthma background therapy 
Screening/Run-in period 
Participants should be on a stable dose of low, medium or high dose ICS in combination with 
a second controller medication (eg, long-acting beta-2 adrenergic receptor agonists [LABA], 
leukotriene receptor antagonists [LTRA]) ≥1 month prior to screening visit and during 
the screening and run-in period. 
Participants requiring a third controller for their asthma will be considered eligible for this study, 
also, at a stable dose ≥1 month prior to screening visit and during the screening and run-in period. 
• Formulation and route(s) of administration: as per label. 
• Dose regimen: as prescribed. 
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Randomized IMP intervention period 
The asthma background therapy should be maintained on a stable dose during the study 
intervention period. 
An asthma background therapy diary will be provided to collect information related to 
noninvestigational medicinal product (NIMP) use.  
Post-treatment period (ie, follow-up period) 
Upon completing the randomized IMP intervention period (or following early discontinuation of 
IMP), participants can continue treatment with the stable dose of ICS maintained over 
the randomized intervention period until the EOS, or modify the treatment based on medical 
judgment. 
Statistical considerations: 
The original sample size of 422 was estimated to power the key secondary endpoint, change from 
baseline in pre-BD FEV1 at Week 24, at 
. By downgrading this endpoint to an exploratory 
endpoint and 
 
 
. 
• Primary endpoints: Each of the 2 primary endpoints will be analyzed using a hybrid 
method of the worst observation carried forward (WOCF) and the multiple imputation 
(MI). With this approach, for participants who undergo surgery for NP or receive SCS for 
any reason during the study, data collected postsurgery or post SCS will be set to missing, 
and the worst postbaseline value on or before the time of surgery or SCS intake will be 
used to impute missing Week 24 value (for participants whose postbaseline values are 
all missing, the baseline will be used to impute). For participants who discontinue 
the treatment without being rescued by surgery or receiving SCS, an MI approach will be 
used to impute the missing Week 24 value. This MI will use all participants who have not 
been rescued by surgery or receiving SCS by Week 24. The data collected after treatment 
discontinuation will be included in the analysis. Each of the imputed complete data will be 
analyzed by fitting an analysis of covariance (ANCOVA) model with corresponding 
baseline value, treatment group, and stratification factors as the covariates. Statistical 
inference on treatment comparisons for the 2 primary endpoints at Week 24 will be 
derived from the ANCOVA model. Descriptive statistics including number of participants, 
mean, standard deviation, and least squares (LS) means will be provided. In addition, 
difference in LS means and the corresponding 95% confidence intervals (CIs) will be 
provided along with the p -values. 
• Main secondary endpoints: The change from baseline in the continuous endpoints to 
Week 24 will be analyzed using the hybrid method of the WOCF and the MI with 
ANCOVA model in the same fashion as for the 2 primary endpoints. 
Data Monitoring Committee: No 
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NP: nasal polyps; NPIF: Nasal Peak Inspiratory Flow; NPS: nasal polyp score; PRO: patient-reported outcome; SAE: serious adverse event; SCS: systemic corticosteroids; SNOT-22: sino-nasal outcome test-22 
Items; TB: tuberculosis; TEAE: treatment-emergent adverse event; UPSIT: University of Pennsylvania Smell Identification Test; V: visit; VAS: visual analogue scale; W: week; WOCBP: woman of childbearing 
potential; WPAI: Work Productivity and Activity Impairment. 
a Although the screening assessments for this study are grouped under the heading of a single visit in this protocol, it is possible for them to be performed over more than 1 site visit if necessary, as long as the 
run-in period window prior to Day 1 (V2) is respected. These participants do not need to sign a new consent form and be allocated a new participants number within this same window. 
The run-in period is 28 days in duration to run-in any participant on MFNS and to collect baseline data. Participants who receive rescue medication including INCS drops or systemic (oral, intravenous, 
intramuscular) steroids and/or surgery during this period will not be randomized, but they can be rescreened. V2 will take place 28±3 days window after V1. Window for subsequent visits is also ±3 days. 
Assessments/procedures at a site visit are performed in the following order (if applicable): PRO and other questionnaires; procedures; safety and laboratory assessments; IMP administration. 
b Interim visits at site for IMP administration.  
c Participants who discontinue treatment early will be assessed as soon as possible using the procedures scheduled for the EOT visit. 
d Phone call visit: The safety follow-up period will be up to 12 weeks after the last IMP dose (Week 22) or until the participant switches to commercialized dupilumab/omalizumab or other biologics, whichever comes 
first. For the participants who switch to commercialized dupilumab/omalizumab (or other biologic product), the phone call visit should be performed prior to the first injection with commercialized 
dupilumab/omalizumab (or other biologic product). 
e A complete physical examination will include, at a minimum, assessments of the skin, nasal cavities, eyes and ears, cardiovascular, respiratory, gastrointestinal, neurological, lymphatic, and musculoskeletal 
systems. 
f 
Past medical history including allergic comorbidities (asthma, aspirin sensitivity, allergic rhinitis, etc). Surgeries for NP will be assessed including: number, type, and dates of sino-nasal surgeries, polypectomies 
in the past. The SCS use (number of courses, doses, way of administration, and duration) in the past 2 years before V1 and/or contraindication/intolerance to SCS, as well as long term antibiotics use (>2 weeks) 
in the previous year will be entered in the eCRF. Non-steroid anti-inflammatory drug (NSAID) Exacerbated Respiratory Disease (ERD) will be assessed through a specific questionnaire (Section 10.12). 
g Spirometry test should be performed before IMP administration, in the morning if possible. If test can only be performed at another time during the day, then it should be done approximately at the same time of the 
day at each visit throughout the study. Spirometry will be performed after a washout period of bronchodilators according to their duration of action. This will be verified before performing the measurements.  
h Nasal endoscopy: endoscopy (including use of decongestants before the procedure) will be performed after all other efficacy assessments have been completed for each visit. Standard video sequences will be 
downloaded by the Investigator and sent to the central reader’s secured internet site. For eligibility, central reading of V1 will be used. At V2, the Investigator will review V1 results from the central reader to confirm 
entry criteria and reconfirm eligibility based on review of Inclusion/Exclusion Criteria and the V2 endoscopy local reading. To confirm eligibility at V2, only the V1 central reading will be made available to the site. 
In addition, at V2 the Investigator will perform the nasal endoscopy to confirm eligibility score. Thus, the participant is considered eligible based on a V1 central reading followed by a V2 local reading NPS score of 
5 or more and at least 2 each side. The final results of central reading from V2 onward will be made available to the site after the end of study. Nasal endoscopy can be repeated once per time point (for quality or 
safety issues). Nasal endoscopy can be repeated once during screening (at the latest 1 week before randomization) in case of not meeting eligibility criteria as per the Investigator discretion. 
i 
Hepatitis screening, comprising HBs Ag, hepatitis B surface antibody (HBs Ab); total HBc Ab; HCV Ab. In case of results showing HBs Ag (negative), HBs Ab (negative), and HBc Ab (positive), the hepatitis B virus 
(HBV) DNA testing will be performed prior to randomization to rule out a false positivity if the Investigator believes the participant is a false positive or to clarify the serological status if the Investigator finds it 
unclear to interpret in the absence of known HBV infection. In case of results showing HCV Ab (positive), the hepatitis C virus (HCV) RNA testing may be performed to rule out a false positivity. Human 
immunodeficiency virus screening: anti-HIV-1 and HIV-2 antibodies. Tuberculosis testing will be performed only on a country-by-country basis according to the routine clinical practice and the local guidelines if 
required by the Regulatory Authorities or Ethics Committees or if TB is suspected by the investigator. 
j 
During the intervention period, IMP will be administered at site after completion of all scheduled clinical assessments (including PROs) and blood sample collection. When operationally feasible and if treating 
physician determines that is appropriate and safe, administration of IMP at study participant’s home by qualified and trained healthcare professionals as well as direct to participant shipment may be arranged. 
These approaches will only be implemented if allowed by local regulations, approved labelling and agreed by the treating physician, while ensuring blinding measures are maintained.  
k Electronic diary/NPIF meter is used for daily recording of MFNS use, morning NPIF (daily), ADSD, and daily symptoms severity (CRSwNP Nasal Symptom Diary) from V1 to EOT. The CRSwNP Nasal Symptom 
Diary will measure: 1) nasal congestion/obstruction; 2) anterior rhinorrhea (runny nose); 3) posterior rhinorrhea (postnasal drip); and 4) loss of sense of smell, scored using a 0 to 3 categorical scale where 0 = no 
symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms. This device is dispensed at V1 and information is downloaded from this device on the other indicated days. Nasal 
congestion/blockade/obstruction and a weekly average severity greater than 1 at time of randomization (V2) is required and will be made available to the site to determine participant’s eligibility. If there are 4 or 
more measurements collected within 7 days prior to randomization, the baseline will be the average of these measurements; if less than 4 measurements are collected, the baseline will be the average of the most 
recent 4 prior to randomization.  
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l 
At V1 and V2 eligibility for surgery will be assessed based on the Investigator’s opinion. During the study intervention and follow-up period, if rescue medication with oral corticosteroids is required, oral prednisone 
or prednisolone will be dispensed by the site to the participant through a scheduled or unscheduled on-site visit. Use of oral steroids for rescue treatment of worsening NP or for another reason will be captured by 
the Investigator (or designee) on the appropriate page(s) of the eCRF and the date and dosing information (daily dose, duration, international nonproprietary name [INN]) will be informed. Details on actual or 
planned date for surgery for NP, type and outcome (whenever possible) of surgery will be recorded in a specific eCRF page. If surgery is performed during the study intervention period or follow-up, a TEAE or SAE 
page will be completed. Participants will be discontinued from study intervention and assessed as soon as possible using the procedures scheduled for the EOT visit. 
m During the study, for the visits during the Intervention Period electronic PRO will be completed by participant in the following order: CRSwNP Morning Diary, NPIF Morning Diary (completed by participant at home 
or after visit, between 04:00 in the morning and 12:30 in the afternoon), SNOT-22, Rhinosinusitis VAS, PGI-Control, PGI-Change, WPAI, ACQ-7, AQLQ, EQ-5D-5L (when participant at site), ADSD evening 
questionnaire (completed by participant at home daily between V1 and V2 and 30 days before the next confirmed visit, between 05:00 in the afternoon and before 11:59 in the evening). 
n Asthma Control Questionnaire-7 (ACQ-7): participants are asked to recall how their asthma has been during the previous week and to respond to the first 6 questions on a 7-point scale (0 = no impairment, 
6 = maximum impairment). Clinic staff will score the FEV1% predicted also on a 7-point scale. At screening visit, Asthma Control Questionnaire (ACQ-5) scores (sum of the responses to the first 5 questions) will 
be derived from ACQ-7. For the statistical analysis, centrally read values pre-bronchodilator FEV1 will be used.  
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2 
INTRODUCTION  
Dupilumab is a human mAb that binds specifically to the shared receptor component for IL-4 and 
IL-13, thus inhibiting the dual signaling pathways of IL-4 and IL-13, key and central drivers of 
type 2 inflammation in CRSwNP and other type 2 inflammatory diseases. 
Dupilumab is indicated for the treatment of AD patients aged six months and older, asthma 
in patients aged six years and older, CRSwNP in adult patients, eosinophilic esophagitis (EoE) 
in patients aged 12 years and older and prurigo nodularis (PN) in adult patients. 
Omalizumab is a recombinant deoxyribonucleic acid (DNA)-derived humanized mAb that 
selectively binds to human IgE. The antibody is an immunoglobulin G1 (IgG1) kappa that 
contains human framework regions with the complementary-determining regions of a murine 
parent antibody that binds to IgE. 
Omalizumab is approved in the EU and the US for the treatment of allergic asthma and CSU. 
In the US, omalizumab is approved for the treatment of nasal polyps, and in EU is approved for 
the treatment of CRSwNP. 
Despite the availability of several biologic therapies to treat asthma and CRSwNP, there is no 
evidence to compare the clinical efficacy of these treatments against each other given that no H2H 
studies have been conducted so far. Head-to-head studies are necessary to determine the best 
therapeutic option for a patient, and to support treating physicians in the decision-making process. 
Therefore, there is a data gap in providing direct comparative data for key clinical outcomes 
in CRSwNP and asthma. 
2.1 
STUDY RATIONALE  
Data from dupilumab and omalizumab CRSwNP pivotal studies suggest that dupilumab has 
the potential to demonstrate superiority compared to omalizumab in reducing the bilateral 
endoscopic NPS and the improving the sense of smell in participants with severe CRSwNP and 
comorbid asthma. 
Additionally, post-hoc results from the indirect treatment comparison (ITC) of dupilumab versus 
omalizumab in CRSwNP showed that dupilumab was associated with statistically significant 
improvements in NPS and the University of Pennsylvania Smell Identification Test (UPSIT) 
changes from baseline at Week 24 when comparing to omalizumab. Among additional key 
endpoints evaluated in this analysis, dupilumab was associated with statistically significant 
improvement in nasal congestion (NC)/obstruction score, loss of smell score, and total symptom 
score (TSS) at Week 24 when comparing to omalizumab. Dupilumab improvements over 
omalizumab were also demonstrated in NPS and NC score in the comorbid asthma population 
(40). 
With regards to asthma-related outcomes, the overall weight of evidence from asthma patients as 
well as patients with CRSwNP and comorbid asthma suggest that dupilumab treatment is 
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associated with greater improvements in pre-bronchodilator forced expiratory volume in 1 second 
(FEV1) than omalizumab. Dupilumab has consistently demonstrated clinically and statistically 
significant FEV1 improvements across populations while omalizumab FEV1 data is limited and 
often not clinically meaningful. 
Therefore, the purpose of this study is to evaluate whether the efficacy profile of dupilumab is 
superior compared to omalizumab in treating participants with severe CRSwNP and comorbid 
asthma. 
The study is designed to assess the superiority of dupilumab versus omalizumab in key clinical 
outcomes, potentially establishing dupilumab as the treatment of choice in the respiratory space 
across type 2 inflammatory diseases. 
2.2 
BACKGROUND  
Severe CRSwNP is a serious, chronic inflammatory disease, predominantly driven by type 2 
inflammation in at least 80% of patients (in western countries) and 50% (in Asian countries) (1). 
Chronic Rhinosinusitis with Nasal Polyps is characterized by bilateral nasal polyps and 
rhinosinusitis, which cause a range of persistent debilitating symptoms, including loss of smell, 
nasal obstruction/congestion, and nasal discharge (2, 3, 4). Chronic Rhinosinusitis with Nasal 
Polyps has an estimated prevalence of 2% to 4% in Europe and the US (4, 5) and is frequently 
associated with multiple type-2 coexisting diseases such as asthma, allergic rhinitis, and/or 
NSAID-ERD, which further contribute to greater disease severity and overall disease burden (6). 
In CRSwNP the type 2 inflammatory signature is characterized by the involvement of type 2 
cytokines interleukin-4 (IL-4)/IL-13 and IL-5 in its pathophysiology, and high levels of tissue IgE 
(7, 8, 9, 10, 11) or presence of coexisting diseases such as asthma, NSAID-ERD, allergic rhinitis, 
or AD (4, 12, 13, 14). 
Approximately 50% to 70% of patients with asthma (15, 16, 17, 18, 19, 20), have evidence of 
type 2 airway inflammation (10, 11, 12, 21), and up to 65% of CRSwNP patients have comorbid 
asthma.  
• In patients with asthma, type 2 inflammation is associated with poor asthma control, 
increased bronchial hyperresponsiveness, greater lung function impairment, and more 
frequent severe exacerbations compared with patients with a lower type 2 inflammatory 
signature.  
• In patients with CRSwNP, the presence of type 2 inflammation is associated with more 
severe disease, a greater risk for post-surgical recurrence, and a higher frequency of 
comorbid asthma. 
As stated above, a high proportion of patients with CRSwNP have comorbid asthma, which adds 
substantially to the overall disease burden, including greater disease severity of both CRSwNP 
and asthma leading to more frequent asthma exacerbations, higher rates of postsurgical polyp 
recurrence, greater cumulative SCS use, and an impaired HRQoL (22, 23, 24). As a result of 
the shared inflammatory pathway underpinning their pathophysiology, type 2 inflammatory 
airway diseases share several common clinical features, notably airway obstruction and/or 
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congestion, and excessive mucus production. Increased nasal sinus opacification (reduced upper 
airway volume) has been associated with evidence of type 2 inflammation (blood/tissue 
eosinophilia) in patients with CRSwNP (25, 26, 27, 28). 
First-line treatment options for CRSwNP comprises INCS and saline nasal irrigations to improve 
the symptoms of disease such as nasal obstruction (29) but INCS show little effect in reducing 
nasal polyp size and improving sense of smell, the most important symptoms reported by 
CRSwNP patients (30, 31). In addition, SCS is prescribed to decrease polyp size and symptom 
burden, but continuous treatment with SCS is not recommended and should be avoided due to 
the known serious systemic side effects - both short and long term (32). In some patients, medical 
management fails and therefore, FESS is indicated to improve sino-nasal symptoms (33). Surgical 
removal of nasal polyps does not specifically target the underlying type 2 inflammation (mediated 
by key type 2 cytokines IL-4, IL-13, and IL-5) in the sinuses, leading to high rates of recurrence 
and revision surgery, and may not restore the sense of smell in many patients (22, 34, 35, 36).  
Recent therapeutic approaches have been focused on the use of biologics in order to control the 
Th2 pathway with subsequent improvement of clinical signs in CRSwNP and associated 
comorbidities. Some biologics are currently approved for the treatment of this disease (dupilumab, 
omalizumab, and recently mepolizumab), while other biologics are in development 
(eg, benralizumab). 
Dupilumab 
Dupilumab is a fully human VelocImmune-derived mAb that inhibits signaling by IL-4 and IL-13, 
which both have an important role in the type 2 inflammation cascade (41, 42, 43). Dupilumab is 
directed against IL-4-Rα, a component of IL-4 receptors Type I and Type II. Type II receptor 
mediate signaling of both, IL-4 and IL-13, whereas Type I receptor just interact with IL-13. 
By binding to IL-4-Rα, dupilumab prevents the activation of IL-4 and IL-13 receptors by 
the respective cytokines. 
Several studies evaluated the impact of dupilumab on positive treatment outcome in patients with 
CRSwNP. In a proof-of-concept study (ACT12340), 60 patients with bilateral NP and chronic 
symptoms of sinusitis refractory to INCS were randomized to dupilumab 300 mg once weekly SC 
administration for 16 weeks or placebo, with background intranasal MFNS (Nasonex). In this 
study, dupilumab demonstrated significant improvement in endoscopic, radiographic and clinical 
measures of NP and sinusitis, as well as improvements in lung function and disease control 
in patients with comorbid asthma (44). Based on these data, the SINUS-24 (EFC14146) and 
SINUS-52 (EFC14280) trials were conducted. The current clinical studies demonstrated 
the robust efficacy of dupilumab in reducing the burden of all facets of CRSwNP disease 
including NPS, NC, and sinus inflammation, in restoring olfactory function, and in improving 
QoL. Dupilumab significantly reduced the proportion of patients requiring SCS and sino-nasal 
surgery. In patients with asthma, treatment with dupilumab improved lung function and asthma 
control. 
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Omalizumab 
Omalizumab interrupts the allergic cascade triggered by cross-linking IgE on the surface of mast 
cells and basophils. Reduction in surface-bound IgE on FcεRI-bearing cells limits the degree of 
release of mediators of the allergic response. Treatment with omalizumab (Xolair) also reduces 
the number of FcεRI receptors on basophils in atopic patients (45). 
The pivotal clinical program in CRSwNP consisted of 2 studies (POLYP 1 and POLYP 2) 
designed to determine the efficacy and safety of omalizumab (Xolair) compared with placebo 
in adult patients with CRSwNP who have had an inadequate response to intranasal corticosteroids. 
Both trials met the coprimary endpoints of change from baseline to Week 24 in average daily NC 
score and NPS. Participants in the studies were administered either omalizumab or placebo by SC 
injection every 2 to 4 weeks in addition to background intranasal corticosteroid (46). 
2.3 
BENEFIT/RISK ASSESSMENT  
2.3.1 Risk assessment  
The anticipated safety risks for dupilumab and omalizumab are outlined below. Please refer to 
dupilumab Investigator’s Brochure and omalizumab locally approved labels. 
Several measures will be taken to ensure the safety of participants enrolled in this study. 
Eligibility criteria have been designed to exclude participants at higher risk for toxicities. 
Participants will undergo safety monitoring during the study, including assessment of the nature, 
frequency, and severity of adverse events (AEs). In addition, guidelines for managing AEs, 
including criteria for treatment interruption or discontinuation are provided in the protocol 
(see Section 10.3 and Section 7.1). 
Dupilumab  
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 2022, 13 577 participants were 
enrolled into the development program for dupilumab and are included in the safety population. 
The number of participants exposed to dupilumab in clinical studies was 10 828 (538 in healthy 
volunteer studies, 4496 in AD [including hand and foot dermatitis] studies, 3591 in asthma 
studies, 526 in rhinosinusitis [CRSwNP, chronic rhinosinusitis without nasal polyposis and 
allergic fungal rhinosinusitis] studies, 405 in EoE studies, 175 in allergy [grass and peanut] 
studies, 748 in chronic obstructive pulmonary disease [COPD ] studies, 152 in PN studies, 
156 in the urticaria [CSU and chronic inducible cold urticaria] studies, 22 in the bullous 
pemphigoid study, and 19 in the allergic bronchopulmonary aspergillosis study). 
Based on the available sales figures and World Health Organization defined daily dose of 21.4 mg 
for parenteral formulations, the cumulative patient exposure in marketed experience could be 
estimated to be 706 212 patient years from 01 March 2017 through 31 March 2022. 
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Dupilumab was generally well tolerated in all populations tested in clinical development programs 
consistent with a favorable benefit/risk profile. The adverse drug reactions (ADR) identified to 
date for dupilumab include injection site reactions, conjunctivitis (including allergic and 
bacterial), oral herpes, herpes simplex, blepharitis, keratitis, dry eye, eye pruritus, arthralgia, 
eosinophilia, angioedema, anaphylactic reaction, and serum sickness. These ADRs were generally 
mild or moderate, transient, and manageable. These ADRs were not observed consistently in all 
indications (see Investigator’s Brochure for further details). More significant serious allergic 
reactions were very rare. Importantly, no increased overall infection risk was observed in patients 
treated with dupilumab. 
Based on the postmarketing safety data, events of angioedema, arthralgia, keratitis, ulcerative 
keratitis, and facial rash have been added as ADRs to the postmarketing section of the company 
core data sheet (CCDS). 
Systemic hypersensitivity is 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 trials.  
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 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 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 with these events has not been 
established. Therefore, health-care providers should be alerted to eosinophilia associated with 
vasculitic 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 reactions. Other potential risks based on 
the safety profile in particular indications are discussed in the Investigator’s Brochure. 
To date, the safety profile of dupilumab has been similar among adult and adolescent patients with 
asthma, AD, EoE, and PN and in adult patients with CRSwNP. While long-term data are still 
accumulating, data from randomized, placebo-controlled trials and open-label extension studies 
have not identified any new safety concern in these populations. 
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It is anticipated that dupilumab in patients with CRSwNP and comorbid asthma will have 
a favorable safety profile as observed across other type-2-driven immunological disorders. 
Omalizumab 
In the Phase 3 studies conducted in patients with CRSwNP, omalizumab was well tolerated, with 
no new or unexpected safety concerns identified in the pooled data. The most common AEs 
observed (headache, injection site reactions, arthralgia, dizziness, upper abdominal pain) have 
been previously reported with omalizumab (47, 48, 49). 
The safety profile of omalizumab is well established in patients with allergic asthma and chronic 
idiopathic urticaria (50), with a cumulative exposure of >16 000 patient-years in clinical trials and 
an estimated cumulative patient exposure of >1 300 000 patient-years to date in the postmarketing 
setting. 
In POLYP 1 and 2 studies, the proportion of patients who experienced ≥1 treatment emergent 
adverse event (TEAE) was 58.5% in placebo-treated patients and 50.4% in omalizumab-treated 
patients. Number of AEs was greater in placebo-treated versus omalizumab-treated patients. Most 
events across both studies were of mild-to-moderate intensity. Two serious adverse events (SAEs) 
were reported in placebo-treated patients (1.5%; myocardial infarction, n = 1; pneumonia, n = 1) 
and 3 in omalizumab-treated patients (2.2%; snake bite, n = 1; hand fracture, n = 1; asthma 
exacerbation/worsening, n = 1). The proportion of patients experiencing ≥1 AE suspected to be 
omalizumab related by the Investigator was 3.8% in placebo-treated patients and 6.7% 
in omalizumab-treated patients. These AEs were mild-to-moderate in intensity and most occurred 
within 24 hours of study drug administration. The most common adverse reactions (≥3% of 
patients) in clinical studies with adult patients included the following: headache, injection site 
reaction, arthralgia, upper abdominal pain, and dizziness. An episode of anaphylaxis, later 
adjudicated as not meeting Sampson’s criteria by an independent anaphylaxis adjudication 
committee, led to discontinuation in placebo-treated patients (46). Please refer to omalizumab 
label for further details (45, 51). 
2.3.2 Benefit assessment  
Dupilumab solution for injection is currently authorized: 
• In over 60 countries worldwide including the US, EU (Centralized Procedure), and Japan 
for the treatment of adults with inadequately controlled moderate-to-severe AD, in over 
60 countries for use in adolescent patients (≥12 years) with AD and in over 50 countries 
for use in pediatric patients (age 6-11 years) with AD. In the US dupilumab is also 
approved for pediatric patients of 6 months to <6 years of age.  
• In over 60 countries worldwide including the US, EU (Centralized Procedure), and Japan, 
as an add-on maintenance treatment for asthma in patients aged 12 years and older, 
dupilumab is approved for the treatment of children aged six years to <12 years with 
asthma in more than 30 countries and is currently under review for the treatment of asthma 
in this age group in multiple countries. 
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• In over 50 countries worldwide including the US for use in adults with inadequately 
controlled CRSwNP, the EU as an add-on therapy with intranasal corticosteroids for the 
treatment of adults with severe CRSwNP for whom therapy with SCS and/or surgery do 
not provide adequate disease control, Canada as an add-on maintenance treatment with 
intranasal corticosteroids in adult patients with severe CRSwNP inadequately controlled 
by SCS and/or surgery, and in Japan for use in adults with CRSwNP (only patients not 
adequately controlled with existing therapies). Review of this indication is ongoing 
in other countries worldwide.  
• In the US for the treatment of adult and pediatric patients, aged 12 years and older, 
weighing at least 40 kg, with EoE and is currently under review for this indication 
in multiple countries, including the EU. 
• In the US for the treatment of adult patients with PN and is currently under review for this 
indication in multiple countries, including the EU and Japan. 
The participants in this study may benefit from receiving a novel treatment for the underlying 
type 2 inflammatory disease process. Based on the efficacy results observed for both dupilumab 
and omalizumab, it is anticipated that the use of both IMP will lead to a reduction on signs and 
symptoms associated with CRSwNP and asthma.  
2.3.3 Benefit/risk assessment related to Coronavirus Disease 2019 (COVID-19)  
The Sponsor recognizes that the “Coronavirus Disease 2019” (COVID-19) pandemic is having 
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]).  
Currently, the Sponsor does not have sufficient data in patients with COVID-19 who are being 
treated with dupilumab. Thus, the safety and efficacy of dupilumab in patients with COVID-19 is 
unknown. There are no data regarding the incidence nor severity of patients with COVID-19 
receiving omalizumab (52). 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. 
2.3.4 Overall benefit: risk conclusion  
Dupilumab has shown clinically relevant benefits in several type-2-driven immunological 
disorders including AD, asthma, and CRSwNP. A satisfactory safety profile for dupilumab has 
been observed so far in completed and currently ongoing studies, as well as postmarketing 
experience. Omalizumab has also shown benefits in allergic asthma, CSU, and CRSwNP with 
a satisfactory safety profile observed to date. 
This study will give all enrolled participants an opportunity to receive a therapy which may 
improve both CRSwNP and asthma-related outcomes. Taking into account risk mitigation 
measures for study participants, the potential risks identified in association with dupilumab and 
omalizumab are justified by the anticipated benefits that may be afforded to participants with 
CRSwNP and comorbid asthma.  
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3 
OBJECTIVES AND ENDPOINTS 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
•
To evaluate the efficacy of dupilumab
compared to omalizumab in reducing the
polyp size and improving sense of smell
•
Change from baseline to Week 24 in Nasal Polyp Score (NPS)
•
Change from baseline to Week 24 in University of
Pennsylvania Smell Identification Test (UPSIT)
Secondary 
Key secondary objectives: 
•
To evaluate the efficacy of dupilumab in
improving chronic rhinosinusitis with
nasal polyps (CRSwNP) symptoms at
Week 24 compared to omalizumab
Key secondary endpoints: 
•
Change from baseline to Week 24 in the loss of smell score of
the CRSwNP Nasal Symptom Diary
•
Change from baseline to Week 24 in the nasal congestion
(NC) score of the CRSwNP Nasal Symptom Diary
Secondary objectives: 
•
To evaluate the efficacy of dupilumab in
improving CRSwNP total symptom score
(TSS) at Week 24 compared to
omalizumab
Secondary endpoints: 
•
Change from baseline to Week 24 in TSS derived from the
CRSwNP Nasal Symptom Diary
•
To evaluate the effect of dupilumab on
health related quality of life (HRQoL) at
Week 24 compared to omalizumab
•
Change from baseline to Week 24 in 22-Item Sino-nasal
Outcome Test (SNOT-22) total score
•
Change from baseline to Week 24 in SNOT-22 nasal domains
score
•
To evaluate the efficacy of dupilumab in
improving nasal peak inspiratory flow at
Week 24 compared to omalizumab
•
Change from baseline to Week 24 in Nasal Peak Inspiratory
Flow (NPIF)
•
To evaluate the effect of dupilumab on
CRSwNP overall disease severity at
Week 24 compared to omalizumab
•
Change from baseline to Week 24 in rhinosinusitis visual
analogue scale (VAS)
•
To evaluate the safety of dupilumab and
omalizumab
•
Incidence of treatment-emergent adverse events (TEAEs) and
serious adverse events (SAEs)
•
Incidence of adverse events of special interest (AESIs)
Tertiary/exploratory 
•
To evaluate the efficacy of dupilumab in
improving lung function at Week 24
compared to omalizumab
•
Change from baseline to Week 24 in pre-bronchodilator forced
expiratory volume in 1 second (FEV1)
•
To evaluate the effect of dupilumab on
asthma control at Week 24 compared to
omalizumab
•
Change from baseline to Week 24 in 7-item Asthma Control
Questionnaire (ACQ-7)
•
To evaluate the efficacy of dupilumab to
improve asthma outcomes including lung
function and patient reported outcomes
at Week 24 compared to omalizumab
•
Annualized rate of severe asthma exacerbations during the
24-week intervention period
•
Change from baseline to Week 24 in Asthma Quality of Life
Questionnaire (AQLQ)
•
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Objectives 
Endpoints 
• 
Change from baseline to Week 24 in FeNO 
• 
 
 
• 
 
 
• 
To evaluate the effect of dupilumab on 
additional HRQoL measures at Week 24 
compared to omalizumab 
• 
Change from baseline to Week 24 in SNOT-22 sleep and 
functional domains score 
• 
To evaluate the efficacy of dupilumab on 
improving health status at Weeks 24 
compared to baseline 
• 
 
 
• 
 
 
 
 
 
• 
 
• 
 
 
 
 
• 
 
 
 
 
 
 
• 
 
• 
 
• 
 
 
 
 
• 
 
 
 
 
• 
To evaluate the efficacy of dupilumab on 
productivity, health-care resource 
utilization (HCRU) and global impression 
of control/change at Week 24 compared 
to omalizumab 
• 
 
 
 
• 
 
  
• 
 
 
• 
 
 
• 
 
 
• 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
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Objectives 
Endpoints 
• 
 
 
 
• 
 
 
 
 
 
 
 
 
 
. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The efficacy assessments consist of clinical endpoints and patient-reported outcome (PRO) 
endpoints which are relevant for the management and monitoring of CRSwNP and asthma. 
See specific information on each measurement in Section 8.1. 
Endpoints for CRSwNP assessment include: 
• NPS 
• UPSIT 
• NC 
• Nasal Peak Inspiratory Flow (NPIF) 
• Rhinosinusitis Visual Analogue Scale (VAS) 
• TSS 
• Loss of smell 
• Sino-Nasal Outcome Test-22 (SNOT-22) 
• Patient Global Impression of Control (PGI-Control) 
• Patient Global Impression of Change (PGI-Change) 
• Investigator Global Assessment of Severity (IGA-Severity) 
• Investigator Global Assessment of Control (IGA-Control) 
• Investigator Global Assessment of Change (IGA-Change) 
• Work Productivity and Activity Impairment (WPAI) Questionnaire -CRSwNP. 
Endpoints for asthma assessment include: 
• Pre-bronchodilator FEV1 
• Forced vital capacity (FVC) 
• Forced expiratory flow (FEF) 25% to 75% 
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• Asthma Daytime Symptom Diary (ADSD)  
• Asthma Control Questionnaire-7 (ACQ-7) 
• Asthma Quality of Life Questionnaire (AQLQ) 
• Severe exacerbations. 
Generic endpoints include EuroQol Visual Analogue Scale (EQ VAS). 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 4, multicenter, parallel group, randomized (1:1), double-blind, active-controlled 
study to compare the efficacy of dupilumab with omalizumab over 24 weeks of treatment in 
adult participants with severe CRSwNP and comorbid asthma. 
Based on enrollment projections at the moment of sample size reduction, a minimum of 
320 participants (160 per group) will be randomized in a 1:1 ratio to receive either dupilumab or 
omalizumab. Randomization will be stratified by prior surgery, ICS doses (low versus 
medium/high dose ICS), presence of AERD and region (EE versus ROW). Based on the subgroup 
analysis from prior SINUS clinical trials, different treatment effects over placebo were observed 
in EE countries versus ROW, across a few endpoints of interest. Therefore, the stratification 
factor by region (EE versus ROW) is included. 
Study duration per participant will be 38 weeks. The study will comprise 3 periods: 
• Screening and run-in period (28±3 days): 
- 
Screening and run-in period: after Visit 1 (screening visit), once the eligibility for 
study entry has been confirmed, participant will enter a run-in period of 28 days to 
determine participant’s eligibility and for run-in/standardization of background INCS 
(MFNS) prior to randomization. All participants will receive MFNS, 2 actuations 
(50 μg/actuation) in each nostril BID (total daily dose of 400 μg), starting at Visit 1. 
If the participants are unable to tolerate the BID regimen or this dose (400 μg daily) is 
not approved in specific countries, they will follow a lower dose regimen of 200 μg 
QD. 
- 
Participant’s MFNS dose will be stabilized during the run-in period. 
- 
Participants should also be on a stable dose of low, medium or high dose ICS 
in combination with a second controller medication (eg, LABA, LTRA) ≥1 month 
prior to screening visit and during the screening and run-in period. 
- 
Participants who receive rescue medication including INCS drops or systemic (oral, 
IV, IM) steroids between Visit 1 and Visit 2 will not be randomized. However, they 
may be rescreened following the procedures described in the protocol. 
• Randomized IMP intervention period (24 weeks from baseline [Day 1, Visit 2]): 
- 
Participant will be randomized to receive dupilumab or omalizumab on Day 1. During 
the randomized intervention period, all participants will continue on the stable dose of 
intranasal MFNS as well as ICS. 
• Follow-up period: up to 12 weeks after the last IMP dose (Week 22) or until the 
participant switches to commercialized dupilumab/omalizumab (or other biologic 
product), whichever comes first. For the participants who switch to commercialized 
dupilumab/omalizumab (or other biologic product), the follow-up phone call visit should 
be performed prior to the first injection with commercialized dupilumab/omalizumab (or 
other biologic product). 
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During the study, participants who report deterioration and requiring medical/surgical intervention 
may come to the site for an endoscopy and clinical evaluation. An unscheduled visit may be 
considered for this purpose and if necessary, the Investigator may consider one of the treatment 
alternatives described in Section 6.5.3. If the date of surgery is scheduled after the planned EOS, 
the EOS will be postponed, and follow-up contact(s) may be required to document the surgery 
date and outcome. 
The schedule of the visits is described in the specific flow chart in Section 1.3. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The aim of this study is to demonstrate the superiority of dupilumab over omalizumab in 
improving key clinical endpoints and PRO endpoints in participants with severe CRSwNP and 
comorbid asthma. 
The 2 primary efficacy endpoints are change from baseline to Week 24 in bilateral endoscopic 
NPS (0 to 8 scale) as graded by the independent physician reviewer and change from baseline to 
Week 24 in UPSIT (0 to 40), administered and graded by blinded study Investigators. These 
endpoints provide both a subjective and objective assessment of efficacy in the target population. 
Secondary and exploratory endpoints will evaluate clinical outcomes, such as nasal and lung 
function, coupled with PROs, such as upper and lower airway respiratory symptoms. 
The 24-week randomized, double-blind period is considered relevant for the efficacy assessments 
and adequate to meet the study goal, since it is in line with the duration of omalizumab Phase 3 
studies (POLYP-1 and 2) as well as dupilumab phased 3 trial (SINUS-24) in CRSwNP, which 
demonstrated significant improvements in the endpoints examined at Week 24. Longer studies 
establishing the efficacy and safety profile of each biologic have already been conducted 
(eg, SINUS-52 and other long-term studies in asthma). 
The goal of this study is to demonstrate superiority of dupilumab over another biologic therapy, 
therefore an active-arm design versus omalizumab is appropriate. The study participants will be 
appropriately informed and will provide written consent to the eventuality of receiving either 
dupilumab or omalizumab during the randomized double-blind intervention period. They may 
withdraw from the study intervention or from the study at any time. In addition, a mitigation 
strategy will be implemented to limit the number of injections in each treatment arm. 
The safety follow-up period will be up to 12 weeks after the last IMP dose (Week 22) or until the 
participant switches to other biologics (including commercialized dupilumab and omalizumab), 
considering that after the last steady-state dose, the median time for dupilumab concentrations to 
decrease below the lower limit of detection, estimated by population pharmacokinetic (PK) 
analyses was 10 to 12 weeks for the 300 mg Q2W. 
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4.2.1 Participant input into design  
In collaboration with the patient advocacy group Allergy & Asthma Network in the USA, a 
patient experience survey was conducted on 61 patients with CRSwNP and comorbid asthma to 
assess different protocol design challenges related to medical procedures, treatment administration 
and PROs. The survey showed a high rate of acceptability on most of the study procedures. Only 
computed tomography scan assessments (originally planned) raised some concerns. These 
assessments were finally not considered for this study. Some recommendation was given to 
decrease patient burden. 
4.3 
JUSTIFICATION FOR DOSE  
The dose regimen for both IMPs will be according to the approved regulatory dose and posology 
in CRSwNP. 
The regulatory approved dose for dupilumab in adult participants with CRSwNP is 300 mg Q2W. 
This dose was evaluated in the pivotal CRSwNP trials and was safe and well tolerated with an 
overall positive benefit/risk profile for dupilumab in comparison to placebo. 
Omalizumab dosing and frequency depends on the participant’s baseline IgE levels and body 
weight, and ranges from 75 to 600 mg administered either Q2W or Q4W. This regimen was 
evaluated in the pivotal CRSwNP studies. 
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 post-treatment follow-up visit. 
The end of the study 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 at least 18 years (or the legal age of consent in the jurisdiction in which 
the study is taking place) of age inclusive, at the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Participants with bilateral sino-nasal polyposis, that despite prior treatment with SCS 
anytime within the past 2 years; and/or medical contraindication/intolerance to SCS; and/or 
prior surgery for NP have: 
• An endoscopic bilateral NPS of at least 5 out of a maximum score of 8 (with 
a minimum score of 2 in each nasal cavity) at Visit 1 (screening visit); 
Note: the participant is considered eligible based on a Visit 1 central reading followed 
by a Visit 2 local reading NPS score AND 
• Ongoing symptoms of NC/blockade/obstruction and loss of smell for at least 8 weeks 
before screening (Visit 1), AND  
• Nasal congestion/blockade/obstruction and a weekly average severity greater than 1 
in the 7 days before randomization (Visit 2), AND 
• Loss of smell symptom severity score 2 or 3 at screening (Visit 1) and a weekly 
average severity of greater than 1 in the 7 days before randomization (Visit 2). 
I 03. Participants with a physician diagnosis of asthma based on the Global Initiative for 
Asthma (GINA) 2020 (53) treated with low, medium or high dose ICS and a second 
controller (ie, LABA) A third controller is allowed but not mandatory. The dose regimen 
should be stable for at least 1 month before Visit 1 (screening visit) and during the 
screening and run-in period. 
I 04. Deleted in Amended protocol 02 
I 05. Asthma Control Questionnaire 5-question version (ACQ-5) score ≥1.5 at Visit 1 or 2. 
I 06. Treatment with intranasal mometasone ≥200 μg QD (or equivalent of another INCS) for 
1 month prior to Visit 1 and during the run-in period (for CRSwNP). 
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Weight  
I 07. Eligibility as per omalizumab drug-dosing table (serum IgE level ≥30 to ≤1500 IU/mL and 
body weight ≥30 to ≤150 kg) and ability to be dosed per the dosing table (see Figure 2). 
Sex 
I 08. Male and/or female 
Contraceptive use by female participants should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least one 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) during the 
intervention period and for at least 12 weeks after the last dose of the study 
intervention. 
- 
A WOCBP must have a negative highly sensitive serum pregnancy test at Visit 1 
(screening visit) and urine or serum pregnancy test (as required by the local 
regulations) on Day 1 before the first dose of study intervention. 
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test will be required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
• Additional requirements for pregnancy testing during and after study intervention are 
specified in Appendix 2 (Section 10.2). 
• The Investigator is responsible for reviewing the participant’s medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a female participant 
with an early undetected pregnancy. 
Informed Consent 
I 09. Capable of giving signed informed consent as described in Section 10.1 of the protocol 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. In countries where legal age of majority is above 
18 years, a specific ICF must also be signed by the participant’s legally authorized 
representative. 
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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. Participants who have undergone any sinus intranasal surgery (including polypectomy) 
within 6 months before Visit 1. 
E 02. Participants who have had a sino-nasal surgery changing the lateral wall structure of the 
nose, making impossible the evaluation of NPS. 
E 03. Participants with conditions/concomitant diseases making them non evaluable at Visit 1 or 
for the primary efficacy endpoint such as: 
• Antrochoanal polyps. 
• Nasal septal deviation that would occlude at least one nostril. 
• Acute sinusitis, nasal infection, or upper respiratory infection. 
• Ongoing rhinitis medicamentosa. 
• Known or suspected diagnosis of cystic fibrosis, primary ciliary dyskinesia 
(eg, Kartagener syndrome) or other dyskinetic ciliary syndromes, 
hypogammaglobulinemia or other immune deficiency syndrome, chronic 
granulomatous disease and granulomatous vasculitis, granulomatosis with polyangiitis 
(eg, Wegener’s Granulomatosis), eosinophilic granulomatous with polyangiitis 
(EGPA) or Allergic granulomatous angiitis (Churg-Strauss syndrome). 
• Radiologic suspicion or confirmed invasive or expansive fungal rhinosinusitis. 
E 04. Participants with nasal cavity malignant tumors and benign tumors (eg, papilloma, 
blood boil). 
E 05. Severe asthma exacerbation requiring treatment with SCS in the last 4 weeks prior to 
Visit 1 and during screening. 
E 06. 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, uncontrolled diabetes (hemoglobin A1c ≥9%), 
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), autoimmune diseases (eg, lupus, inflammatory bowel 
disease, rheumatoid arthritis), or other severe endocrinological, gastrointestinal, metabolic, 
pulmonary, psychiatric, or lymphatic diseases. The specific justification for participants 
excluded under this criterion will be noted in the study documents (chart notes, case report 
forms [CRFs], etc). 
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E 07. Participants with active tuberculosis (TB), non-tuberculous mycobacterial infection, or 
a history of incompletely treated TB will be excluded from the study unless it is well 
documented by a specialist that the participant has been adequately treated and can 
subsequently start treatment with a biologic agent, in the medical judgment of 
the Investigator and/or an infectious disease specialist. Tuberculosis testing will be 
performed on a country-by-country basis according to the routine clinical practice and 
the local guidelines if required by the regulatory authorities or ethics committees or if TB 
is suspected by the investigator. 
E 08. Diagnosed with, suspected of, or at high risk of endoparasitic infection, and/or use of 
antiparasitic drugs within 2 weeks before Visit 1 (screening visit) or during the screening 
and run-in period. 
E 09. History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at 
Visit 1 (screening visit). 
E 10. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antifungals, or receiving only symptomatic treatment (eg, influenza or COVID-19) within 
2 weeks before Visit 1 (screening visit) or during the screening and run-in period. 
E 11. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections (eg, TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, and 
aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal 
frequency or prolonged duration suggesting an immune compromised status, as judged by 
the Investigator. 
E 12. Active malignancy or history of malignancy within 5 years before Visit 1 (screening visit), 
except completely treated in situ carcinoma of the cervix and completely treated and 
resolved non metastatic squamous or basal cell carcinoma of the skin. 
E 13. History of systemic hypersensitivity or anaphylaxis to dupilumab and omalizumab, 
including any excipient. 
E 14. Recent history of myocardial infarction, unstable angina, cerebrovascular accident, 
transient ischemic attack, or a known history of a hypercoagulable disorder. 
E 15. History or clinical evidence of COPD or any other significant respiratory disease. 
E 16. Current smoker or cessation of smoking within 6 months prior to Visit 1.  
E 17. Known or suspected alcohol and/or drug abuse. 
E 18. Participants with any other medical or psychological condition including relevant 
laboratory or electrocardiogram (ECG) abnormalities at screening that, in the opinion of 
the Investigator, suggest a new and/or insufficiently understood disease, may present an 
unreasonable risk to the study participant as a result of his/her participation in this clinical 
trial, may make 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, eCRF, etc). 
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Prior/concomitant therapy 
E 19. Any biologic therapy (including dupilumab and omalizumab) or any 
immunosuppressant/immunomodulator within 4 weeks prior to Visit 1 or 5 half-lives, 
whichever is longer.  
E 20. Current participation to any clinical trial of an investigational drug or device or 
participation within 3 months before the screening visit or 5 half-lives of 
the investigational compound, whichever is longer.  
E 21. Participants who have taken leukotriene antagonists/modifiers within 4 weeks before 
Visit 1 (screening visit) or 5 half-lives, whichever is longer, unless the participant is on 
a continuous treatment for at least 4 weeks before Visit 1 (screening visit). 
E 22. Initiation of allergen immunotherapy within 3 months prior to Visit 1 (screening visit) or 
a plan to begin therapy or change its dose during the run-in period or the randomized 
intervention period. 
E 23. Treatment with a live (attenuated) vaccine (see Section 6.5.1 for examples of vaccine) 
within 4 weeks before Visit 1 (screening visit). 
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 
the vaccine can be postponed until after the EOS, or preponed to before the start of 
the study without compromising the health of the participant: 
- 
Participant 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 24. Either intravenous immunoglobulin (IVIG) therapy and/or plasmapheresis within 4 weeks 
before Visit 1 (screening visit). 
E 25. Planned or anticipated use of any prohibited medications and procedures during 
the screening and study intervention periods (see Section 6.5). 
Diagnostic assessments 
E 26. Participants with any of the following result at Visit 1 (screening visit): 
• Positive (or indeterminate) hepatitis B surface antigen (HBs Ag) or, 
• Positive total hepatitis B core antibody (HBc Ab) confirmed by positive hepatitis B 
virus (HBV) DNA or, 
• Positive hepatitis C virus antibody (HCV Ab) confirmed by positive hepatitis C virus 
(HCV) RNA. 
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Other exclusions 
E 27. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
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 who are employees of the clinical study site or other individuals directly 
involved in the conduct of the study, or immediate family members of such individuals 
(in conjunction with Section 1.61 of the International Council for Harmonisation 
[ICH]-Good Clinical Practice [GCP] Ordinance E6). 
E 30. Any specific situation during study implementation/course that may raise ethics 
considerations. 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
Participants should not eat or drink 1 hour prior to having the fractional exhaled nitric oxide 
(FeNO) levels measured, as this may affect the results. 
5.3.2 Activity  
Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to FeNO and 
FEV1 assessments. 
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. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure reasons, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) during 
the run-in period may be rescreened.  
The participants may be rescreened once during the open screening period. There is no 
requirement for a waiting period between the screen failure date and the rescreening date. 
Participants who are rescreened must sign a new consent form and all screening procedures must 
be repeated. A different participant identification number will be issued. The Interactive Web 
Response System (IWRS) report will flag rescreened participants.  
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Nasal endoscopy can be repeated once during screening (at the latest 1 week before 
randomization) in case of not meeting eligibility criteria as per the Investigator discretion.  
5.5 
CRITERIA FOR TEMPORARY DELAYING SCREENING/RANDOMIZATION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed 
in Appendix 9 (Section 10.9) should be considered for screening/randomization. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
All participants will randomly receive either dupilumab or omalizumab during the treatment 
period. In some cases, placebo injections may be used to preserve the blinding given 
the differences in dose regimens between dupilumab and omalizumab. 
Table 2 - Overview of study interventions administered  
ARM name 
Dupilumab 
Omalizumab 
Placebo of Dupilumab 
and Omalizumab 
Intervention name 
Dupilumab 300 mg 
Omalizumab 150 mg or 
Omalizumab 75 mg 
Placebo* 
Type  
Biological 
Biological 
Other 
Dose formulation 
Dupilumab 300 mg:  
A 150 mg/mL dupilumab 
solution in a prefilled 
syringe to deliver 300 mg 
in 2 mL 
Omalizumab 150 mg:  
A 150 mg/mL omalizumab solution 
in a prefilled syringe to deliver 
150 mg in a 1 mL injection 
 or 
Omalizumab 75 mg:  
A 150 mg/mL omalizumab solution 
in a prefilled syringe to deliver 
75 mg in a 0.5 mL injection 
Dupilumab placebo will be 
supplied as an identical 
formulation to the active 
formulation without 
dupilumab, in a prefilled 
syringe to deliver placebo 
2 mL  
Unit dose 
strength(s) 
300 mg 
150 mg or 75 mg 
0 mg 
Dosage level(s) 
One injection of 300 mg 
Q2W  
75 to 600 mg Q2W/Q4W 
according to the dosing table 
(see Figure 2) 
As needed to blind number of 
active dupilumab and 
omalizumab injections 
Route of 
administration 
Subcutaneous injection 
Subcutaneous injection 
Subcutaneous injection 
Use 
Experimental 
Active comparator 
Placebo (to blind the number 
of active dupilumab and 
omalizumab injections) 
IMP and NIMP 
IMP 
IMP 
IMP 
Packaging and 
labeling 
Each dose of dupilumab 
will be supplied as 1 glass 
prefilled syringe packed in 
a participant kit box. Both 
glass prefilled syringe and 
box will be labeled as 
Each dose of omalizumab will be 
supplied as 1 prefilled syringe 
packed in a participant kit box 
(commercial box). The commercial 
box will be labeled as required per 
country requirement 
Each dose of placebo will be 
supplied as 1 glass prefilled 
syringe packed in a 
participant kit box. Both glass 
prefilled syringe and box will 
be labeled as required per 
country requirement 
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ARM name 
Dupilumab 
Omalizumab 
Placebo of Dupilumab 
and Omalizumab 
required per country 
requirement 
Current name(s) or 
alias(es) 
Dupixent 
Xolair 
Not applicable 
IMP: investigational medicinal product; NIMP: noninvestigational medicinal product; Q2W: every 2 weeks; Q4W: every 4 weeks 
*An algorithm will be used to randomly lower the number of placebo injection in some cases for the participants randomized in the dupilumab arm  
Investigational medicinal Products 
The IMP will be administered every 14±3 days (Q2W) during the 24-week intervention period 
(with the last IMP administration at Week 22), as per the instruction provided in the pharmacy 
manual. 
The IMP will be administered at site following clinical procedures and blood collection. 
When operationally feasible and if treating physician determines that is appropriate and safe, 
administration of IMP at study participant’s home by qualified and trained healthcare 
professionals as well as direct to participant shipment may be arranged. These approaches will 
only be implemented if allowed by local regulations, approved labeling and agreed by the treating 
physician, while ensuring blinding measures are maintained. Participants should be monitored for 
at least 30 minutes. The monitoring period may be extended as per country-specific or local 
site-specific requirements. 
Subcutaneous injection sites should be alternated as per the instructions provided in the pharmacy 
manual.  
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: Contingency Measures for a regional or national emergency that is declared by 
a governmental agency (Section 10.9). 
Non investigational medicinal Product(s) 
Background therapies and rescue therapies will be supplied by the Sponsor’s local affiliate as 
locally required or by the sites. Reimbursement will be provided when deemed necessary and as 
per country regulation. 
Intranasal corticosteroid background therapy 
Throughout the study, the participant will use a diary to record daily use of MFNS 50 μg/actuation 
Nasal Spray, suspension. 
Before study entry, treatment with intranasal mometasone ≥200 μg QD or equivalent of another 
INCS is required for 1 month prior to Visit 1. After Visit 1 only MFNS is allowed for a better 
standardization of background medication. 
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Screening/Run-in period 
After Visit 1 (screening visit), once the eligibility for study entry has been confirmed, all 
participants will enter a run-in period of 28 days where they will receive MFNS: 
• Two actuations (50 μg/actuation) in each nostril BID (total daily dose of 400 μg) starting 
at Visit 1. If the participants are unable to tolerate the BID regimen or this dose is not 
approved in specific countries, they will follow a QD regimen (total daily dose of 200 μg). 
• Participant’s MFNS dose will be stabilized during the run-in period. 
Mometasone furoate nasal spray will be self-administered by the participant, and at each visit the 
Investigator must ensure that the participant has the necessary doses up to the next visit, knowing 
that one MFNS device (1 bottle) contains sufficient doses for either 2 weeks of BID 
treatment/regimen or 4 weeks of QD treatment/regimen. 
Participant who receive rescue medication including INCS drops or systemic (oral, IV, IM) 
steroids between Visit 1 and Visit 2 will not be randomized, but they can be rescreened. 
Randomized IMP intervention period 
During the randomized intervention period, all participants will continue on the stable dose of 
MFNS. 
Post-treatment period (ie, follow-up period) 
Upon completing the randomized intervention period (or following early discontinuation of IMP), 
participants can continue treatment with the stable dose of MFNS maintained over the randomized 
intervention period until the EOS, or modify treatment based on medical judgment. 
Asthma background therapy 
Screening/Run-in period 
Participants should be on a stable dose of low, medium or high dose ICS in combination with 
a second controller medication (eg, LABA, LTRA) ≥1 month prior to screening visit and during 
the screening and run-in period. 
Participants requiring a third controller for their asthma will be considered eligible for this study, 
also, at a stable dose ≥1 month prior to screening visit and during the screening and run-in period. 
• Formulation and route(s) of administration: as per label. 
• Dose regimen: as prescribed. 
Randomized IMP intervention period 
The asthma background therapy should be maintained on a stable dose during the study 
intervention period. 
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An asthma background therapy diary will be provided to collect information related to NIMP use.  
Post-treatment period (ie, follow-up period) 
Upon completing the randomized IMP intervention period (or following early discontinuation of 
IMP), participants can continue treatment with the stable dose of ICS maintained over the 
randomized intervention period until the EOS, or modify the treatment based on medical 
judgment. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 Storage and handling  
1. The Investigator or designee must confirm appropriate temperature conditions (dupilumab, 
omalizumab, and placebo to be maintained between +2°C to +8°C) have been maintained 
during transit for all IMP received and any discrepancies are reported and resolved before 
use of the IMP. 
2. Only participants enrolled in the study may receive IMP and only authorized healthcare 
professionals may supply or administer IMP. At the study site, 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 authorized 
unblinded site staff. 
3. The Investigator, institution, or the unblinded site staff (where applicable) is responsible 
for IMP accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, 
and final disposition records). 
6.2.2 Responsibilities  
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.7). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by 
the Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for 
direct-to-participant shipment, for which a courier company has been approved by the Sponsor), 
allow the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP 
in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
• The randomized intervention kit number list is generated centrally by Sanofi. The IMPs 
are packaged in accordance with this list. 
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• The randomization and intervention allocation are performed centrally by Interactive 
Response Technology (IRT). The IRT generates the participant randomization list and 
allocates the intervention number and the corresponding intervention kits to 
the participants according to it. Before the study is initiated, the log in information and 
directions for the IWRS will be provided to each site. 
• Participants will be randomized in a 1:1 ratio to dupilumab and omalizumab treatment 
arms. 
• Randomization will be stratified by prior surgery, ICS doses (low versus medium/high 
dose ICS), presence of AERD and region (EE versus ROW).  
• Participant’s dose and dosing frequency will be based on serum total IgE levels and body 
weight measured before starting study intervention (see Figure 2). 
• At Visit 1 (screening visit), the Investigator or designee will contact the IRT to receive 
the participant number. Participants who are rescreened are required to sign a new ICF. 
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. 
• IMP will be dispensed by an unblinded authorized personnel at the time points specified 
in the Schedule of Activities (SoA) (see Section 1.3).  
Methods of blinding 
• Dupilumab 300 mg (2 mL of solution for injection per prefilled syringe), omalizumab 
150 mg (1 mL of solution for injection per prefilled syringe), and omalizumab 75 mg 
(0.5 mL of solution for injection per prefilled syringe) prefilled syringes are visually 
different (for appearance and filled volume of solution). Dupilumab placebo (identical 
formulation to the active formulation without dupilumab) will be provided in the prefilled 
syringes of 2 mL solution to blind the number of active dupilumab or omalizumab 
injections between the IMP intervention groups. 
• Kits will be labeled with a treatment kit number. Treatment kits will not be blinded due to 
the different prefilled syringe characteristics, and different volume size (2 mL versus 1 mL 
versus 0.5 mL) of the dose level of omalizumab/dupilumab that will be used according 
different body weight and IgE levels. 
• Investigators will remain blinded to each participant’s assigned IMP group throughout the 
course of the study. In order to maintain this blind, unblinded study site personnel will be 
responsible for the dispensation and administration of IMPs and will endeavor to ensure 
that there are no differences in time taken to dispense following randomization. 
This third party will instruct the participant to avoid discussing the dosing frequency, or 
packaging of the IMP with the Investigator. 
• To minimize the risk of potential bias, the unblinded study site personnel who are 
responsible for reconstituting and/or administering study drug will not be permitted to 
conduct any safety or efficacy evaluations. Each center will identify an individual 
(eg, pharmacist) responsible for IMP administration procedures. This individual will 
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prepare the IMP for each participant prior to administration. An individual not involved 
with evaluating the participant must be identified to administer the IMP. 
• In the event of a Quality Assurance audit, the auditor(s) will be allowed access to 
unblinded study intervention records at the site(s) to verify that randomization/dispensing 
has been done accurately. 
• All participants will wear an eye sleep mask during IMP administration to minimize 
the risk of unblinding. 
• The following individuals/groups will be blinded to treatment assignment throughout 
the study: participants, the designated evaluating physician(s) and study nurses, the central 
image readers, and the Sponsor and Sponsor’s agents. The following are exceptions to 
the blinding: IWRS service provider, unblinded study site personnel, and bioanalytical 
laboratory personnel. To minimize risk of potential bias arising from access to laboratory 
results that could potentially unblind treatment assignments (eg, free IgE levels), access to 
these results will be restricted to the site and the Sponsor until study completion. 
Treatment assignment may be unblinded to the personnel analyzing the data from 
the intervention period when all data through Week 24 are in the database and the data 
have been cleaned and verified.  
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 IMP 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If the Investigator decides that unblinding is warranted, the Investigator should 
make every effort to contact the Sponsor prior to unblinding a participant’s IMP assignment 
unless this could delay emergency treatment of the participant. If a participant’s IMP 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 eCRF, as 
applicable. 
If the code is broken at the site level, the participant must withdraw from IMP administration. 
Sponsor safety staff may unblind the intervention assignment for any participant with an SAE for 
the purpose of expedited regulatory reporting (see Section 8.3.2). Sponsor staff involved 
in the conduct of the study will remain blinded to the participant intervention assignment. 
6.4 
STUDY INTERVENTION COMPLIANCE  
• When participants are dosed at the site, they will receive IMP directly from the unblinded 
site personnel. The date and time of each dose administered at the site will be recorded 
in the source documents and recorded in the eCRF. 
• Measures taken to ensure and document intervention compliance and accountability 
include: 
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- 
Proper recording of intervention kit number as required on appropriate eCRF page for 
accounting purposes. 
- 
The unblinded site personnel tracks intervention accountability/compliance, by 
counting the number of used intervention kits and fills in the appropriate page 
(Intervention Log Form). 
- 
The Investigator or his/her delegate records the dosing information on the appropriate 
page(s) of the eCRF (record kit number and injection site). 
- 
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. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest) 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. 
The Sponsor Representative should be contacted if there are any questions regarding concomitant 
or prior therapy. 
6.5.1 Prohibited medications  
The following concomitant treatments are not permitted during the screening, run-in, and 
the randomized intervention periods: 
• Any systemic immunosuppressive treatment including but not limited to methotrexate, 
cyclosporine, mycophenolate, tacrolimus, gold, penicillamine, sulfasalazine, 
hydroxychloroquine, azathioprine, and cyclophosphamide. 
• Allergen immunotherapy (except if initiated more than 3 months prior to Visit 1 and dose 
stable 1 month prior to Visit 1). 
• Intranasal corticosteroid drops; intranasal steroid emitting devices/stents; and nasal spray 
using Exhalation Delivery System such as Xhance. 
• Long term courses (>2 weeks) of SCS. Systemic corticosteroids can only be used to treat 
severe asthma exacerbation and are not allowed to be used for other conditions from 
1 month or at least 5 half-lives prior to Visit 1, whichever is longer, or during the 
screening and run-in period or the randomized intervention period. 
• Short term courses (≤2 weeks) of SCS (oral or parenteral) are prohibited only between 
Visit 1 and Visit 2 and they are allowed as rescue treatment after Visit 2. 
• Live, attenuated vaccines. Examples include, but are not limited to Bacillus 
Calmette-Guérin (BCG), chickenpox (varicella), FluMist-influenza, intranasal influenza, 
measles (rubeola), measles-mumps-rubella (MMR) combination, 
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measles-mumps-rubella-varicella (MMRV) combination, mumps, oral polio (Sabin), oral 
typhoid, rotavirus, rubella, smallpox (vaccinia), varicella zoster (shingles), and yellow fever. 
• Bronchial thermoplasty. 
• IVIG therapy. 
• Beta-adrenergic receptor blockers (except for a selective beta-1 adrenergic receptor 
blocker used with dose stabled 1 month prior to Visit 1). 
• Use of asthma relievers other than salbutamol/albuterol or levosalbutamol/levalbuterol is 
not recommended during the study period. In case of use in exceptional circumstances 
(eg, prescribed by a physician not participating in the study), it will be documented 
in the participant's file and reported in the eCRF. 
• Other investigational drugs. 
• Other mAbs (biological immunomodulators), including but not limited to anti-IL-5 and 
anti- tumor necrosis factor, etc. 
• During the screening period, the following treatments for chronic rhinosinusitis (CRS) are 
not allowed: antifungals, and antibiotics. 
Participants who receive any of the prohibited treatments, or are treated with systemic (oral, IV, or 
IM) corticosteroids, or undergo surgery between Visit 1 and Visit 2 will not be randomized. 
However, they may be rescreened following the procedures described in the protocol. 
6.5.2 Permitted concomitant medication  
The following treatments are allowed: 
• MFNS during the run-in period and throughout the whole study. 
• Intranasal normal saline. 
• Single topical decongestants administration (eg, oxymetazoline hydrochloride to reduce 
the swelling and widen the path for the endoscope), as well as a topical anesthetic 
(eg, lidocaine are allowed before endoscopy). 
• Administration of antibiotics for a concurrent infection is allowed during the study except 
during screening period (reason for and duration of treatment should be documented 
in the eCRF). 
• Short-acting beta-2 agonists (SABA), LABA, and long-acting muscarinic antagonists 
(LAMA). Nebulizer solutions maybe used as an alternative delivery method. 
• Methylxanthines (eg, theophylline, aminophylline).  
• ICS. 
• Systemic antihistamines.  
• Leukotriene antagonists/modifiers are permitted during the study, only for participants 
who were on a continuous treatment for ≥30 days prior to Visit 1. 
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• Allergen immunotherapy in place for ≥3 months and dose stable for 1 month prior to 
Visit 1 is permitted. 
• SCS (to treat severe asthma exacerbation or in case of CRSwNP worsening). 
6.5.3 Rescue medicine for CRSwNP  
The following rescue medications may be used: 
1. Nasal lavage with saline and/or systemic antibiotics (up to 2 weeks in case of acute 
infection). 
2. Short course SCS (prednisone or prednisolone up to 2 weeks). 
3. Sino-nasal surgery for NP. 
Participants receiving rescue treatment other than surgery during the study should continue on 
study drug unless the Investigator decides to withdraw the study intervention. Before starting 
treatment with SCS, participants should come to the study site for the clinical assessments 
including endoscopy and PROs. 
For participants who undergo or are planned for surgery for NP, the Investigator may decide to 
continue the IMP up to the time of surgery or end of treatment (EOT), whichever comes first. 
At the time of surgery participants will be permanently discontinued from the IMP and assessed 
as soon as possible using the procedures scheduled for the EOT visit. 
6.5.3.1 Rescue medications for asthma  
Short-acting beta-2 agonists (SABA) may be used as rescue medication during the study if 
needed. Nebulizer solutions maybe used as an alternative delivery method. Systemic 
corticosteroids are also allowed after Visit 2 to treat severe exacerbations. 
The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations will be recorded 
daily by the participants in a diary/peak expiratory flow meter. Each participant should be 
reminded that salbutamol/albuterol or levosalbutamol/levalbuterol should be used only as needed 
for symptoms, not on a regular basis or prophylactically. 
6.6 
DOSE MODIFICATION  
No dose modification is allowed during the conduct of the study. Omalizumab should be 
discontinued in participants who experience a severe hypersensitivity reaction. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
Sponsor will not be responsible for intervention after the EOS. Intervention after the EOS will be 
at the discretion of 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 (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, 
the participant will remain in the study to be evaluated for efficacy and safety. See the SoA 
(Section 1.3) for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
Discontinuation of study intervention for abnormal liver function should be considered by 
the Investigator when a participant meets the condition outlined in the algorithm “increase of 
alanine aminotransferase (ALT)” (Appendix 6, Section 10.6) or if the Investigator believes that it 
is in best interest of the participant.  
Regular monitoring of liver function is not required in this study since no safety concerns with 
respect to hepatobiliary disorders have been identified with dupilumab/omalizumab treatment. 
(Appendix 6, Section 10.6) provides adequate guidance on the management of elevated ALT, 
in a proactive manner in order to support participating investigators should any events be reported 
during routine clinical care. 
Participants must be permanently withdrawn from the IMP for the following reasons:  
• At their own request or at the request of their legally authorized representative (legally 
authorized representative is considered to be an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective participant to the 
participant’s participation in the procedure 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.  
• If the participant misses 2 consecutive IMP doses. 
• In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor.  
• If the randomization code is broken at the request of the Investigator.  
• Pregnancy. 
• Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (see Section 10.10).  
• Diagnosis of a malignancy during the 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).  
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• Serum ALT >3 × upper limit of normal (ULN) and total bilirubin >2 × ULN 
(see Section 10.6).  
• Serum ALT >5 × ULN if baseline ALT ≤2 ×ULN, or ALT >8 × ULN if baseline 
ALT >2 × ULN (see Section 10.6). 
If a clinically significant finding is identified after enrollment, the Investigator or qualified 
designee will determine if the participant can continue in the study and if any change 
in participant management is needed. Any new clinically relevant finding should be reported as 
an AE. 
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. 
Handling of participants after definitive intervention discontinuation 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
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.  
Participants will be followed up according to the study procedures specified in this protocol up to 
the scheduled date of EOT visit, or up to recovery or stabilization of any AE to be followed up as 
specified in this protocol, whichever comes last. 
For participants who discontinue the study intervention prematurely (prior to completing the 
24-week intervention period), the early study discontinuation (ESD) visit will be performed as 
soon as possible with all the assessments scheduled for the EOT visit, to assure a complete 
clinical assessment in close temporal proximity to the premature termination of study intervention 
is available. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure scheduled for the last dosing day with the IMP. 
Under exceptional circumstances when a participant cannot come to the site for a scheduled visit, 
a phone contact can be made. During the phone contact, at least information about AEs, 
concomitant medication, and the status of CRSwNP should be collected. 
All cases of definitive intervention discontinuation must be recorded by the Investigator 
in the appropriate pages of the eCRF when considered as confirmed. 
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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 a regional or national emergency declared 
by a governmental agency (Appendix 9: Contingency Measures for a regional or national 
emergency that is declared by a governmental agency, Section 10.9). For all temporary 
intervention discontinuations, duration should be recorded by the Investigator in the appropriate 
pages of the eCRF.  
Temporary intervention discontinuation decided by the Investigator corresponds to at least 1 dose 
not administered to the participant. Following a temporary interruption or missed dose, the 
treatment should be reinitiated at the next scheduled administration, maintaining the planned dose. 
If 2 consecutive IMP doses have been missed, the study intervention will be definitively 
discontinued (see Section 7.1.1). Investigator must contact the participant to instruct not to take 
any subsequent injection. 
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 in the occurrence of the concerned 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: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency (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, as shown in the SoA. See SoA (Section 1.3) for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
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• All study withdrawals should be recorded by the Investigator in the appropriate screens of 
the eCRF and in the participant’s medical records. In the medical record, at least the date 
of the withdrawal and the reason should be documented. 
• In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of 
consent for follow-up visits and from withdrawal of consent for non-participant contact 
follow-up, eg, medical record checks. The site should document any case of withdrawal of 
consent. 
• Participants who have withdrawn from the study cannot be rerandomized 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 site for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue 
in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• If a participant continues 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). 
• Patient-reported outcome questionnaires should be completed by the participants before 
the consultation and/or clinical tests in a quiet place (at home in electronic PRO/electronic 
device [eDevice] and at study site). 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. Participants will 
be instructed on the use of the eDevice and eDiary. During the study, the PROs should be 
completed by the participant in the electronic PRO device before seeing the physician, 
electronic PRO will be completed by participant in the following order for the visits during 
Intervention Period: CRSwNP Morning Diary, NPIF Morning Diary (completed by 
participant at home or after visit, between 04:00 in the morning and 12:30 
in the afternoon); SNOT-22, Rhinosinusitis VAS, PGI-Control, PGI-Change, WPAI, 
ACQ-7, AQLQ, EuroQol-5 dimensions 5 Level (EQ-5D-5L ) (when participant at site), 
ADSD evening questionnaire (completed by participant at home daily between V1 and V2 
and 30 days before the next confirmed visit, between 05:00 in the afternoon and before 
11:59 in the evening). 
• The total volume of blood required for all assessments as per protocol is expected to be 
within the recommended safe limit for human in clinical trials by the local Institutional 
Review Boards (IRBs) and Ethics Committees. 
• For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Appendix 9: Contingency Measures for a regional or national 
emergency that is declared by a governmental agency (Section 10.9). 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 Nasal polyp score  
The NPS (54, 55) is assessed by central video recordings of nasal endoscopy. The score (NPS) is 
the sum of the right and left nostril scores, as evaluated by means of nasal endoscopy. The NP is 
graded based on polyp size described in Table 3. 
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Table 3 - Endoscopic nasal polyp score  
Polyp Score 
Polyp Size 
0 
No polyps 
1 
Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate 
2 
Polyps reaching below the lower border of the middle turbinate  
3 
Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate 
4 
Large polyps causing complete obstruction of the inferior nasal cavity 
Nasal endoscopy should be performed after all other efficacy assessments have been completed 
and before the administration of IMP. It must be preceded by local administration of anesthetic 
drugs in combination with a decongestant.  
Standard video sequences will be downloaded and sent to centralized reader. Centralized imaging 
data assessments and scoring by independent physician reviewer(s) for the imaging data will be 
performed for all endoscopies. To confirm eligibility at Visit 2, only the Visit 1 central reading 
will be made available to the site. In addition, at Visit 2 the Investigator will perform the nasal 
endoscopy to confirm eligibility score. Thus, the participant is considered eligible based on 
a Visit 1 central reading followed by a Visit 2 local reading NPS score of 5 or more and at least 2 
each side. The final results of central reading from Visit 2 onward will be made available to 
the site after the EOS. 
Nasal endoscopy can be repeated once per time point (for quality or safety issues). Nasal 
endoscopy can be repeated once during screening (at the latest 1 week before randomization) 
in case of not meeting eligibility criteria as per the Investigator discretion. 
For the analysis of primary endpoint, central reading of Visit 2 will be used for comparison with 
Week 24 reading. The sites will remove participant-identifying information from the imaging data 
header prior to sending the imaging data to the central reader.  
Nasal endoscopy will be performed at the time points specified in the SoA (see Section 1.3). 
8.1.2 University of Pennsylvania Smell Identification Test (UPSIT)  
The UPSIT (UPSIT 40 odorant test) is a rapid and easy-to-administer method to quantitatively 
assess human olfactory function. The UPSIT shows a high test-retest reliability (r: 0.981) and 
scores on this test are strongly correlated with the detection threshold for phenyl ethyl alcohol 
in the same individuals. When the UPSIT is administered in the standardized manner, clinical 
subjects show a high degree of uniformity in UPSIT performance when tested in different 
laboratories. 
The test consists of 4 booklets, each containing 10 odorants with 1 odorant per page. The test-time 
is about 15 minutes. The stimuli are embedded in 10 to 50 (mu) diameter plastic microcapsules on 
brown strips at the bottom of each page. Above each odorant strip is a multiple choice question 
with 4 alternative words to describe the odor. The participant will be asked to release the odorant 
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by rubbing the brown-strip with the tip of a pencil and to indicate which of 4 words best describes 
the odor. Thus, each participant receives a score out of 40 possible correct answers. The final 
score will be recorded in the eCRF. The odorants of the UPSIT test utilized in this study will 
consider the cultural differences. 
The 40-odorant UPSIT is used in over 1500 clinics and laboratories throughout the US, Canada, 
South America, and Europe, and has been administered to nearly 200 000 people since its 
development in the early 1980s. A particular strength of this test is that it provides an olfactory 
diagnosis based on comparing the participant test score with normative data, providing 
a percentile score of an individual relative to his or her age-matched normal group. Furthermore, 
a clinician can distinguish participants with a normal sense of smell ("normosmia") from those 
with different levels of reduction ("mild, moderate, and severe microsmia") or loss ("anosmia") 
(56).  
The Investigator will administer, score, and complete the UPSIT at the time points specified in 
the SoA (see Section 1.3). 
8.1.3 Nasal Peak Inspiratory Flow (NPIF)  
Nasal peak inspiratory flow evaluation represents a physiologic measure of the air flow through 
both nasal cavities during forced inspiration expressed in liters per minute. The NPIF is the best 
validated technique for the evaluation of nasal flow through the nose. Nasal inspiration correlates 
most with the subjective feeling of obstruction and is the best validated technique for monitoring 
nasal flow in clinical trials. 
At Visit 1 participants will be issued an NPIF meter for recording morning (AM) NPIF. 
Participants will be instructed on the use of the device, and written instructions on the use of 
the NPIF meter will be provided to the participants. In addition, the Investigator will instruct 
the participants on how to record the following variables in the eDiary. 
• Morning (AM) NPIF will be performed within 15 minutes after arising (before 12 noon) 
prior to taking MFNS. 
Three NPIF efforts will be performed by the participant; all 3 values will be recorded by 
the participant in the eDiary, and the highest value will be used for evaluation. The procedure 
takes about 5 minutes. 
Baseline morning (AM) NPIF will be the mean AM measurement recorded for the 7 days prior to 
the first dose of IMP. If less than 4 measurements are collected during the 7 days, the average of 
the most recent 4 prior to randomization during the run-in period will serve as the baseline. 
The nasal flow is expressed in liter per minute, and consecutive measurements are performed. 
Taking the best of 3 outcomes with less than 10% variation is considered to be the best means of 
expression of the result (56). 
Participants will record the NPIF values in the eDiary at the time points specified in the SoA 
(see Section 1.3). 
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8.1.4 Spirometry  
A spirometer that meets the 2005 American Thoracic Society (ATS)/European Respiratory 
Society (ERS) (57) recommendations will be used. Spirometry should be performed in accordance 
with these recommendations. 
Spirometry will be performed before IMP administration and after withholding the standard of 
care asthma treatment as described in Table 4. Forced expiratory volume in 1 second, FVC, and 
FEF at 25% to 75% of forced vital capacity (FEF 25-75) will be determined at the designated 
treatment visits. 
Table 4 - Washout period of asthma controllers and rescue medication before lung function 
assessments  
Drug/Medication name 
Washout period 
Oral Xanthine derivatives 
72 hours 
Long-acting beta agonists (LABA) (eg, salmeterol) 
24 hours 
Long-acting muscarinic antagonist (LAMA) (eg, Tiotropium) 
48 hours 
Inhaled corticosteroids (ICS)/LABA 
24 hours 
Ultralong ICS/LABA combinations 
48 hours 
Inhaled and/or nebulized short-acting beta-2 agonists 
(SABAs) (eg, salbutamol) 
6 hours 
Inhaled and/or nebulized short-acting muscarinic antagonist 
(SAMA) (eg, ipratropium) 
8 hours 
SABA/SAMA combination 
8 hours 
Inhaled and/or nebulized corticosteroids 
12 hours 
At all specified visits (as per SoA, Section 1.3), spirometry should be performed before IMP 
administration, in the morning, if possible. The spirometer provided by the service provider 
should be used and standard spirometric techniques, including calibration, will be used to perform 
spirometry at all specified visits and, whenever possible, the same person should perform 
the measurements. Afternoon/evening is allowable in the exceptional circumstance when morning 
spirometry cannot be performed. Spirometry should be done at approximately the same time 
at each specified visit (as per SoA [Section 1.3]) throughout the study. 
Pulmonary function tests will be measured in the sitting position if possible. If the testing was 
made with the participant in another position, this should be noted in the spirometry report. 
For any participant, the position should be consistent throughout the study. 
Three measurements fulfilling the ATS acceptability and repeatability criteria should be obtained 
at each specified visit. The acceptability criteria must be applied before the repeatability criteria. 
Unacceptable maneuvers must be discarded before applying the repeatability criteria. If a 
participant fails to provide repeatable maneuvers, an explanation should be recorded in the eCRF. 
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At least 2 acceptable curves must be obtained. 
The largest FEV1 should be recorded after the data from all of the acceptable curves have been 
examined, even if they do not come from the same curve. 
The spirometer must be calibrated following the principles of the ATS/ERS guidelines prior to 
spirometry. The calibration records should be kept in a reviewable log. It is preferred that 
the equipment that is used to calibrate the spirometer (ie, 3 L syringe) be subjected to a validated 
calibration according to the manufacturer’s specifications. 
8.1.5 Severe asthma exacerbation  
A severe exacerbation event during the study is defined as a deterioration of asthma requiring:  
• Use of SCS for ≥3 days; or  
• Hospitalization or emergency room visit because of asthma, requiring SCS.  
8.1.6 Patient-reported outcome (PRO) questionnaires  
8.1.6.1 CRSwNP nasal symptom diary including nasal congestion/obstruction, loss of 
smell, and total symptom score  
The Nasal Symptom Diary is designed to assess the severity of CRS nasal symptoms on a daily 
basis. These symptoms include NC/obstruction, loss of smell, anterior rhinorrhea, and posterior 
rhinorrhea (2). Each of the individual items of the diary are scored from 0 (“No symptoms”) 
to 3 (“Severe symptoms - symptoms that are hard to tolerate, cause interference with activities, or 
daily living”). Higher scores on the items of the individual symptoms denote greater symptom 
severity (see Table 5).  
The TSS is a composite score (ranging between 0 and 9) consisting of the sum of the following 
symptoms assessed daily in the morning: NC/obstruction, decreased/loss of sense of smell, and 
rhinorrhea (average of anterior/posterior nasal discharge). Higher scores on the TSS indicate 
greater symptom severity. 
Table 5 - Nasal symptom score  
Response scale 
Response choices 
0 
No symptoms 
1 
Mild symptoms (symptoms clearly present, but minimal awareness and 
easily tolerated) 
2 
Moderate symptoms (definite awareness of symptoms that is bothersome 
but tolerable) 
3 
Severe symptoms (symptoms that are hard to tolerate, cause interference 
with activities or daily living) 
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The psychometric properties of NC as an individual item, including validity, reliability and ability 
to detect changes have been demonstrated in adult participants with CRSwNP. Within-person 
(responder definition) meaningful threshold has been determined in the CRSwNP population as 
follows: -0.48 to -1.14 for NC, -0.88 to -1.00 for loss of smell, and -1.15 to -3.60 for TSS. 
The electronic PRO collected in an eDevice is used for daily recording of participant’s answers to 
the questionnaires. This eDevice will be dispensed at Visit 1 (screening visit), including 
instructions for use. Participants will be instructed on the use of the eDevice. Recorded 
information will be downloaded from this device daily. At EOT visit, the eDevice will be 
downloaded and returned to the site. On a regular basis, the site staff should review on the 
vendor’s website the information downloaded from participants’ eDevice. They should 
particularly check status of the disease reviewing as well as compliance to background/rescue 
therapy and overall electronic PRO compliance. The site should follow-up with the participant as 
appropriate.  
The CRSwNP Nasal Symptom Diary will be administered electronically. Participants will 
complete the Nasal Symptom Diary at the time points specified in the SoA (Section 1.3). 
8.1.6.2 Sino-Nasal Outcome Test-22-Items (SNOT-22)  
The SNOT-22 is a PRO questionnaire designed to assess the impact of CRS on patients’ HRQoL 
(58). The SNOT-22 has 22 items covering symptoms, social/emotional impact, productivity, and 
sleep consequences of CRS. The recall period is past 2 weeks. Each item is rated on a 6-point 
Likert scale response option, ranging from 0 (‘No problem’) to 5 (‘Problem as bad as it can be’). 
A global score ranging from 0 to 110 is calculated by summing the responses to all items; higher 
score indicates greater rhinosinusitis-related health burden. The questionnaire is an easy, valid, 
and reliable tool. The minimally important difference that is the smallest change in SNOT-22 
score that can be detected by a participant was found to be 8.9 points (58). The SNOT-22 is 
categorized into 5 domains, these include: Nasal (Items 1, 2, 3, 4, 5, 6, 7, and 12); Ear/Facial 
(Items 8, 9, 10, and 11); Sleep (Items 13, 14, 15, and 16); Function (Items 17, 18, and 19); 
Emotion (Items 20, 21, and 22). The score of each domain is the sum of response to each question 
in that domain. 
Participants will complete the SNOT-22 at the time points specified in the SoA (Section 1.3). 
8.1.6.3 Rhinosinusitis Severity Visual Analogue Scale (rhinosinusitis VAS)  
The rhinosinusitis severity VAS is used to evaluate the overall severity of the rhinosinusitis. It is a 
recommended scale to determine the patient’s disease severity and to guide the treatment for CRS. 
The participant is asked to answer the following question: “How troublesome are your symptoms 
of your rhinosinusitis” on a 10 cm VAS from 0 (‘not troublesome’) to 10 (‘worst thinkable 
troublesome’). Based on their score on the VAS, the severity of rhinosinusitis can be divided into 
3 categories as follows: 
• Mild = VAS 0 to 3  
• Moderate = VAS >3 to 7 
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• Severe = VAS >7 to 10 
Participants will complete the rhinosinusitis severity VAS at the time points specified in the SoA 
(Section 1.3). 
8.1.6.4 Asthma Daytime Symptom Diary (ADSD)  
The ADSD is a PRO measure developed by the PRO Consortium’ Asthma Working Group. Both 
instruments have been designed to measure asthma symptoms in adult and adolescent (12 years of 
age and older) patients diagnosed with mild to severe asthma. The ADSD assesses asthma 
severity based on patient self-report of asthma core symptoms, ie, difficulty breathing; wheezing; 
shortness of breath; chest tightness; chest pain; and cough. Participants are asked to complete 
the ADSD every night before they go to bed, thinking about their asthma symptoms today, from 
when they got up this morning until now. 
It has demonstrated adequate evidence of content validity and cross-sectional measurement 
properties in asthma patients (ie, internal consistency reliability, test-retest reliability, convergent 
validity, and known-groups validity) to measure symptoms of asthma. It is composed of 6 items 
rated using an 11-point numeric rating scale that ranges from 0 = None to 10 = As bad as you can 
imagine. 
Participants will record their daytime asthma symptoms in an eDiary, once in the evening. 
Participants will complete the ADSD at the time points specified in the SoA (see Section 1.3). 
8.1.6.5 Work Productivity and Activity Impairment Questionnaire: Chronic Rhinosinusitis 
Version 2.0  
The WPAI Questionnaire is designed to assess the impact of a disease on patient’s productivity 
(59). The WPAI is a 6-item, validated questionnaire to measure impairments in work and 
activities over a 7-day recall period, and yields 4 types of scores:  
1. Absenteeism (work time missed) 
2. Presenteeism (impairment at work/reduced on-the-job effectiveness) 
3. Work productivity loss (overall work impairment/absenteeism plus presenteeism) 
4. Activity Impairment. 
The WPAI Specific Health Problem version 2.0 will be used; the term “Problem” in the questions 
will be replaced by chronic rhinosinusitis (WPAI-chronic rhinosinusitis).  
The WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity.  
Participants will complete the WPAI-chronic rhinosinusitis in an eDiary at the time points 
specified in the SoA (see Section 1.3). 
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8.1.6.6 Asthma Control Questionnaire 7-item version (ACQ-7)  
The ACQ was designed to measure both the adequacy of asthma control and change in asthma 
control which occurs either spontaneously or as a result of treatment (60).  
The ACQ-7 has 7 questions, with the first 5 items assessing the most common asthma symptoms: 
1. Frequency in past week awoken by asthma during the night 
2. Severity of asthma symptoms in the morning 
3. Limitation of daily activities due to asthma 
4. Shortness of breath due to asthma 
5. Frequency of wheezing  
Plus short-acting bronchodilator use and FEV1 (pre-bronchodilator use, % and % predicted use). 
The participants are asked to recall how their asthma has been during the previous week and to 
respond to the first 6 questions on a 7-point scale (0 = no impairment, 6 = maximum impairment). 
Clinic staff score of the FEV1% predicted is also on a 7-point scale. 
A global score is calculated as follows: the questions are equally weighted, and the ACQ-7 score 
is the mean of the 7 questions and, therefore, falls between 0 (totally controlled) and 6 (severely 
uncontrolled). Higher score indicates lower asthma control. Participants with a score below 1.0 
reflect adequately controlled asthma and participants with scores above 1.0 reflect inadequately 
controlled asthma. On the 7-point scale of the ACQ-7, a change or difference in score of 0.5 is 
the smallest change that can be considered clinically important, corresponding to the Minimal 
Clinically Important Difference (MCID) defined by the developer. 
Participants will complete the ACQ-7 at the time points specified in the SoA (see Section 1.3). 
The ACQ-5 score is the mean of the first 5 questions and, therefore, ranges between 0 (totally 
controlled) and 6 (severely uncontrolled). Higher score indicates lower asthma control. 
Participants with a score below 1.0 reflect adequately controlled asthma and participants with 
scores above 1.0 reflect inadequately controlled asthma. On the 7-point scale of the ACQ-5, 
a change or difference in score of 0.5 is the smallest change that can be considered clinically 
important, corresponding to the MCID. 
At screening visit, ACQ-5 scores (sum of the responses to the first 5 questions) will be derived 
from ACQ-7.  
8.1.6.7 Asthma quality of life questionnaire with standardized activities (self-
administered)  
Asthma Quality of Life Questionnaire with Standardized Activities Self-Administered 
(AQLQ[S]) - was designed as a self-administered participant reported outcome to measure 
the functional impairments that are most troublesome to adolescents ≥12 years of age and adults 
as a result of their asthma.  
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The instrument is comprised of 32 items, each rated on a 7-point Likert scales from 1 to 7. 
The AQLQ(S) has 4 domains.  
The domains and the number of items in each domain are as follows: 
• Symptoms (12 items) 
• Activity limitation (11 items) 
• Emotional function (5 items) 
• Environmental Stimuli (4 items) 
A global score is calculated ranging from 1 to 7 and a score by domain. Higher scores indicate 
better quality of life. The instrument has been used in many clinical trials, and it has been shown 
to be reliable, valid (participant interviews), and sensitive to change. The MCID for AQLQ(S) is 
0.5 (61). 
Participants will complete the AQLQ(S) at the time points specified in the SoA (see Section 1.3). 
8.1.6.8 Cumulative number of health-care resource utilization (HCRU)  
A questionnaire about health-care resource utilization (HCRU) and productivity (missed 
workdays) will be collected by the Investigator for all participants at the time points specified in 
the SoA (see Section 1.3) through eCRF. 
8.1.6.9 EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire (EQ-5D)  
The 5-level version of EQ-5D is a standardized PRO to provide a simple, generic measure of 
health for clinical and economic appraisal. 
The EQ-5D consists of 2 parts: the descriptive system and the EQ VAS. The EuroQol-5 
Dimensions-5 Levels descriptive system is comprised of 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression). These dimensions have 5 levels of perceived 
problems: “no problem”, “slight problems”, “moderate problems”, “severe problems” and 
“extreme problems ” (62). 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.  
The EQ VAS records the respondent’s self-rated health on a vertical, VAS which ranges from 
“best imaginable health state (100)” to “worst imaginable health state (0)”. This provides a simple 
measure of general health status, and in which a change of ≥8 points is considered clinically 
important (63), and the scores can also be compared with population norm scores which ranges 
from 70.4 to 83.3 (64). 
8.1.6.10 Patient Global Impression of Control and Change in CRSwNP  
The PGI-Control is a 1-item questionnaire that asks participants to provide the overall 
self-assessment of their CRSwNP control on a 5-point scale during the past 7 days. Response 
options range from 1=“Not controlled at all” to 5=“completely controlled”. 
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The PGI-Change is a 1-item questionnaire that asks the participant to provide the overall 
self-assessment of change in their CRSwNP on a 7-point scale compared to just before the 
participant started taking the study intervention. The response choices range from 1=“Very Much 
Improved” to 7=“Very Much Worse” 
8.1.6.11 Investigator Global Assessment (Severity, Control, Change) in CRSwNP  
The Investigator Global Assessments are 1-item questionnaires that asks the Investigator to assess 
the current a) severity (IGA-Severity) and b) control (IGA-Control) of the patient’s CRSwNP. 
The scales range from 1 (no disease) to 4 (severe), and 1 (Not controlled at all) to 5 (completely 
controlled), respectively.  
The Investigator Global Assessment of Change (IGA-Change) of CRSwNP is a 1-item 
questionnaire that asks the Investigator to provide the overall assessment of change 
in the patient’s CRSwNP on a 7-point scale compared to just before the initiation of the study 
intervention. The scale ranges from 1 (very much improved) to 7 (very much worse). 
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, at a minimum, assessments of the skin, 
nasal cavities, eyes and ears, respiratory, cardiovascular, gastrointestinal, neurological, 
lymphatic, and musculoskeletal systems. Height and weight will also be measured and 
recorded. Height (cm) will be only measured at baseline. Weight (kg) will be measured 
at the time points specified in the SoA (Section 1.3). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Vital signs  
• Body temperature (degrees Celsius), heart rate (beats per minute), respiratory rate (breaths 
per minute), and blood pressure (mmHg) will be assessed. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings 
will be recorded on the eCRF. 
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8.2.3 Electrocardiograms 
Single 12-lead ECG will be obtained locally as outlined in the SoA (see Section 1.3) for screening 
purpose. 
8.2.4 Clinical safety laboratory assessments 
•
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and
to the SoA (Section 1.3) for the timing and frequency.
•
The laboratory tests, pregnancy, and other screening tests will be performed by the local
laboratories according to routine clinical practice at site and country level. Considering
this, any leftover blood sample will not be used for any other research purposes related to
the study (re-analyses) or for future exploratory use (secondary use).
•
A central laboratory will be used to assess the serum total IgE levels and eosinophils.
•
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, unless judged by the Investigator to be more severe than expected for
the participant’s condition.
•
All laboratory tests with values considered clinically significantly abnormal during
participation in the study should be repeated until the values return to normal or baseline
or are no longer considered clinically significant by the Investigator or medical monitor.
-
If such values do not return to normal/baseline within a period of time judged
reasonable by the Investigator, the etiology should be identified and the Sponsor
notified.
-
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2),
must be conducted in accordance with the laboratory manual and the SoA.
-
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.
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Adverse event will be reported by the participant (or, when appropriate, by a caregiver, 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).  
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8.3.1 Time period and frequency for collecting AE and SAE information 
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA (Section 1.3). 
All AE will be collected from the signing of the ICF at the time points specified in the SoA 
(Section 1.3). 
All SAEs and adverse event of special interest (AESI) 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 data to 
the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify 
the Sponsor. 
8.3.2 Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
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 AEs, SAEs, and 
AESIs (as defined in Section 8.3.6), 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). 
8.3.4 Regulatory reporting requirements for SAEs 
•
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of
a study intervention under clinical investigation are met.
•
The Sponsor has a legal responsibility to notify both the local regulatory authority and
other regulatory agencies about the safety of a study intervention under clinical
investigation. The Sponsor will comply with country-specific regulatory requirements
relating to safety reporting to the regulatory authority, IRBs/Independent Ethics
Committees (IECs), and Investigators.
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• Adverse events that are considered expected will be specified in the reference safety 
information (Investigator’s Brochure for dupilumab and Summary of Product 
Characteristics).  
• Suspected unexpected serious adverse reactions (SUSARs) 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 a 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 Investigator’s Brochure 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. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until the outcome has been 
determined. 
• 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). 
• In the event of pregnancy in a female participant, the IMP should be permanently 
discontinued. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant /pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor. While the Investigator is 
not obligated to actively seek this information in former study participants /pregnant 
female partner, 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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8.3.6 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. 
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described in Section 10.3 even if not fulfilling a seriousness criterion, using the 
corresponding pages in the CRF (to be sent) or screens in the eCRF. Adverse event of special 
interests for this study include:  
• Anaphylactic reactions (Appendix 10 [Section 10.10]) 
• Systemic hypersensitivity reactions 
• Helminthic infections 
• Any severe type of conjunctivitis or blepharitis 
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms) 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring 
in a female partner of a male participant entered in the study with IMP; 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial will be qualified as an SAE 
only if it fulfills one of the seriousness criteria. 
- 
In the event of pregnancy in a female participant, IMP should be discontinued. 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
• Significant ALT elevation 
- 
ALT >5 × ULN in participants with baseline ALT ≤2 × ULN; 
OR 
- 
ALT >8 × ULN if baseline ALT >2 × ULN. 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP. 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by 
the Investigator or spontaneously notified by the participant and defined as at least 
twice the intended dose during an interval of less than 11 days. The circumstances 
(ie, accidental or intentional) should be clearly specified in the verbatim and 
symptoms, if any, entered on separate AE forms. 
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- 
An overdose (accidental or intentional) with any NIMP is an event suspected by 
the Investigator or spontaneously notified by the participant and defined as at least 
twice the maximum prescribed daily dose, within the intended therapeutic interval. 
The circumstances (ie, accidental or intentional) should be clearly specified in 
the overdose form. 
8.3.7 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator/unblinded site 
personnel to the monitoring team that will complete a product complaint form within required 
timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
Overdose is an AESI (defined in Section 8.3.6) in this study. No antidote is available for 
dupilumab or omalizumab. The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Provide symptomatic care. 
2. Contact the medical monitor immediately. 
3. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
dupilumab or omalizumab can no longer be detected systemically. 
4. Obtain a plasma sample for PK analysis as soon as possible if requested by the medical 
monitor (determined on a case-by-case basis). 
5. Document appropriately in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
Pharmacokinetic parameters are not evaluated in this study. 
8.6 
PHARMACODYNAMICS  
Pharmacodynamic parameters are not evaluated in this study. 
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8.7 
GENETICS  
Genetics are not evaluated in this study. 
8.8 
BIOMARKERS  
Whole blood biomarkers: Blood eosinophil count, IgE counts and allergan-specific IgE will be 
measured at the time points mentioned in the SoA (Section 1.3). 
Fractional exhaled nitric oxide levels: FeNO test should be conducted prior to spirometry and 
following a fasting of ≥1 hour. Further details on the procedure for measuring FeNO will be 
provided in a separate instruction manual. Fractional exhaled nitric oxide levels will be measured 
at the time points mentioned in the SoA (Section 1.3). 
8.9 
IMMUNOGENICITY ASSESSMENTS  
Immunogenicity assessments will not be performed. 
8.10 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS  
The WPAI-chronic rhinosinusitis and the HCRU questionnaires are described in Section 8.1. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The null statistical hypothesis is there is no treatment difference between dupilumab and 
omalizumab for both primary endpoints. The alternative statistical hypothesis for the 2 primary 
endpoints is that dupilumab 300 mg Q2W is superior to omalizumab on at least one of 
the 2 primary endpoints. 
Assuming that the resulting 2-sided p-values for the 2 primary endpoints, ordered from lower to 
higher, are p1 and p2, the alternative hypothesis will be considered to have been met if either of 
the condition is met: 
• p1 ≤ p2 ≤0.05 and both endpoints are in favor of dupilumab, or, 
• p1 ≤0.025 and is in favor of dupilumab irrespective of the value of p2. 
The alternative statistical hypothesis for each of the secondary efficacy endpoints is also that 
dupilumab 300 mg Q2W is superior to omalizumab. A multiplicity control procedure will be 
provided in SAP to test the multiple hypotheses to control the familywise Type I error rate at 
two-sided 0.05 level.  
9.2 
SAMPLE SIZE DETERMINATION  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Considering the multiplicity testing procedure described above, this sample size will provide 
 
  
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The original sample size of 422 was estimated to power the key secondary endpoint, change from 
baseline in pre-BD FEV1 at Week 24, at
. By downgrading this endpoint to an exploratory 
endpoint and with a minimum total sample size of 320 participants (160 participants per arm), 
the estimated power for NPS and UPSIT are about 
 
. 
9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 6): 
Table 6 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the informed consent form 
Randomized 
Randomized participants consist of all participants with a treatment kit number 
allocated and recorded in the Interactive Web Response System (IWRS) database, 
regardless of whether the treatment kit was used or not.  
Participants treated without being randomized will not be considered as randomized 
and will not be included in any efficacy population. Data from these participants will 
be summarized separately. 
Intent-to-treat (ITT) 
The analysis population for the efficacy endpoints will be the ITT population: all 
randomized participants will be included in the ITT population and analyzed 
according to the treatment group allocated by randomization. 
Safety (As-treated) 
All randomized participants who take at least 1 dose of study intervention will be the 
safety population. Participants will be analyzed according to the intervention they 
actually received. 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will be developed and finalized prior to the database lock and it 
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 key secondary endpoints. 
9.4.1 General considerations  
A multiplicity control procedure and the whole list of secondary endpoints to be tested 
in the hierarchical order will be specified in the SAP. 
The baseline value is generally defined as the last available value before randomization. 
For endpoints collected on the daily basis in the screening period, baseline value is defined as 
the average of the scores in the 7 days prior to randomization. If fewer than 4 measurements are 
collected during the 7 days, the average of the most recent 4 prior to randomization during 
the screening period will serve as the baseline. 
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All efficacy analyses will be performed on the intent-to-treat (ITT) population, unless otherwise 
noted. All safety analyses will be performed on the safety population. 
9.4.2 Primary endpoints  
The 2 primary endpoints are change from baseline in NPS and UPSIT at Week 24 assessed for 
dupilumab 300 mg Q2W versus omalizumab. The primary estimand for the 2 primary endpoints is 
the hypothetical/treatment policy strategy as described below. 
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Table 7 - Summary of primary estimand for the primary endpoints  
Endpoint 
Category 
(estimand) 
Estimands 
 
Endpoints 
Population 
Intercurrent event(s) 
handling strategy and 
missing data handling 
Population-level 
summary 
Primary objectives: To evaluate the efficacy of dupilumab compared to omalizumab in reducing the polyp size and improving 
sense of smell  
2 primary endpoints 
(treatment policy 
/hypothetical 
strategy) 
Change from baseline 
to Week 24 in nasal 
polyp score (NPS) 
 
Change from baseline 
to Week 24 in 
University of 
Pennsylvania Smell 
Identification Test 
(UPSIT) 
Intent-to-
treat (ITT) 
population 
The intercurrent events will be 
handled as follows: 
• 
Undergoing surgery for NP or 
receiving systemic 
corticosteroids (SCS) for any 
reason prior to Week 24: data 
after surgery or SCS use will 
be set to missing, and the 
worst postbaseline value on 
or before the time of surgery 
or SCS use will be used to 
impute missing values (for 
participants whose 
postbaseline values are all 
missing, the baseline will be 
used to impute hypothetical 
strategy) 
• 
Discontinuing the study 
intervention due to 
coronavirus disease 2019 
(COVID-19) pandemic: 
off-study intervention data will 
be set to missing (hypothetical 
strategy) 
• 
Discontinuing the study 
intervention not due to 
COVID-19 pandemic: all data 
collected after treatment 
discontinuation will be used in 
the analysis (treatment policy 
strategy). 
For missing data, a multiple 
imputation approach will be used 
to impute missing Week 24 values, 
and this multiple imputation will 
use all participants excluding those 
who have undergone surgery/SCS 
use on or before Week 24. 
Analysis of Covariance 
(ANCOVA) model with 
treatment group, 
stratification factors, 
and corresponding 
baseline measurement 
as covariates is used. 
Statistical inference 
obtained from all 
imputed data by 
ANCOVA model will 
be combined using 
Rubin’s rule. 
Each of the 2 primary endpoints will be analyzed using a hybrid method of the WOCF and the 
MI. For participants discontinuing the study intervention before Week 24 not due to the 
COVID-19 pandemic, off-study intervention efficacy assessments measured up to Week 24 will 
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be included in this analysis. In contrast, for any participants discontinuing the study intervention 
due to the COVID-19 pandemic, off-study intervention data will be set to missing. 
For participants who undergo surgery for NP or receive SCS for any reason during the study, data 
collected postsurgery or post SCS will be set to missing, and the worst postbaseline value on or 
before the time of surgery or SCS intake 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). For 
participants who discontinue without being rescued by surgery or receiving SCS, an MI approach 
will be used to impute missing Week 24 value. This MI will use all participants who have not 
been rescued by surgery or receiving SCS by Week 24. The data collected after treatment 
discontinuation will be included in the analysis. Each of the imputed complete data will be 
analyzed by fitting an ANCOVA model with corresponding baseline value, treatment group, and 
stratification factors as the covariates. Statistical inference on treatment comparisons for the 
2 primary endpoints at Week 24 will be derived from the ANCOVA model. Descriptive statistics 
including number of participants, mean, standard deviation, and LS means will be provided. 
In addition, difference in LS means and the corresponding 95% CIs will be provided along with 
the p-values.  
The sensitivity analysis for the 2 primary endpoints may be performed, and details will be 
provided in the SAP. 
9.4.3 Secondary endpoints  
Differences will be assessed between dupilumab and omalizumab in the following secondary 
efficacy endpoints, and the list of the selected secondary endpoints to be tested in the hierarchy 
will be provided in SAP. In addition, the primary estimand and details about the intercurrent 
events strategy and missing data handling will be presented in SAP as well: 
Key secondary endpoints: 
• Change from baseline to Week 24 in the loss of smell score of the CRSwNP Nasal 
Symptom Diary. 
• Change from baseline to Week 24 in the NC score of the CRSwNP Nasal Symptom Diary. 
Secondary endpoints: 
• Change from baseline to Week 24 in TSS derived from the CRSwNP Nasal Symptom 
Diary. 
• Change from baseline to Week 24 in SNOT-22 total score. 
• Change from baseline to Week 24 in SNOT-22 nasal domain score. 
• Change from baseline to Week 24 in NPIF. 
• Change from baseline to Week 24 in rhinosinusitis VAS. 
The change from baseline in the above continuous endpoints to Week 24 will be analyzed using 
the hybrid method of the WOCF and the MI with ANCOVA model in the same fashion as for 
the 2 primary endpoints. 
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The frequency of TEAE, SAE, and AESI will be used to evaluate the safety of dupilumab and 
omalizumab. 
9.4.4 Tertiary/exploratory endpoints  
Analysis of exploratory endpoints will be described in the SAP which will be finalized before 
database lock. No formal testing will be performed. 
9.4.5 Other safety analyses  
All safety analyses will be performed on the safety population. The summary of safety results will 
be presented by treatment group. 
Analyses of Adverse Events 
Treatment-emergent adverse event frequency tables will be presented by Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class (SOC) (sorted by internationally agreed 
order), MedDRA high level group term (HLGT)and preferred term (PT), 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. The denominator for computation 
of percentages is the safety population within each treatment group. Proportion of participants 
with at least one TEAE, serious TEAE, TEAE leading to death, and TEAE leading to permanent 
treatment discontinuation will be tabulated by treatment group. In addition, TEAEs will be 
described according to maximum intensity and relation to the study drug. Serious AEs and AEs 
leading to study discontinuation that occur outside the treatment-emergent period will be 
summarized separately. 
The frequency of the AESIs and other AE groupings will be tabulated by treatment group. 
The AESIs and other AE groupings definitions and the method to identify them will be specified 
in the SAP. 
Analyses of laboratory and vital signs parameters 
Results and change from baseline for the laboratory and vital signs parameters will be 
summarized by treatment group for baseline and each post baseline time point, endpoint, 
minimum and maximum value. Summary statistics will include number of participants, mean, 
standard deviation, median, Q1, Q3, minimum, and maximum. 
9.4.6 Other analyses  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency (Section 10.9). 
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9.5 
INTERIM ANALYSES  
Not applicable. 
9.6 
DATA MONITORING COMMITTEE (DMC)  
No DMC is planned for this study. 
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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, Investigator Brochure, 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 Determining whether an incidental finding should be 
returned to a participant and, if it meets the appropriate criteria, to ensure the finding is 
returned (an incidental finding is a previously undiagnosed medical condition that is 
discovered unintentionally and is unrelated to the aims of the study for which the tests 
are being performed). The following should be considered when determining the return 
of an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
health-care professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where 
the study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
- 
The participant in a clinical study has the right to opt out of being notified by 
the Investigator of such incidental findings. In the event that the participant has 
opted out of being notified and the finding has consequences for other individuals, 
eg, the finding relates to a communicable disease, Investigators should seek 
independent ethical advice before determining next steps. 
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- 
In case the participant has decided to opt out, the Investigator must record 
in the site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 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. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
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. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• Participants must be informed that their participation is voluntary. Participants or their 
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.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• 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. 
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The ICF will contain a separate section that addresses the use of remaining mandatory samples or 
new extra samples for optional exploratory research. The Investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate consent will be required to document a participant's 
agreement to allow any remaining specimens to be used for exploratory research. Participants who 
decline to participate in this optional research will not provide this separate consent. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency (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 applicable laws and regulations including the GDPR (General Data Protection Regulation).  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on afro American population for the Food and Drug Administration or on 
Japanese population for the Pharmaceuticals and Medical Devices Agency in Japan). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers, when applicable, 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. 
• 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. 
• Participant data are intended to be used for the whole drug development program from 
collection to reimbursement. 
• Personal data of professionals will be retained by Sanofi for up to twenty-five (25) years, 
unless further retention is required by applicable regulations. Professionals have the right 
to request the access to and the rectification of their personal data, as well as their erasure 
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(where applicable) by contacting the Sanofi Data Protection Officer: Sanofi DPO - 46 
avenue de la Grande Armee-75017-PARIS - France (to contact Sanofi by email, visit 
https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-policy/contact). 
10.1.5 Committees structure  
There will be no study committees.  
10.1.6 Dissemination of clinical study data and results 
At the end of the clinical study, the Sponsor may publish the study results in scientific journal(s). 
As part of the review for publication, independent scientists may need to use “coded” data of all 
the study participants to independently verify the study’s results.  
Sanofi shares information about clinical trials 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, euclinicaltrials.eu, and sanofi.com, as well as some 
national registries. For pediatric and adult trials, the results will generally be submitted/released 
6 and 12 months, respectively, after the end of the clinical trial worldwide (ie, the last active, 
participating country). 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported 
in the publication, interested researchers are directed to submit their request to vivli.org. 
Individual participant data and supporting clinical documents are available for request at vivli.org. 
While making information available we continue to protect the privacy of participants in our 
clinical trials. Details on data sharing criteria and process for requesting access can be found 
at this web address: vivli.org.  
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on the eCRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
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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 eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data: source data is all information in original 
records and certified copies of original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents. Source documents are original documents, 
data and records such as hospital records, clinic and office charts, laboratory reports, 
notes, memoranda, pharmacy dispensing records, recorded data from automated 
instruments etc. Data downloaded from the local laboratories, pharmacy dispensing 
records, spirometry, ECG, patient diaries, electronic PROs/eDevice will be considered 
source data. 
10.1.9 Study and site start and closure  
The first act of recruitment is the first participant screened and will be the study start date. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up. 
10.1.10 
Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The laboratory tests detailed in Table 8 will be performed by the local laboratories except 
the serum total IgE level and eosinophils that will be done in a central laboratory. 
• The result of each laboratory test must be entered into the eCRF. 
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• 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. 
• Pregnancy testing (serum at screening visit and then urine or serum as required by 
the local regulations) should be conducted as mentioned in the SoA (Section 1.3). 
• Pregnancy testing should be conducted at the end of relevant systemic exposure 
corresponding with the time frame for female participant contraception in Section 5.1, 
Inclusion Criteria. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the Investigator or required by local regulation, to establish the absence of pregnancy 
at any time during the participant's participation in the study. 
Table 8 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
Eosinophils 
Biomarker 
Serum total IgE levels 
Other screening tests 
• 
Highly sensitive serum hCG pregnancy test (as needed for 
WOCBP)a at screening visit (urine or serum pregnancy test as 
required by the local regulations at other time points) 
• 
Serologyb: HBs Ag, HBs Ab, total HBc Ab, HCV Ab; HIV screen 
(Anti-HIV-1 and HIV-2 antibodies) 
• 
Tuberculosis testc 
• 
All study-required laboratory assessments will be performed by 
the local laboratories, with an exception of serum total IgE levels 
and eosinophils. 
HBc Ab: hepatitis B core antibody; HBs Ab: hepatitis B surface antibody; HBs Ag: hepatitis B surface antigen; HBV: hepatitis B virus; hCG: 
human chorionic gonadotropin; HCV: hepatitis C virus; HCV Ab: hepatitis C virus antibodies; HIV: human immunodeficiency virus; IgE: 
immunoglobulin E; IEC: Independent Ethics Committee; IRB: Institutional Review Board; WOCBP: women of childbearing potential 
NOTES: 
a After screening local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
b In case of results showing HBs Ag (negative), HBs Ab (negative) and HBc Ab (positive), an HBV DNA testing may be performed prior to 
randomization to rule out a false positivity if the Investigator believes the participant is a false positive, or to clarify the serological status if 
the Investigator finds it unclear to interpret in absence of known HBV infection. In case of results showing HCV Ab (positive), an HCV 
RNA testing may be performed to rule out a false positivity, if the Investigator believes the participant is a false positive.  
c Tuberculosis testing will be performed on a country-by-country basis according to the routine clinical practice and the local guidelines if 
required by the regulatory authorities or ethics committees or if TB is suspected by the investigator. 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results (IgE levels) 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. 
Definition of unsolicited and solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant who has signed the informed consent. Unsolicited AEs 
include serious and nonserious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring 
a hospitalization, emergency room visit, or visit to/by a health care provider). 
The participants will be instructed to contact the site as soon as possible to report 
medically attended events, as well as any events that, though not medically attended, are 
of participant concern. Detailed information about reported unsolicited AEs will be 
collected by qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant will be collected during an interview with the participants and by review of 
available medical records at the next visit. 
• Solicited AEs are predefined local [at the injection site] and systemic events for which 
the participant is specifically questioned, and which are noted by the participants in their 
home dosing diary. 
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), eg:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
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• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• Protocol defined asthma exacerbation events are collected as efficacy endpoints via 
the “Asthma Exacerbation Events” form. These events should not be reported as AEs 
unless they fulfill a seriousness criterion. 
• 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.  
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 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. 
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c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition. These events should usually be 
considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
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 CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE/SAE CRF page. 
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• There may be instances when copies of medical records for certain cases are requested by 
the 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’s representative. 
• 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 Investigator’s Brochure 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’s 
representative. 
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• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative 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’s representative with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• 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’s representative will be 
the electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the protocol. 
SAE reporting to 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. 
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• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY  
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 site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
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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 9. 
Table 9 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation  
• 
Oral  
• 
Intravaginal  
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly effective methods that are user independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
women of child bearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
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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 to male participants who receive study intervention (dupilumab or omalizumab). 
• 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 study intervention. 
10.5 
APPENDIX 5: GENETICS  
Not applicable. 
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10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.8 
APPENDIX 8: OMALIZUMAB DOSING TABLE  
Figure 2 - Omalizumab dosing table  
 
 
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10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
For European countries contingency measures are currently only applicable for the COVID-19 
pandemic. 
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 below and in Sections 5.5, 6.1, 7.1.2, 7.1.2.1, 8.0, 9.4.6, 
and 10.1.3 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. 
Section 5.5: CRITERIA FOR TEMPORARILY DELAYING 
SCREENING/RANDOMIZATION 
Temporary delay of screening/randomization may be considered by the sponsor, in case of any 
public health emergency, and the site is unable to adequately follow protocol mandated 
procedures, in order to ensure participants’ safety. Implementation of such mechanisms may differ 
country-by-country, depending on the country-specific regulations and local business continuity 
plans. 
Section 6.1: STUDY INTERVENTION(S) ADMINISTERED 
If on-site visits are not possible, remote visits (eg, with home nurses, home health vendor, etc) 
may be planned for the administration of IMP where allowed by local regulations, local label, and 
approved by the participant. 
Section 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 a regional or national emergency declared 
by a governmental agency. 
Temporary intervention discontinuation decided by the Investigator corresponds to at least 1 dose 
not administered to the participant. Following a temporary interruption or missed dose, the 
treatment should be reinitiated at the next scheduled administration, maintaining the planned dose. 
If 2 consecutive IMP doses have been missed, the study intervention will be definitively 
discontinued (see Section 7.1.1). Investigator must contact the participant to instruct not to take 
any subsequent injection. 
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Section 7.1.2.1: RECHALLENGE 
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 IMPs to the occurrence of the epidemic event (eg, COVID-19) was unlikely. 
Section 8: 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. 
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
• If on-site visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc) may be planned for the administration of IMP and collection of possible safety data, 
PROs, and participants’ diary. 
• If on-site visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely. 
• Use of local clinic or laboratory locations may be allowed and phone call visits may be 
scheduled for collection of safety data. 
• Implementation of above mechanisms may differ country-by-country, depending on the 
country-specific regulations and local business continuity plans. Additionally, no waivers 
to deviate from protocol enrollment criteria due to any regional or national emergency (or 
public health emergency) will be granted.  
• All temporary mechanisms utilized, and deviations from planned study procedures are to 
be documented as being related to regional or national emergency (or public health 
emergency) and will remain in effect only for the duration of the public health emergency. 
Section 9.4.6: OTHER ANALYSES 
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). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
Section 10.1.3: 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 labs). 
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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” (65). 
Clinical criteria for diagnosing anaphylaxis 
 
 
10.11 APPENDIX 11: LIST OF OPPORTUNISTIC INFECTION  
• 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: DIAGNOSISOF NERD IN CRSWNP PATIENTS (± diagnosed asthma)  
 
10.13 APPENDIX 13: ABBREVIATIONS  
 
ACQ-5: 
Asthma Control Questionnaire-5 item 
ACQ-7: 
Asthma Control Questionnaire-7 item 
AD: 
atopic dermatitis 
ADR: 
adverse drug reaction 
ADSD: 
Asthma Daytime Symptom Diary 
AE: 
adverse event 
AERD: 
aspirin‑exacerbated respiratory disease 
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AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AQLQ: 
Asthma Quality of Life Questionnaire  
AQLQ(S): 
Asthma Quality of Life Questionnaire with Standardized Activities 
ATS: 
American Thoracic Society 
BID: 
twice a day  
CFR: 
Code of Federal Regulations 
CI: 
confidence interval 
COPD: 
chronic obstructive pulmonary disease 
COVID-19: 
Coronavirus Disease 2019 
CRF: 
case report form 
CRS: 
chronic rhinosinusitis  
CRSwNP: 
chronic rhinosinusitis with nasal polyps  
CSU: 
chronic spontaneous urticaria 
DNA: 
deoxyribonucleic acid  
ECG: 
electrocardiogram 
eDevice: 
electronic device 
EE: 
Eastern European 
EoE: 
eosinophilic esophagitis 
EOS: 
end of study 
EOT: 
end of treatment 
EQ VAS: 
EuroQol Visual Analogue Scale 
EQ-5D-5L: 
EuroQol-5 Dimensions 5 Level 
ERS: 
European Respiratory Society 
EU: 
European Union 
FEF: 
forced expiratory flow  
FeNO: 
fractional exhaled nitric oxide 
FESS: 
functional endoscopic sinus surgery 
FEV1: 
forced expiratory volume in 1 second 
FSH: 
follicle stimulating hormone 
FVC: 
forced vital capacity  
GCP: 
Good Clinical Practice 
GDPR: 
General Data Protection Regulation 
H2H: 
head-to-head 
HBc Ab: 
hepatitis B core antibody 
HBs Ab: 
hepatitis B surface antibody 
HBs Ag: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HCRU: 
health-care resource utilization 
HCV: 
hepatitis C virus 
HCV Ab: 
hepatitis C virus antibody 
HIV: 
human immunodeficiency virus 
HLGT: 
high level group term 
HRQoL: 
health related quality of life 
HRT: 
hormonal replacement therapy 
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ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
ICS: 
inhaled corticosteroids 
IEC: 
Independent Ethics Committees 
IGA-Change: 
Investigator Global Assessment of Change 
IGA-Control: 
Investigator Global Assessment of Control 
IGA-Severity: 
Investigator Global Assessment of Severity 
IgE: 
Immunoglobulin E 
IL: 
interleukin 
IM: 
intramuscular 
IMP: 
investigational medicinal product 
INCS: 
intranasal corticosteroid sprays 
IRB: 
Institutional Review Board 
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
IV: 
intravenous 
IVIG: 
intravenous immunoglobulin 
IWRS: 
Interactive Web Response System 
LABA: 
long-acting beta-2 adrenergic receptor 
LS: 
least squares 
LTRA: 
leukotriene receptor antagonists 
mAb: 
monoclonal antibody 
MCID: 
minimal clinically important difference 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MFNS: 
mometasone furoate nasal spray 
MI: 
multiple imputation 
NC: 
nasal congestion 
NIMP: 
noninvestigational medicinal product 
NPIF: 
Nasal Peak Inspiratory Flow 
NPS: 
nasal polyp score 
NSAID-ERD: 
Non-Steroidal Anti-Inflammatory Drug Exacerbated Respiratory Disease  
PGI-Change: 
Patient Global Impression of Change  
PGI-Control: 
Patient Global Impression of Control 
PK: 
pharmacokinetic 
PN: 
prurigo nodularis 
PRO: 
patient-reported outcome 
Q2W: 
every 2 weeks 
Q4W: 
every 4 weeks 
QD: 
once daily 
ROW: 
rest of the world 
SABA: 
short-acting beta-2 agonists 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SCS: 
systemic corticosteroids 
SNOT-22: 
Sino‑Nasal Outcome Test-22 
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SoA: 
Schedule of Activities 
SUSAR: 
suspected unexpected serious adverse reaction 
TB: 
tuberculosis 
TEAE: 
treatment emergent adverse event 
Th2: 
T-helper Type 2 cell 
TSS: 
total symptom score 
ULN: 
upper limit of normal 
UPSIT: 
University of Pennsylvania Smell Identification Test 
US: 
United States 
VAS: 
Visual Analogue Scale 
WOCBP: 
woman of childbearing potential 
WOCF: 
worst observation carried forward 
WPAI: 
Work Productivity and Activity Impairment Questionnaire 
 
10.14 APPENDIX 14: PROTOCOL AMENDMENT HISTORY  
Amended protocol 02 (13 December 2022) 
This amended protocol (amendment 02) is considered to be non-substantial based on the criteria 
set forth in Article 2(2)(13) of the Regulation No 536/2014 of the European Parliament and 
the Council of the European Union [because it does not significantly impact the safety or rights of 
the participants and/or the reliability and robustness of the data generated in the clinical trial]. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main reason for this amendment is to provide more flexibility in the trial eligibility 
assessments. 
Additionally, minor clarifications and updates have been implemented across the document. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 2.2 Background 
Text is updated to reflect mepolizumab is 
approved for treatment of CRSwNP. 
Text is updated to reflect current status 
of mepolizumab. 
Section 1.1 Synopsis  
Section 4.1 Overall design 
Study duration is updated to 38 weeks. 
To ensure consistency within protocol 
sections. 
Section 1.1 Synopsis 
Section 4.1 Overall design 
Section 6.3 Measures to 
minimize bias: randomization 
and blinding 
Following text is deleted 
No more than 50% participants should be on low 
ICS dose, and no more than 35% participants 
should be from EE countries. 
This information is simply deleted from 
protocol as it is part of IWRS 
specification. 
Section 1.1 Synopsis 
Intranasal corticosteroid background therapy is 
clarified. 
To clarify that prior to the study entry, 
equivalent INCS could be used, 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1 Study 
intervention(s) administered 
whereas during the study only 
mometasone can be used. 
Section 1.1 Synopsis  
Section 1.2 Schema 
Section 1.3 Schedule of 
Activities (SOA) 
Section 4.1 Overall design 
Section 6.1 Study 
intervention(s) administered 
Screening/run-in period is changed from 
4 weeks±1 week to 28±3 days. 
To ensure consistency within protocol 
sections. 
Section 1.3 Schedule of 
Activities (SOA) 
Following changes are done to the study 
procedures 
Spirometry (pre-bronchodilator FEV1, FVC, FEF 
25% to 75%) is removed from Screening/run-in 
period and footnote “g” is updated to remove 
instruction regarding eligibility based on 
spirometry. 
Timepoint for Nasal Peak Inspiratory Flow and 
CRSwNP nasal symptom diary collection is 
clarified.  
Collection timepoint for Asthma Daytime/ 
Symptom Diary is clarified.  
Footnote “h”, “i”, “k” and “m” are updated. 
These changes are made to provide 
further guidance on study procedures 
and allow more flexibility in eligibility 
criteria. 
Section 10.2 Appendix 2 
clinical laboratory tests 
Table 8 
Table 8 updated to reflect changes done in SOA 
Footnote “i” 
Section 2 Introduction 
Approved treatment indications for dupilumab are 
added. 
To provide upto date information. 
Section 2.3 
Benefit/Risk assessment 
The section is updated with latest data. 
Section 5.1  
Inclusion criteria 
The eligibility criteria 02 is updated to clarify that 
eligibility is based on Visit 1 endoscopic bilateral 
NPS central reading followed by a Visit 2 local 
reading.  
To ensure consistency with 
Section 8.1.1. 
Section 5.1 Inclusion criteria 
Section 5.2 Exclusion criteria 
The eligibility criteria 03 is updated.  
The eligibility criteria 16 is updated. 
To facilitate participant recruitment. 
Section 5.1 Inclusion criteria 
Section 5.2 Exclusion criteria 
The eligibility criteria 04 is removed. 
The eligibility criteria 14 is updated. 
To provide more flexibility in the trial 
eligibility assessments. 
Section 5.2 Exclusion criteria 
The eligibility criteria 07 is updated. 
To provide guidance on TB testing. 
Section 5.2 Exclusion criteria 
The eligibility criteria 19 and 20 have been 
modified to avoid overlapping between them and 
to clarify wash out periods. 
To ensure consistency with other 
Dupilumab studies.  
Section 5.4 Screen failures 
Rescreening procedure added. 
To facilitate participant recruitment.  
Section 6.5.1 
Prohibited medications 
The term “severe” is added for use of systemic 
corticosteroids to treat asthma exacerbation. 
Text is updated to clarify that short term courses 
To ensure consistency within protocol 
sections. 
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Section # and Name 
Description of Change 
Brief Rationale 
of SCS is not limited to use as rescue treatment 
for asthma exacerbation. 
Section 6.5.2 
Permitted concomitant 
medication 
Text is updated to specify that antibiotics are 
allowed to treat infection irrespective of causality 
to CRS exacerbations except during screening 
period. 
To ensure consistency between 
allowed and prohibited medications 
sections. 
Section 6.5.3.1 
Rescue medications for asthma 
The term “Short courses” from short courses of 
systemic corticosteroids is removed. 
Section 7.1.1 
Definitive discontinuation 
Following reason for permanent discontinuation 
of IMP is removed 
• If the participant is treated with the specific 
prohibited medications mentioned in 
Section 6.5.1. 
Study completion date and early discontinuation 
visit are replaced by EOT and ESD visit, 
respectively for handling of participants after 
definitive intervention discontinuation. 
To ensure consistency with other 
Dupilumab Phase 4 studies. 
Section 8 Study assessments 
and procedures 
Section 8.1.1 Nasal Polyp score 
Reference to study reference manual is deleted. 
Study reference manual is not 
available. 
Section 8 Study assessments 
and procedures 
The order of electronic PRO at the visits during 
the Intervention Period is updated. 
To ensure consistency with eCOA set 
up. 
Section 8.1.1 
Nasal Polyp score 
The text is updated to allow retesting of nasal 
endoscopy once during screening in case of not 
meeting eligibility criteria as per the Investigator 
discretion. 
To facilitate participant recruitment. 
Section 8.1.4 
Spirometry 
The information regarding recording result of 
FEV1 (% of predicted normal), FVC, and FEF 25-
75 in eCRF is deleted. 
To ensure consistency with the 
centralized spirometry data collection 
procedure. 
Section 8.1.4 
Spirometry 
This section is updated as per removal of 
inclusion criteria 4. 
To ensure consistency within protocol 
sections.  
Section 8.1.6.2 Sino-Nasal 
Outcome Test-22 Items 
(SNOT-22) 
The text is updated for the domain score 
calculation. 
To ensure consistency with SAP. 
Section 9.1 
Statistical hypotheses 
Section 9.4.2 
Primary endpoints 
The criterion for alternative hypothesis is 
updated. 
Intercurrent event(s) handling for study 
intervention discontinuation due to COVID-19 is 
added. 
To have a more accurate description. 
Section 9.1 
Statistical hypotheses 
Reference to multiplicity control procedure in SAP 
is added 
To clarify that the multiplicity control 
strategy will be specified in SAP. 
Section 9.3 
Populations for analyses 
Table 6 
Definition for Safety (as-treated) population 
updated to include randomized. 
To have a more accurate description of 
the populations.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.4.1 
General considerations 
Criteria for meeting primary endpoints is deleted. 
To remove the duplicate information 
from Section 9.1. 
Appendix 3 
Section 10.3.1 
Definition of AE 
Following statement added 
Protocol defined asthma exacerbation events are 
collected as efficacy endpoints via the “Asthma 
Exacerbation Events” form”. These events should 
not be reported as AEs unless they fulfill a 
seriousness criterion. 
To clarify that asthma exacerbation is 
not an AE. 
Throughout the text 
Following sections are updated 
Section 6.3-Measures to minimize bias: 
Randomization and Blinding 
Section 8.3.5- Pregnancy 
Appendix 1 Section 10.1.4-Data protection 
Appendix 1 Section 10.1.6-Dissemination of 
clinical study data and results 
Appendix 1 Section 10.1.9-Study and site start 
and closure 
Appendix 9-Contingency Measures for a regional 
or national emergency that is declared by 
a governmental agency 
Appendix 3 Section 10.3.1- Definition of AE 
unsolicited and solicited AE added 
Following sections are deleted as they are not 
applicable 
Section 8.3.6- Cardiovascular and death events 
Section 8.3.7- Disease related events and/or 
disease-related outcomes not qualifying as AEs 
or SAEs 
To follow recent template instructions. 
Throughout the text 
Minor grammatical, editorial, and/or 
administrative changes. 
To improve the readability and/or clarity 
of the protocol. 
Amended protocol 01 (10 June 2021) 
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 [because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study]. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main reason for this amendment is to fulfill the condition raised by agencies from EU 
member states participating to VHP. 
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Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
Section 5.2 
Exclusion 
criteria 
Additional wording on EC 10 to exclude patients with 
infections receiving symptomatic treatment. 
E 10: Active chronic or acute infection requiring treatment with 
systemic antibiotics, antivirals, antifungals or receiving only 
symptomatic treatment (e.g influenza or COVID 19) within 
2 weeks before Visit 1(screening visit) or during the screening 
and run-in period. 
To provide clarification on EC 10 as per 
Regulatory Agency request 
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