A Randomized, Double-blind, Placebo-controlled Efficacy and Safety Study of Dupilumab, in Chinese Adult Participants With Chronic Rhinosinusitis With Nasal Polyposis (CRSwNP) on a Background Therapy With Intranasal Corticosteroids
Phase: PHASE3
Conditions: Chronic Rhinosinusitis With Nasal Polyps
Sponsor: Sanofi

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According to Template: Sanofi OneDocument Version 7.1, dated 30-MAR-2022 
Page 1 
CLINICAL TRIAL PROTOCOL 
Protocol title: 
A randomized, double-blind, placebo-controlled 
efficacy and safety study of dupilumab, in Chinese 
adult participants with chronic rhinosinusitis with 
nasal polyposis (CRSwNP) on a background therapy 
with intranasal corticosteroids 
Protocol number: 
EFC17026 
Amendment number: 
Original protocol 
Compound number 
(INN/Trademark): 
SAR231893 
dupilumab/Dupixent 
Brief title: 
Dupilumab in Chinese adult participants with CRSwNP 
Acronym: 
Not applicable 
Study phase: 
Phase 3 
Sponsor name: 
sanofi-aventis groupe 
Legal registered address: 
54, rue La Boétie, 75008 Paris, France 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
EUDAMED: 
Other: 
Not applicable 
Not applicable 
NCT05878093 
U1111-1256-9711 
Not applicable 
Not applicable 
Date: 
14-Sep-2022 
Total number of pages: 100 
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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ....................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 7 
LIST OF FIGURES .......................................................................................................................................... 7 
1 
PROTOCOL SUMMARY ................................................................................................................. 8 
1.1 
SYNOPSIS ....................................................................................................................................... 8 
1.2 
SCHEMA ........................................................................................................................................ 14 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 15 
2 
INTRODUCTION............................................................................................................................ 19 
2.1 
STUDY RATIONALE ..................................................................................................................... 19 
2.2 
BACKGROUND ............................................................................................................................. 20 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 22 
2.3.1 
Risk assessment ............................................................................................................................ 22 
2.3.2 
Benefit assessment ........................................................................................................................ 24 
2.3.3 
Overall benefit/risk conclusion ....................................................................................................... 25 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ......................................................................... 26 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 27 
4 
STUDY DESIGN ............................................................................................................................ 29 
4.1 
OVERALL DESIGN ........................................................................................................................ 29 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 30 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 31 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 32 
5 
STUDY POPULATION .................................................................................................................. 33 
5.1 
INCLUSION CRITERIA .................................................................................................................. 33 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 34 
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5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 37 
5.4 
SCREEN FAILURES ..................................................................................................................... 38 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ............................................................................... 38 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 39 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 39 
6.1.1 
Investigational medicinal product(s)............................................................................................... 41 
6.1.2 
Non-investigational medicinal product(s) ....................................................................................... 42 
6.1.2.1 
Intranasal corticosteroid background therapy ................................................................................ 42 
6.1.3 
Devices .......................................................................................................................................... 43 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ........................................... 43 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 44 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 45 
6.5 
DOSE MODIFICATION .................................................................................................................. 45 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY ...................... 46 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 46 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 46 
6.8.1 
Prohibited concomitant medication ................................................................................................ 46 
6.8.2 
Permitted concomitant medication ................................................................................................. 47 
6.8.3 
Rescue medicine............................................................................................................................ 48 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 49 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 49 
7.1.1 
Permanent discontinuation ............................................................................................................ 49 
7.1.2 
Liver chemistry stopping criteria .................................................................................................... 51 
7.1.3 
QTc stopping criteria ...................................................................................................................... 51 
7.1.4 
Temporary discontinuation ............................................................................................................. 51 
7.1.5 
Rechallenge ................................................................................................................................... 51 
7.1.5.1 
Study intervention restart or rechallenge after liver stopping criteria are met ............................... 51 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 52 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 53 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 54 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 54 
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8.1.1 
Nasal polyps score (NPS) .............................................................................................................. 55 
8.1.2 
Nasal congestion/obstruction scores (NCS) .................................................................................. 55 
8.1.3 
Proportion of participants during the treatment period who receive SCS rescue or are 
planned to undergo surgery for NP ................................................................................................ 56 
8.1.4 
Disease specific daily symptom assessment and total symptom score (TSS) .............................. 57 
8.1.5 
Decreased/loss of sense of smell .................................................................................................. 57 
8.1.6 
22-Item sino-nasal outcome test (SNOT-22) ................................................................................. 57 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 57 
8.2.1 
Physical examinations ................................................................................................................... 58 
8.2.2 
Vital signs ....................................................................................................................................... 58 
8.2.3 
Electrocardiograms ........................................................................................................................ 58 
8.2.4 
Clinical safety laboratory tests ....................................................................................................... 58 
8.2.5 
Pregnancy testing .......................................................................................................................... 59 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 59 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 59 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 60 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 60 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 60 
8.3.5 
Pregnancy ...................................................................................................................................... 61 
8.3.6 
Adverse events of special interest ................................................................................................. 61 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 62 
8.3.7.1 
Medical device deficiencies ........................................................................................................... 63 
8.4 
PHARMACOKINETICS .................................................................................................................. 63 
8.5 
GENETICS ..................................................................................................................................... 63 
8.6 
BIOMARKERS ............................................................................................................................... 63 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 63 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 63 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 63 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 65 
9.1 
POPULATIONS FOR ANALYSES ................................................................................................. 65 
9.2 
STATISTICAL ANALYSES ............................................................................................................ 65 
9.2.1 
General considerations .................................................................................................................. 66 
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9.2.2 
Primary endpoint(s) analyses ........................................................................................................ 67 
9.2.3 
Secondary endpoint(s) analyses .................................................................................................... 68 
9.2.4 
Tertiary/exploratory endpoint(s) analyses ...................................................................................... 68 
9.2.5 
Multiplicity adjustment .................................................................................................................... 69 
9.2.6 
Other safety analyses .................................................................................................................... 69 
9.2.6.1 
Adverse events .............................................................................................................................. 69 
9.2.6.2 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 70 
9.2.7 
Other analyses ............................................................................................................................... 70 
9.3 
INTERIM ANALYSES  ................................................................................................................... 71 
9.4 
SAMPLE SIZE DETERMINATION................................................................................................. 71 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 72 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 72 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 72 
10.1.2 
Financial disclosure ....................................................................................................................... 73 
10.1.3 
Informed consent process .............................................................................................................. 73 
10.1.4 
Data protection ............................................................................................................................... 74 
10.1.5 
Committees structure ..................................................................................................................... 76 
10.1.6 
Dissemination of clinical study data ............................................................................................... 76 
10.1.7 
Data quality assurance .................................................................................................................. 77 
10.1.8 
Source documents ......................................................................................................................... 78 
10.1.9 
Study and site start and closure ..................................................................................................... 78 
10.1.10 Publication policy ........................................................................................................................... 79 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 79 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 81 
10.3.1 
Definition of AE .............................................................................................................................. 81 
10.3.2 
Definition of SAE ............................................................................................................................ 83 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 84 
10.3.4 
Reporting of SAEs ......................................................................................................................... 86 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 87 
10.4.1 
Definitions ...................................................................................................................................... 87 
10.4.2 
Contraception guidance ................................................................................................................. 89 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 90 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS  ........................................................................................................................... 90 
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10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................... 91 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 91 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 91 
10.10 
APPENDIX 10: ADDITIONAL APPENDICES ................................................................................ 92 
10.10.1 List of prohibited live attenuated vaccines ..................................................................................... 92 
10.10.2 SNOT-22 ........................................................................................................................................ 93 
10.10.3 Definition of anaphylaxis ................................................................................................................ 94 
10.10.4 List of opportunistic infections ........................................................................................................ 94 
10.11 
APPENDIX 11: ABBREVIATIONS ................................................................................................. 95 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY ................................................................ 97 
11 
REFERENCES............................................................................................................................... 98 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 26 
Table 2 - Summary of primary estimands for primary endpoint .................................................................... 27 
Table 3 - Study intervention(s) administered ................................................................................................ 40 
Table 4 - Study arm(s) ................................................................................................................................... 41 
Table 5 - Endoscopic nasal polyp score........................................................................................................ 55 
Table 6 - Symptom severity score ................................................................................................................. 56 
Table 7 - Populations for analyses ................................................................................................................ 65 
Table 8 - Protocol-required laboratory tests .................................................................................................. 80 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 14 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A randomized, double-blind, placebo-controlled efficacy and safety study of dupilumab, in 
Chinese adult participants with chronic rhinosinusitis with nasal polyposis (CRSwNP) on a 
background therapy with intranasal corticosteroids 
Brief title: 
Dupilumab in Chinese adult participants with CRSwNP 
Rationale: 
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a clinical condition characterized by the 
bilateral presence of multiple polyps in the nasal cavity, long-term symptoms, and T helper (Th)-2 
polarization with tissue eosinophilia, increased levels of interleukin (IL)-4, IL-5 and IL-13, as 
well as high local production of immunoglobulin E (IgE). The prevalence of CRSwNP was 
reported to be 1.1% in China (1). CRSwNP has a high burden of symptoms and relapse rate after 
treatment, which impacts greatly upon a patient’s quality of life (QoL).  
The therapeutic armamentarium of clinically proven medical interventions for CRSwNP is limited 
to topical corticosteroids (intranasal corticosteroid [INCS]), and short courses of oral steroids as 
adjunctive therapy to INCS. However, the effect of INCS in reducing polyp size and on 
improving the sense of smell, a cardinal symptom of CRSwNP is limited (2, 3). The long-term use 
of systemic steroids for the treatment of nasal polyps is not recommended as the risk of prolonged 
systemic steroids use is not outweighed by the benefit (4). The only alternative for most patients 
that respond inadequately to medical treatment is surgery of the sinuses. However, even after 
surgical treatment, continued use of at least INCS is needed and disease recurrence requiring 
repeated surgeries is high. 
Dupilumab is a fully human monoclonal antibody (mAb) directed against the IL-4 receptor alpha 
subunit (IL-4Rα), which is a component of IL-4 receptors type 1 and type 2, as well as the IL-13 
type 2 receptor. The binding of dupilumab to IL-4Rα results in blockade of IL-4 and IL-13 
intracellular signaling. Dupilumab has demonstrated efficacy across a broad range of diseases 
driven by type 2 inflammation, including atopic dermatitis (AD), asthma, CRSwNP and 
eosinophilic esophagitis (EoE). Clinically significant efficacy in reducing nasal polyps burden and 
nasal congestion (NC), in addition to statistically significant improvement in sinus opacification and 
well tolerated safety profile have been demonstrated with dupilumab treatment in two global pivotal 
studies in participants with CRSwNP (LIBERTY NP SINUS-24, LIBERTY NP SINUS-52) (5). For 
complete information regarding the preclinical and clinical evaluation of dupilumab to date, see 
the Investigator’s Brochure (IB). 
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As there remains high unmet need for novel therapies to treat CRSwNP in China, the Sponsor will 
investigate the efficacy and safety of dupilumab on a background of INCS in Chinese patients 
with moderate-to-severe signs and symptoms of CRSwNP who are not controlled on standard of 
care. 
Objectives and endpoints: 
 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of dupilumab compared to 
placebo on a background of budesonide nasal 
spray in reducing endoscopic nasal polyps score 
(NPS) in Chinese participants with bilateral nasal 
polyposis (NP). 
• 
Change from baseline in NPS at Week 24. 
Secondary 
 
• 
To evaluate the efficacy of dupilumab in reducing 
nasal congestion/obstruction (NC) severity. 
• 
Change from baseline in NC score (NCS) based on 
the participant daily morning assessment at 
Week 24. 
• 
To evaluate the efficacy of dupilumab in improving 
total symptoms score (TSS). 
• 
Change from baseline in TSS at Week 24: 
composite severity score consisting of the 
participant daily morning assessed NC, 
decreased/loss of sense of smell, anterior/posterior 
rhinorrhea. 
• 
To evaluate the efficacy of dupilumab in improving 
sense of smell. 
• 
Change from baseline in the severity of 
decreased/loss of smell assessed daily by 
participants at Week 24. 
• 
To evaluate the effect of dupilumab on patient 
quality of life. 
• 
Change from baseline in total score of 22-item sino-
nasal outcome test (SNOT-22) at Week 24. 
• 
To evaluate the ability of dupilumab to reduce 
proportion of participants who require treatment with 
systemic corticosteroid (SCS) or surgery for NP. 
• 
Proportion of participants receiving SCS for any 
reason or undergo surgery for nasal polyps during 
the study treatment. 
• 
To evaluate the safety of dupilumab in Chinese 
participants with bilateral NP. 
• 
Safety (incidence of treatment-emergent adverse 
events [TEAEs], of treatment-emergent serious 
adverse events [TESAEs], and TEAEs leading to 
treatment discontinuation), laboratory values, vital 
signs. 
 
 
 
 
Overall design: 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group study 
to assess the efficacy and safety of dupilumab 300 mg every 2 weeks (Q2W) compared to 
placebo, in Chinese adult participants with moderate-to-severe signs and symptoms of bilateral 
nasal polyposis (NP) on a background treatment with intranasal corticosteroids.  
Disclosure Statement: This is an interventional study with 2 arms that are blinded to 
both participants and investigators. 
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Brief summary:  
This is a parallel group, Phase 3, 2-arm study for treatment.  
The purpose of this study is to evaluate dupilumab subcutaneous (SC) injections compared to 
placebo in Chinese adult participants with CRSwNP, on a background therapy with intranasal 
corticosteroids (budesonide nasal spray). 
Study details include: 
• The study duration will be up to 40 weeks. 
• The treatment duration will be up to 24 weeks. 
• The number of visits will be 7. 
Number of participants: 
Approximately 62 participants (31 per arm) with CRSwNP will be randomized 1:1 to receive 
either dupilumab or matching placebo. 
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: 
• Arm A: dupilumab 300 mg Q2W up to Week 24. 
• Arm B: placebo matching dupilumab Q2W up to Week 24. 
Study intervention(s) 
Investigational medicinal product(s) 
Dupilumab 300 mg and placebo matching dupilumab 300 mg will be supplied in visually 
indistinguishable prefilled syringes. 
Dupilumab: 
• Formulation: a 150 mg/mL dupilumab solution in a prefilled syringe to deliver 300 mg in 
a 2 mL injection 
• Route of administration: SC injection 
• Dose regimen: one injection of dupilumab 300 mg Q2W 
Placebo: 
• Formulation: identical formulation to the active 300 mg formulation without dupilumab, in 
a prefilled syringe to deliver placebo in a 2 mL injection 
• Route of administration: SC injection 
• Dose regimen: one injection of placebo matching dupilumab 300 mg Q2W 
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Noninvestigational medicinal product(s) 
Budesonide (RHINOCORT®) 64 μg/actuation nasal spray, suspension.  
• Formulation: nasal spray (suspension) is provided in a bottle that contains 120 actuations 
(64 μg/actuation) of product formulation. 
• Route of administration: nasal spray. 
• Dose regimen: budesonide nasal spray 2 actuations (64 μg/actuation) in each nostril 
each morning (QM), or 1 actuation in each nostril twice daily (BID) (total daily dose of 
256 μg). One actuation in each nostril once daily (total daily dose of 128 μg) if the 
participants are unable to tolerate BID, in which case they can stay on a lower dose 
regimen (128 μg) of budesonide nasal spray. 
Posttrial access to study medication 
Posttrial access to study medication will not be provided. 
Duration of study intervention 
• Run-in period: 4 weeks +/-3 days 
• Randomized treatment period: up to 24 weeks +/-3 days 
• 
Follow-up period: 12 weeks +/-3 days 
Statistical considerations: 
Randomization 
Participants will be randomized to dupilumab 300 mg Q2W or matching placebo in a 1:1 ratio at 
randomization visit (Day 1). 
Plan to enroll at least 85% (approximately 52) participants with screening blood eosinophil count 
≥300 cells/mm3. Randomization will be stratified by screening blood eosinophil count 
(≥300 cells/mm3 or <300 cells/mm3). 
To ensure enrollment according to the intended distribution of screening blood eosinophil count, 
alerts will be built into the IRT to control the number of participants in each stratification group as 
follows: 
• ≥300 cells/mm3: approximately 26 participants per arm, 
• <300 cells/mm3: up to approximately 5 participants per arm. 
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Sample size consideration 
The primary endpoint is the change from baseline in nasal polyps score (NPS) at Week 24. 
A sample size of 31 participants per arm will provide at least 90% power to detect a difference of 
-1.8 in the change from baseline in NPS at Week 24 between dupilumab 300 mg Q2W and 
matching placebo, assuming a common standard deviation (SD) of 1.83 at the 5% significance 
level (2-sided) and a 25% dropout rate. Assumptions are based on the following: 
• Mean treatment difference = -1.8 (lowest observed effect size of NPS at Week24 in the 
EFC14146 [SINUS-24] and EFC14280 [SINUS-52])  
• SD=1.83 (highest SD of NPS reduction at Week24 in the EFC14146 [SINUS-24] and 
EFC14280 [SINUS-52]) 
• Dropout rate 25% (higher than 10% due to COVID-19 uncertainties) 
Primary analysis population 
The analysis population for the efficacy endpoints will be the intent-to-treat (ITT) population, 
defined as all randomized participants analyzed according to the treatment group allocated by 
randomization, regardless of whether treatment kit is used or not. 
Analysis of primary and main secondary endpoints 
• Primary endpoint:  
In the primary analysis approach for the primary endpoint (change from baseline in NPS at 
Week 24), for participants who undergo surgery for NP or receive systemic corticosteroids 
(SCS) for any reason, data collected post-surgery or SCS will be set to missing and the 
worst post-baseline value on or before the time of surgery or SCS will be used to impute 
missing Week 24 values (ie, worst observation carried forward [WOCF] approach). For 
participants with no post-baseline values, the baseline value will be used. For participants 
taking other prohibited/rescue medications, all data collected after use will be used in the 
analysis. Participants who discontinue the study intervention prematurely are encouraged 
to follow the planned clinical visits. For participants who discontinue the study 
intervention without being rescued by surgery or receiving SCS by Week 24, data 
collected after study intervention discontinuation will be included in the analysis. In case 
there is missing data, a multiple imputation will be used to impute missing Week 24 
values, and this multiple imputation will use all participants excluding those who have 
undergone surgery or received SCS on or before Week 24. Each of the imputed completed 
data will be analyzed by fitting an analysis of covariance (ANCOVA) model with the 
baseline covariate and factor for study intervention and screening blood eosinophil count 
strata. Statistical inference obtained from all imputed data will be combined using Rubin’s 
rule. Descriptive statistics including number of participants, mean, standard error, and 
least squares (LS) means will be provided. In addition, difference in LS means and the 
corresponding 95% confidence intervals (CI) will be provided along with the p-values. 
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• Main secondary endpoints:  
Continuous secondary efficacy endpoints will be analyzed using the hybrid method of the 
WOCF and the MI in the same fashion as for the primary endpoint. 
Proportion of participants with first SCS rescue for any reason or surgery (actual or 
planned) for NP during the 24-week study intervention period will be derived and 
analyzed using the Cox proportional hazards model and log rank test stratified by 
screening blood eosinophil count strata, by considering the first SCS use or surgery for NP 
(actual or planned) as the event. Descriptive statistics including number of participants 
with rescue SCS or surgery and number of participants without rescue SCS or surgery 
(censored) and the corresponding rates will be provided by study intervention group. The 
estimates of the hazard ratio and corresponding 95% CI will be provided for the 
dupilumab group versus the placebo group. 
The safety variables, including adverse events (AEs), laboratory parameters, and vital 
signs, will be summarized using descriptive statistics. 
Multiplicity considerations 
A hierarchical procedure is proposed to strongly control the family wise type-I error rate at the 
2-sided 0.05. The primary endpoint will be tested first, followed by selected secondary endpoints. 
The detailed hierarchical testing procedures will be defined in the study statistical analysis plan 
(SAP). 
Planned Database lock date 
A primary database lock is currently planned to be performed when all randomized participants 
have completed the 24-week treatment period, including early dropouts. 
The database will be updated at the end of the study for all participants to include the post-
treatment follow-up information and updates for the events previously ongoing at the time of the 
primary lock. Additional data collected between the primary database lock and last participant 
completing last visit will be summarized in a separate clinical study report (CSR) addendum, as 
needed. Details will be included in the SAP. 
Data Monitoring/Other committee: No 
 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
EOS: end of study; EOT: end of treatment; Q2W: every 2 weeks; R: randomization; V: visit; W: week 
 
Investigational medicinal product (IMP): Regardless of the treatment group, all randomized participants will receive Q2W SC administrations of dupilumab 300 mg or placebo. Every other week IMP administrations 
must be separated by at least 11 days. At Day 1 (W0 [V2]) the Investigator or delegate will prepare and perform the injection, in front of the participant (or caregiver). The participant (or caregiver) will prepare and 
inject the IMP under the supervision of the Investigator or delegate at W2 (V3). From W4 (except W8 [V4] and W16 [V5]), every other week home administration of IMP is possible if the participant (or the caregiver) 
has been trained. If the participant (or caregiver) is unable or unwilling to administer IMP, arrangements (ie, unscheduled visits) must be made for qualified site personnel and/or healthcare professionals to administer 
IMP for the doses not scheduled to be given at the study site. Patients will be monitored for at least 30 minutes after IMP administration. The planned last dose of IMP is at W22. 
Non-investigational medicinal product (NIMP): Budesonide nasal spray will be self-administered by the participant every day. At each visit the Investigator must ensure that the participant has the necessary and 
sufficient doses up to the next visit. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
 
Procedure 
Run-ina 
Randomized treatment period 
EOTc 
EOS 
Visit 
1 
2 
3 
 
4 
 
5 
 
6 
7 
Week 
W-4 
W0 
W2 
W4,6b 
W8 
W10, 12, 
14b 
W16 
W18, 20, 
22b 
W24 
W36 
Day +/-3 days 
D-28 
D1 
D15 
 
D57 
 
D113 
 
D169 
D253 
Informed consents 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Participant demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical/medication historyd 
X 
 
 
 
 
 
 
 
 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) (local reading) 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Treatment 
 
IMP: dupilumab/placebo injectionf 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Call IVRS (IWRS) at scheduled and 
unscheduled visit as needed 
X 
-------------------------------------------------------X---------------------------------------------------------- 
X 
X 
Review IMP and/or NIMP complianceg 
 
-------------------------------------------------------X---------------------------------------------------------- 
X 
 
Dispense or download electronic diary for 
symptomsh 
-----------------------------------------------------------------------------------X------------------------------------------------------------------------------------ 
NIMP: Budesonide nasal spray 
-----------------------------------------------------------------------------------X------------------------------------------------------------------------------------ 
Record concomitant medication 
-----------------------------------------------------------------------------------X------------------------------------------------------------------------------------ 
Record planned surgery for NP, SCS use, 
and other rescue medication usei 
-----------------------------------------------------------------------------------X------------------------------------------------------------------------------------ 
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Procedure 
Run-ina 
Randomized treatment period 
EOTc 
EOS 
Visit 
1 
2 
3 
 
4 
 
5 
 
6 
7 
Week 
W-4 
W0 
W2 
W4,6b 
W8 
W10, 12, 
14b 
W16 
W18, 20, 
22b 
W24 
W36 
Day +/-3 days 
D-28 
D1 
D15 
 
D57 
 
D113 
 
D169 
D253 
Efficacy 
 
Nasal endoscopyj 
X 
X 
 
 
 
 
X 
 
X 
 
Patient reported outcomes/HRQoLk 
 
Severity score (0-3) for nasal 
congestion/obstruction 
-----------------------------------------------------------------------------------X------------------------------------------------------------------------------------ 
Severity score (0-3) for rhinorrhea 
-----------------------------------------------------------------------------------X------------------------------------------------------------------------------------ 
Severity score (0-3) for decreased/loss of 
sense of smell 
-----------------------------------------------------------------------------------X------------------------------------------------------------------------------------ 
22-item sino-nasal outcome test (SNOT-22) 
X 
X 
 
 
 
 
X 
 
X 
 
Safety 
 
AE/serious adverse event (SAE) recording 
-----------------------------------------------------------------------------------X------------------------------------------------------------------------------------ 
Vital signs, weight and heightl 
X 
X 
X 
 
X 
 
X 
 
X 
 
Physical examination 
X 
 
 
 
 
 
 
 
X 
X 
Laboratory testing 
 
Clinical laboratory testingm 
X 
X 
 
 
X 
 
X 
 
X 
 
Pregnancy test (for women of childbearing 
potential [WOCBP])n 
X 
X 
 
X (W4) 
X 
X (W12) 
X 
X (W20) 
X 
X 
a The run-in period is 28 days in duration to run in any participant on budesonide nasal spray, and to collect baseline data. Participants receiving rescue medication with SCS and/or surgery during this period will not be 
randomized. V2 will take place 28 days +/-3 days window after V1. Window for subsequent visits is also +/-3 days. Assessments/procedures at a site visit will be performed in the following order as applicable: 
Patient-reported outcomes and other questionnaires; Procedures; Safety and laboratory assessments; IMP administration. Although the screening assessments are grouped under the heading of a single visit, it is 
possible for them to be performed over more than 1 site visit if necessary, as long as the visit window prior to Day 1 (V2) is respected. 
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b IMP will be administered Q2W. Home administration can be performed at home by participant or caregiver at W4, 6, 10, 12, 14, 18, 20, 22 after 1st IMP administration performed by the study site team at W0 (V2) 
and successful preparation and injection performed by participant or caregiver at W2 (V3) under investigator supervision. Optional interim visits could be scheduled at site for IMP/NIMP supply or IMP administration. 
The planned last dose is at W22. 
c Participants who discontinue treatment early should be assessed as soon as possible using the procedures normally planned for the EOT Visit and should be instructed to return to the study site. 
d 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. Systemic corticosteroids (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 electronic case report form (e-CRF).  
e Chest X-ray if no chest imaging (X-ray, CT, magnetic resonance imaging [MRI]) is available within the previous year of V1.  
f 
IMP should be administered after completion of all scheduled clinical assessments and sample collections at the visit or at home. 
g For doses not given at the study site participants will complete a dosing e-diary to document compliance with self-injection (or caregiver) of IMP, location of injection, and any symptoms. The e-diary will also be used 
for daily recording of budesonide nasal spray use. The e-diary will be kept as source data in the participant’s study file. 
h Electronic diary will be used for daily recording of symptoms severity from V1 to end of study: 1) nasal congestion/obstruction, 2) anterior rhinorrhea (runny nose), 3) posterior rhinorrhea (post nasal drip), and 4) loss 
of sense of smell, scored using a 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms). This device of e-diary will be dispensed at V1 and information 
will be downloaded from this device on the other indicated days. For nasal congestion, a severity ≥2 on V1 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 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. 
i 
At baseline (V1 and V2) eligibility to surgery based on Investigator opinion will be assessed. During the study treatment and follow-up, if rescue medication with systemic corticosteroids is required, oral prednisone, 
prednisolone or equivalent can be prescribed by the investigate to the participant through a scheduled or unscheduled site visit. Use of systemic steroids for rescue treatment of worsening nasal polyps or for another 
reason will be captured by the Investigator (or designee) on the appropriate source document and the date and dosing information (daily dose, duration, INN) will be informed. Details on actual or planned date for 
surgery for NP, type and outcome (wherever possible) will be recorded in a specific e-CRF page. If surgery is performed during the study treatment period or follow-up period, an AE or SAE page will be completed. 
They will be discontinued from study treatment and assessed as soon as possible using the procedures normally planned for the EOT/EOS visit and will be instructed to return to the study site. If surgery is scheduled 
after the planned end of study, end of study will not be delayed. A follow up contact(s) should be performed around the time of planned surgery to document the surgery date and outcome. Surgery data will be 
collected until e-CRF closure of the trial. 
j 
Nasal endoscopy (NE): endoscopy (including use of decongestants before the procedure) is performed after all other efficacy assessments have been completed for pre-specified visit; standard video sequences 
will be downloaded by the Investigator to the central reader’s secured internet site. For eligibility, central reading of V1 is used. At V2, Investigator will review V1 results from 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 NE to confirm eligibility score and enter the result in the e-CRF. 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 on each side. The final results of central reading from V2 onward will be made available to the site after the study completion. 
k During the study the patient reported outcomes (PROs) will be completed by the participant in the e-diary, in the following order: daily symptoms of NC, decrease/loss of smell and anterior and posterior rhinorrhea; 
SNOT-22. 
l 
Vital signs, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per minute), oral body temperature (degrees Celsius) and body weight (kg) will be measured at the screening 
and randomization visits (V1 and V2) and subsequent visits pre-specified in the SoA. Height (cm) will be measured at screening (V1) only. Vital signs will be measured prior to receiving IMP at the on-site visits in 
the sitting position using preferably the same arm at each visit. 
m Hematology: hemoglobin, hematocrit, platelet count, total white blood cell (WBC) count with five-part differential count, and total red blood cell (RBC) count. Serum chemistry: creatinine, blood urea nitrogen, glucose 
[nonfasting], uric acid, total cholesterol, total protein, albumin, total bilirubin (in case of values above the normal range, differentiation in conjugated and nonconjugated bilirubin), alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, lactate dehydrogenase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. Endocrinology: follicle stimulating hormone (FSH) level in the 
postmenopausal range should be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). Clinical laboratory testing at V1 includes hepatitis 
screen covering hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), total hepatitis B core antibody (HBcAb), hepatitis C virus antibodies (HCVAb), Human Immunodeficiency Virus (HIV) 
screen (anti-HIV-1 and HIV-2 antibodies). In case of results showing HBsAg (negative), and HBcAb (positive), an HBV DNA testing will be performed and should be confirmed negative prior to randomization. In case 
of results showing HCVAb (positive), HCV RNA testing will be performed and should be confirmed negative prior to randomization. Hematology testing at all visits will be performed by central lab. Other clinical lab 
testing will be performed by local or central lab. 
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n Serum pregnancy test at V1 and urine pregnancy tests every 4 weeks thereafter. A negative result is required between V1 and V2 prior to randomization visit. Urine pregnancy test could be performed at home as 
part of visit with or without the assistance of a home care provider. In case of positive urinary test, the study treatment should be withhold and a serum pregnancy test to confirm the pregnancy should be performed 
as soon as possible. Pregnancy resulted in definitive treatment discontinuation in all cases. 
 
Abbreviations: AE: adverse event; D: day; EC: ethic committee; ECG: electrocardiogram; e-CRF: electronic case report form; EOS: end of study; EOT: end of treatment; FU: follow-up; HRQoL: health-related quality of 
life; IgE: immunoglobulin E; IMP: investigational medicinal product; IVRS: interactive voice response system; IWRS: interactive web response system; MRI: magnetic resonance imaging; NC: nasal congestion;  
NIMP: noninvestigational medicinal product; NE: nasal endoscopy; NP: nasal polyposis; PROs: patient reported outcomes; SAE: serious adverse event; SCS: systemic corticosteroids; SNOT-22: sino-nasal outcome 
test; V: visit; W: week; WBC: white blood cell; WOCBP: women of child bearing potential. 
 
 
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2 
INTRODUCTION  
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a clinical condition characterized by the 
bilateral presence of multiple polyps in the nasal cavity, originating from within the osteomeatal 
complex, and clinically characterized by long-term symptoms of nasal obstruction and congestion, 
reduction in or loss of sense of smell, anterior and posterior rhinorrhea, which impact greatly upon 
a patient’s QoL. NP has a high burden of symptoms and a high relapse rate after treatment. The 
prevalence of CRSwNP was reported to be 1.1% in China (1).  
Despite the significant morbidity associated with CRSwNP, treatment options are limited to local 
or systemic corticosteroids (SCS) and functional endoscopic sinus surgery (FESS). Patients with 
CRSwNP and comorbid asthma (~30% of patients with NP) have a characteristically poor 
therapeutic response and a high recurrence rate, and their disease tends to be more resistant (6, 7). 
Both IL-4 and IL-13 signaling pathways are implicated in atopic diseases and by blocking the 
activity of these cytokines, dupilumab has been shown to be an effective treatment for atopic 
conditions, including CRSwNP, AD, EoE and asthma (eosinophilic type 2). Dupilumab 
(Dupixent®) is authorized for marketing in over 60 countries worldwide, and has been approved 
as add-on maintenance treatment for CRSwNP in more than 50 countries including United States 
(US), European Union (EU) and Japan. In China, dupilumab is authorized for the treatment of 
patients aged 6 years and older with moderate-to-severe AD whose disease is not adequately 
controlled with topical therapies or when those therapies are not advisable. This study is designed 
to evaluate the efficacy and safety of dupilumab in Chinese participants with moderate-to-severe 
signs and symptoms of CRSwNP who are not controlled on standard of care. 
2.1 
STUDY RATIONALE  
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group study 
evaluating the efficacy and safety of dupilumab 300 mg every 2 weeks (Q2W) comparing to 
placebo on a background of INCS, in Chinese participants with moderate-to-severe signs and 
symptoms of CRSwNP who are not controlled on standard of care. 
Dupilumab is a fully human mAb directed against the interleukin 4 receptor alpha subunit (IL-4Rα), 
which is a component of IL-4 receptors type 1 and type 2, as well as the IL-13 type 2 receptor. The 
binding of dupilumab to IL-4Rα results in blockade of IL-4 and IL-13 intracellular signaling. As 
a targeted/specific immunomodulatory agent, dupilumab is expected to inhibit selectively the Th2 
pathway and is designed to achieve the desired therapeutic effect without the side effects typically 
associated with the use of less selective immunosuppressants. Dupilumab has demonstrated efficacy 
across a broad range of diseases driven by type 2 inflammation, including AD, asthma, CRSwNP 
and EoE. In the AD Phase 3 study in China (EFC15116), treatment with dupilumab 300 mg Q2W 
resulted in statistically significant and clinically meaningful improvements in the proportion of 
patients with both Investigator's global assessment (IGA) 0 or 1 and a reduction from baseline of 
≥2 points compared to placebo at Week 16. Moreover, these results had comparable safety and 
efficacy to the overall global pivotal studies (SOLO1, SOLO2).  
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Dupilumab has been shown to be an effective treatment for CRSwNP in two successful Phase 3 
pivotal studies (LIBERTY NP SINUS-24, LIBERTY NP SINUS-52) of 24- and 52-weeks 
duration in which participants with CRSwNP were dosed with 300 mg Q2W dupilumab as add-on 
treatment to background therapy of topical corticosteroids (mometasone nasal spray) in 
participants with CRSwNP. Significant efficacy was observed in these studies regarding reduction 
of endoscopic nasal polyps score, nasal congestion, and overall sinus opacification assessed by 
computed tomography (CT) scan. The effect extended to all analyzed secondary endpoints 
including QoL, sense of smell, and symptoms of rhinosinusitis as well as in asthma symptoms and 
lung function in participants with co-morbid asthma. Furthermore, dupilumab significantly 
reduced the need for systemic steroids for CRSwNP and sino-nasal surgery. In subgroups defined 
by eosinophils <300 cells/mm3 or ≥300 cells/mm3, the nasal polyp scores LS mean treatment 
difference in dupilumab versus placebo were similar (-1.56 [95%CI: -1.9, -1.21] and -2.13 
[95%CI: -2.44, -1.82], respectively). In a pooled safety analysis of SINUS-24 and SINUS-52, the 
incidence of the most commonly reported AEs was more frequent with placebo than dupilumab. 
Dupilumab was generally well tolerated and had an acceptable safety profile in the treatment of 
participants with inadequately controlled CRSwNP as well as long-term treatment (5). 
In global pivotal Phase 3 studies (SINUS-24 and SINUS-52) of CRSwNP, the trend of slightly 
higher exposure in Asians/Japanese compared to the Caucasians/Non-Japanese was mainly caused 
by differences in body weight, while there were no clinically significant differences in efficacy 
and safety across race groups or ethnic groups. In addition, the safety and efficacy of dupilumab 
in Chinese adult AD participants in study EFC15116 was similar to the global pivotal AD studies. 
Therefore, no clinically meaningful difference in efficacy and safety between Chinese and non-
Asian participants with CRSwNP is expected. Dupilumab, therefore, offers promise of significant 
benefit above and beyond current standard of care and may provide an alternative for Chinese 
adult patients with inadequately controlled CRSwNP and may obviate the need for repeated 
surgeries. 
As there remains high unmet need for novel therapies to treat CRSwNP in China, the Sponsor will 
investigate the efficacy and safety of dupilumab on a background of INCS in Chinese adult 
participants with moderate-to-severe signs and symptoms of CRSwNP who are not controlled on 
standard of care. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of dupilumab is 
provided in the Investigator’s Brochure (IB). 
2.2 
BACKGROUND  
Chronic rhinosinusitis is characterized by inflammation of the nasal mucosa and paranasal sinuses 
and can be further divided into chronic rhinosinusitis with and without nasal polyps. Nasal polyps 
are inflammatory hyperplastic growths that protrude into the nasal passages. Clinically, chronic 
rhinosinusitis with nasal polyposis (CRSwNP) is defined by long-term symptoms of nasal 
obstruction and congestion, reduction in or loss of sense of smell, and anterior and posterior 
rhinorrhea. These symptoms can impact greatly a patient’s quality of life (QoL). The presence or 
absence of polyps is confirmed by performing endoscopy. With an estimated prevalence of 
2.5% to 4% (in Europe and US), NP has a high burden of symptoms and a high relapse rate after 
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treatment (7). The prevalence of CRSwNP in China was reported to be 1.1% (1), corresponding to 
over 15 million patients. Despite the significant morbidity associated with CRSwNP, treatment 
options are limited to local or systemic corticosteroids (SCS) and functional endoscopic sinus 
surgery (FESS). Patients with CRSwNP and comorbid asthma (~30% of patients with NP) have 
a characteristically poor therapeutic response and a high recurrence rate, and their disease tends to 
be more resistant (6, 7).  
The pathogenesis of nasal polyps is unknown. Nasal polyps are most commonly thought to be 
caused by allergy, although a significant number are associated with nonallergic adult asthma or 
no respiratory or allergic trigger that can be demonstrated. Risk factors include genetic 
susceptibility, anatomic abnormalities, infection, local immunologic imbalance and eicosanoid 
dysmetabolism (manifested as aspirin intolerance), some or most of which may play a role in its 
pathogenesis (8, 9, 10). 
Pathophysiologically, CRSwNP is an inflammatory and remodeling process affecting the mucosa 
of the nose and paranasal sinuses often associated with mucocilliary impairment, bacterial 
infection, allergic disease, and/or anatomical abnormalities (11, 12, 13). Uncontrolled severe 
CRSwNP is typically a Th2 driven inflammatory process in which eosinophils are the 
predominant inflammatory cell found in the sinuses and nasal polyps, and is frequently associated 
with asthma and aspirin sensitivity (14). The extent of sinomucosal involvement, the size of the 
polyps, and the severity of nasal disease correlate with the extent of eosinophilic inflammation 
(15). The chronic inflammation associated with eosinophilic polyps exhibits elevated levels of 
interleukin-5 (IL)-5 (promoter of eosinophil survival, differentiation and taxis), eosinophil 
cationic protein (eosinophil activation product), eotaxins (eosinophil chemoattractants), and IgE in 
the nasal polyps and local secretions (16). High tissue eosinophilia (HTE) appears to be the most 
significant predictor of polyp recurrence among several factors. Eosinophilic CRSwNP presents 
more uncontrolled severe clinical features and higher recurrence rate following surgery. In 
European and US populations, more than 80% of patients with CRSwNP have eosinophilic upper 
airway inflammation. In the past studies, it was shown the CRSwNP patients in Asian showed 
lower eosinophilic inflammation than Western patients (7). But some recent studies show that the 
proportion of eosinophilic CRSwNP has significantly increased from 59.1% to 73.7% over the 
recent decade in China, which is comparable to the data from Western countries (17, 18, 19). 
Type 2 CRSwNP is associated with elevated blood eosinophils (20); elevated blood eosinophils 
are associated with tissue eosinophilia in Chinese CRSwNP patients (21, 22). 
The therapeutic armamentarium of clinically proven medical interventions for CRSwNP is 
limited. First-line treatment is topical corticosteroids. Intranasal corticosteroid (INCS) sprays 
improve the symptoms of nasal obstruction (4), secretion, and sneezing to some extent. However, 
their effect in reducing polyp size and on improving the sense of smell, a cardinal symptom of 
CRSwNP is limited (2, 3). Overall, due to the relatively modest effects on the symptoms of 
CRSwNP, in many instances, INCSs do not address the main QoL issues for patients. Short 
courses of oral steroids are also prescribed as adjunctive therapy to INCS or in cases of severe 
disease (23); however, the long-term use of systemic steroids for the treatment of nasal polyps is 
not recommended as the risk of prolonged systemic steroids use is not outweighed by the benefit 
(4).The current US practice guidelines indicate that the duration of clinical benefit of oral 
corticosteroids (OCS) is variable and may decrease with repeated courses of treatment (24). 
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The only alternative for most patients that respond inadequately to medical treatment is surgery of 
the sinuses. However, even after surgical treatment, continued use of at least INCS is needed and 
disease recurrence requiring repeated surgeries is high. It was shown in a recent study in Chinese 
patients with CRSwNP and asthma who were randomly assigned to FESS, radical endoscopic 
sinus surgery (RESS), or RESS+Draf 3 surgery that recurrence rates were similarly high in all the 
groups at 5 years postoperatively, reaching 95.6-96.1% (25). 
The goals of new treatments include reduction of symptoms and systemic corticosteroid use and 
avoidance of surgery, as well as improved quality of life. Recent therapeutic approaches have 
been focused on trying to control the Th2 response and clinical improvement in NP and associated 
symptoms were observed in other studies of biological therapies, including the anti-IgE mAB 
omalizumab (26), the anti-IL-5 mAB mepolizumab (27), or the anti-IL-4Rα mAB dupilumab (5). 
In China there are currently no advanced therapies that are approved specifically for the treatment 
of CRSwNP. There remains great unmet need in identifying a novel therapy that addresses 
inflammatory underpinnings of the disease processes, reduces polyp size, improves symptoms and 
HRQoL, prevents recurrence, minimizes the need for systemic corticosteroids and recurrent nasal 
polyps surgery, and is well tolerated. 
2.3 
BENEFIT/RISK ASSESSMENT  
Dupilumab has shown clinically relevant benefit in several type 2 driven immunological 
disorders, such as AD, asthma, CRSwNP and EoE. Data showed similar efficacy, safety, and 
pharmacokinetics in adult and adolescents. A satisfactory safety profile has been observed so far 
in completed and ongoing studies, including those in AD, CRSwNP, asthma and EoE participants. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of dupilumab is available in the Investigator’s Brochure. 
2.3.1 Risk assessment  
No tissue targets or specific hazards to humans were identified in nonclinical general and 
reproductive toxicology studies. 
Dupilumab has an extensive safety database. As of 28 March 2022 (data cut-off date), 
13 577 subjects were enrolled into the development program for dupilumab and are included in 
the safety population: 564 as healthy volunteers, 4998 from AD studies, 4195 from asthma 
studies, 880 from rhinosinusitis (chronic rhinosinusitis with nasal polyposis [CRSwNP], chronic 
rhinosinusitis without nasal polyposis [CRSsNP] and allergic fungal rhinosinusitis [AFRS]) 
studies, 468 from eosinophilic esophagitis (EoE) studies, 275 from allergy (grass and peanut) 
studies, 1495 from the chronic obstructive pulmonary disease (COPD) study, 309 from prurigo 
nodularis studies, 311 from urticaria (chronic spontaneous urticaria [CSU] and chronic inducible 
cold urticaria [CICU]) studies, 45 from the bullous pemphigoid (BP) study, and 37 from the 
allergic bronchopulmonary aspergillosis (ABPA) study. The number of subjects exposed to 
dupilumab in clinical studies was 10 828 (538 in healthy volunteer studies, 4496 in AD studies, 
3591 in asthma studies, 526 in rhinosinusitis [CRSwNP, CRSsNP and AFRS] studies, 405 in EoE 
studies, 175 in allergy [grass and peanut] studies, and 748 in the COPD study, 152 in PN studies, 
156 in the urticaria [CSU and CICU] studies, 22 in the BP study, and 19 in the ABPA study). 
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Based on the sales figure and World Health Organization’s defined daily dose for dupilumab of 
21.4 mg/day, the cumulative post marketing exposure to dupilumab could be estimated to be 
706 212 patient-years from 01 March 2017 through 31 March 2022.  
Dupilumab has been generally well tolerated in all populations tested in clinical development 
programs consistent with a positive benefit/risk profile. The adverse drug reactions (ADRs) 
identified to date for dupilumab include injection site reactions, conjunctivitis (including allergic 
and bacterial), oral herpes, herpes simplex, blepharitis, dry eye, eye pruritus, eosinophilia, serum 
sickness, angioedema, arthralgia, facial rash, and keratitis (including ulcerative). These ADRs 
were generally mild or moderate, transient, and manageable. These ADRs were not consistently 
observed in all indications (see IB for greater details). More significant serious allergic reactions 
were very rare. Importantly, no increased overall infection risk was observed in patients treated 
with dupilumab. 
The important identified risks associated with dupilumab are: 
• Systemic hypersensitivity: Anaphylactic reaction and angioedema are listed ADRs in 
addition to serum sickness and serum sickness-like reaction. 
• Conjunctivitis and keratitis related events in AD patients: Conjunctivitis, keratitis and 
ulcerative keratitis are listed ADRs. 
An 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 (EGPA), conditions which are often treated with systemic corticosteroid therapy. 
These events have been seen in other drug development programs for severe asthma and usually, 
but not always, have been associated with the reduction of oral corticosteroid therapy suggesting 
possible unmasking of these conditions with tapering of corticosteroids during dupilumab therapy. 
The association of dupilumab treatment and these events has not been established. Health care 
providers should be alert to eosinophilia associated with vasculitic rash, worsening of pulmonary 
symptoms, pulmonary infiltrate, cardiac complications, and/or neuropathy presenting in their 
patients, especially upon reduction of systemic corticosteroids. 
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 dupilumab pediatric asthma 
study included patients age 6 to <12 years of age. The safety profile in these patients through 
Week 52 was similar to the safety profile from studies in adults and adolescents with moderate-to-
severe asthma, with the additional adverse reaction of enterobiasis. Enterobiasis was reported in 
1.8% (5 patients) in the dupilumab groups and none in the placebo group. All enterobiasis cases 
were mild to moderate and patients recovered with anti-helminth treatment without treatment 
discontinuation. An imbalance of cases of enterobiasis was not observed in other dupilumab 
clinical trials, including the study in patients 12 years and older with moderate-to severe asthma. 
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Other potential risks based on the safety profile in particular indications are discussed in the IB. 
While long-term data are still accumulating, data from randomized, placebo-controlled trials and 
open-label extension studies to date have not identified any new safety concern in these 
populations. It is anticipated that dupilumab in patients with CRSwNP will have a favorable 
safety profile as observed across other type 2-driven immunological disorders. 
COVID-19 related risk assessment 
Currently, there are insufficient data in patients with Coronavirus Disease 2019 (COVID-19) who 
are being treated with dupilumab. Thus, the safety and efficacy of dupilumab in COVID-19 
patients are unknown. During the course of clinical trials conducted during the COVID-19 
pandemic, respiratory infections including viral infections and COVID-19 infections were 
monitored and these events are not listed as ADRs for dupilumab. 
There are currently no clinical data available on concomitant use of dupilumab with any 
SARS-CoV-2 vaccine. Concomitant use of non-live SARS-CoV-2 vaccines is not prohibited. 
Based on available data, no attenuation of the vaccination response is expected. 
The Sponsor also recognizes that the COVID-19 pandemic may have an impact on the conduct of 
clinical trials. The Sponsor will monitor the situation closely and ensure the integrity of the trial 
conduct and data (see Section 10.9). 
2.3.2 Benefit assessment  
Dupilumab has been shown to be an effective treatment for CRSwNP in two successful Phase 3 
pivotal studies (LIBERTY NP SINUS-24, LIBERTY NP SINUS-52) of 24- and 52-weeks 
duration in which 300 mg Q2W of dupilumab used on top of topical corticosteroids (mometasone 
nasal spray) in participants with CRSwNP. Statistically significant and clinically relevant efficacy 
was observed in these studies regarding reduction of endoscopic nasal polyps score, nasal 
congestion, and overall sinus opacification assessed by CT scan. The effect extended to 
all analyzed secondary endpoints including QoL, sense of smell, and symptoms of rhinosinusitis 
as well as in asthma symptoms and lung function in participants with co-morbid asthma. 
Furthermore, dupilumab significantly reduced the need for systemic steroids and sino-nasal 
surgery. In a pooled safety analysis, the incidence of the most commonly reported AEs was more 
frequent with placebo than dupilumab. Dupilumab was generally well tolerated and had an 
acceptable safety profile in the treatment of participants with inadequately controlled CRSwNP as 
well as long-term treatment (5). 
The CRSwNP patients who will participate in this study may have the potential benefit of 
receiving a novel treatment for the underlying type 2 inflammatory disease process. Based on the 
efficacy results observed for CRSwNP in global pivotal studies, and for other type-2 mediated 
disorders, it is anticipated that use of IMP will lead to reduced signs and symptoms associated 
with CRSwNP and improved function and quality of life for these patients. 
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Dupixent® (dupilumab) is authorized for marketing in over 60 countries worldwide including the 
US, European Union (EU) (Centralized Procedure), Japan, China, Canada, and Australia for the 
adult AD indication. Dupilumab is also authorized in the US, EU, and other jurisdictions for the 
pediatric (6 to <18 years of age) AD indications, and in the US, EU, Japan, and other jurisdictions 
for the adult and adolescent asthma indication. Dupilumab also has approval for its CRSwNP 
indication in the US, EU, and other jurisdictions. 
2.3.3 Overall benefit/risk conclusion  
Taking into account the measures taken to minimize risk to participants participating in this study, 
the potential risks identified in association with dupilumab are justified by the anticipated benefits 
that may be afforded to participants with inadequately controlled CRSwNP patients on standard of 
care. 
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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of dupilumab compared to 
placebo on a background of budesonide nasal 
spray in reducing endoscopic nasal polyps score 
(NPS) in Chinese participants with bilateral nasal 
polyposis (NP). 
• 
Change from baseline in NPS at Week 24. 
Secondary 
 
• 
To evaluate the efficacy of dupilumab in reducing 
nasal congestion/obstruction (NC) severity. 
• 
Change from baseline in NC score (NCS) based on 
the participant daily morning assessment at 
Week 24. 
• 
To evaluate the efficacy of dupilumab in improving 
total symptoms score (TSS). 
• 
Change from baseline in TSS at Week 24: 
composite severity score consisting of the 
participant daily morning assessed NC, 
decreased/loss of sense of smell, anterior/posterior 
rhinorrhea. 
• 
To evaluate the efficacy of dupilumab in improving 
sense of smell. 
• 
Change from baseline in the severity of 
decreased/loss of smell assessed daily by 
participants at Week 24. 
• 
To evaluate the effect of dupilumab on patient 
quality of life. 
• 
Change from baseline in total score of 22-item sino-
nasal outcome test (SNOT-22) at Week 24. 
• 
To evaluate the ability of dupilumab to reduce 
proportion of participants who require treatment with 
systemic corticosteroid (SCS) or surgery for NP. 
• 
Proportion of participants receiving SCS for any 
reason or undergo surgery for nasal polyps during 
the study treatment. 
• 
To evaluate the safety of dupilumab in Chinese 
participants with bilateral NP. 
• 
Safety (incidence of treatment-emergent adverse 
events [TEAEs], of treatment-emergent serious 
adverse events [TESAEs], and TEAEs leading to 
treatment discontinuation), laboratory values, vital 
signs. 
Exploratory 
 
Not applicable 
  
 
 
Primary estimands defined for primary efficacy endpoints are summarized in Table 2 below. More 
details are provided in Section 9.2. 
For all these estimands, the comparison of interest will be the comparison of dupilumab 300 mg 
Q2W vs. placebo. 
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Table 2 - Summary of primary estimands for primary endpoint  
Endpoint 
Estimands 
Category  
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level summary  
(Analysis and missing 
data handling) 
Primary objective:  
To evaluate the efficacy of dupilumab compared to placebo on a background of budesonide nasal spray in reducing endoscopic 
nasal polyps score (NPS) in Chinese participants with bilateral nasal polyposis (NP). 
Primary 
endpoint  
Change from 
baseline in 
NPS at 
Week 24. 
 
ITT 
The intercurrent events will be 
handled as follows: 
• Undergoing surgery for 
CRSwNP or taking SCS for 
any reason prior to Week 24: 
data after surgery/SCS will be 
set to missing and the worst 
post-baseline value on or 
before the time of 
surgery/SCS will be used to 
impute missing Week 24 
value (WOCF). For 
participants with no post-
baseline values, the baseline 
value will be used (composite 
strategy). 
• Taking other 
prohibited/rescue 
medications: all data 
collected after use will be 
used in the analysis 
(treatment policy strategy). 
• Discontinuing the study 
intervention (but not 
undergoing surgery for 
CRSwNP or taking SCS for 
any reason prior to Week 24): 
all data collected after 
discontinuation will be used in 
the analysis (treatment policy 
strategy). 
Mean change difference between 
interventions from ANCOVA model 
with study intervention and 
screening blood eosinophil count 
strata, and baseline measurement 
as covariates is used. Statistical 
inference obtained from all imputed 
data by ANCOVA model will be 
combined using Rubin’s rule. 
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 or received 
SCS for any reason on or before 
Week 24. 
ITT: intent-to treat; CRSwNP: chronic rhinosinusitis phenotype with nasal polyps; SCS: systemic corticosteroids; ANCOVA: analysis of 
covariance; WOCF: worst observation carried forward. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The proposed study design and endpoints will answer important clinical questions about the 
efficacy on symptoms and objective signs of the disease and the effect of dupilumab on reduction 
of SCS rescue therapy and surgery, which are the most relevant clinical practice assessments and 
reflect current standard of care. 
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Endoscopic nasal polyps score (NPS) 
The bilateral endoscopic NPS is chosen as the primary endpoint in this study. It was the objective 
component of the co-primary endpoints of global pivotal CRSwNP studies. NPS ranges from 0 to 
8 points and is the sum of the right and left scores (from 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) (26, 27, 28). 
Nasal congestion/obstruction score (NCS) 
Medical and surgical intervention decisions are mainly driven by the nasal polyp symptom burden 
and response to standard therapy with topical and SCS. Nasal congestion/obstruction is a major 
clinical symptom in CRSwNP and will be measured by a nasal congestion/obstruction score 
(patient reported outcomes [PRO]) to evaluate the disease activity as a secondary endpoint. Nasal 
congestion/obstruction severity score consisting of the monthly average of the daily morning 
(AM) patient-assessed daily symptom severity (using a 0 to 3 categorical scale). The NCS is 
assessed by the participant on a daily basis from V1 and throughout the study, using an electronic 
diary (e-diary) using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms,  
2 = moderate symptoms and 3 = severe symptoms) (7). 
Other measurements 
The proposed study design and endpoints will answer important clinical questions about the 
efficacy on symptoms and objective signs of the disease and the effect of dupilumab on reduction 
of SCS rescue therapy and surgery, which are the most relevant clinical practice assessments and 
reflect current standard of care. 
Other efficacy assessments in other PRO (ie, total symptom score [TSS]) and patient health-
related quality of life (HRQoL) and safety assessments to evaluate the potential real-life benefit 
will be performed too. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group study 
evaluating the efficacy and safety of dupilumab 300 mg every 2 weeks (Q2W) compared to 
placebo, in Chinese adult participants with moderate-to-severe signs and symptoms of bilateral 
nasal polyposis (NP) on a background treatment with intranasal corticosteroids. 
Randomization will be stratified by screening blood eosinophil count (≥300 cells/mm3 or 
<300 cells/mm3). 
To ensure enrollment according to the intended distribution of screening blood eosinophil count, 
alerts will be built into the IRT to control the number of participants in each stratification group as 
follows: 
• ≥300 cells/mm3: approximately 26 participants per arm, 
• <300 cells/mm3: up to approximately 5 participants per arm. 
The clinical study consists of 3 periods: 
• Run-in period (4 weeks +/-3 days): to determine a participant’s eligibility and for run-
in/standardization of background INCS (budesonide nasal spray) prior to randomization.  
• Randomized dupilumab/placebo treatment period (24 weeks +/-3 days): to randomize the 
participant into a treatment arm and treat with dupilumab or placebo dose regimen. 
- 
Arm A: dupilumab 300 mg SC Q2W. 
- 
Arm B: placebo matching dupilumab SC Q2W. 
• Follow-up period (12 weeks +/-3 days): to continue to collect data for safety after the 
participant has completed the study drug treatment period. 
During the whole study duration, participants will continue budesonide nasal spray stable dose 
started at Visit 1 (V1) except if dose is changed due to AE. 
During the study, patients who report deterioration requiring medical/surgical intervention may 
come to the site for an endoscopy and clinical evaluation. An unscheduled visit may be used for 
this purpose and, if necessary, the Investigator may consider one of the treatment alternatives 
described in Section 6.8.3.  
Overall, this study will evaluate the potential real life benefit that dupilumab may provide for 
participants that failed currently available treatment options. 
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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The population of the EFC17026 will be composed of participants with bilateral NP (endoscopic 
bilateral nasal polyp score [NPS] has to be ≥5 out of a maximum score of 8) that present with 
chronic symptoms of nasal congestion (NC) (moderate/severe) and another symptom such as loss 
of smell and/or rhinorrhea despite background treatment with INCS and maximum therapy with 
standard of care including systemic corticosteroids (in the previous 2 years) and/or surgery in the 
past.  
Older publications have noted Chinese population may have a lower prevalence of CRSwNP 
type 2 endotype compared to Western countries which have a prevalence of ~85% (29); however, 
one publication reports the type 2 CRSwNP prevalence is increasing in China (22). Elevated 
blood eosinophils are associated with tissue eosinophilia in CRSwNP (20); in studies of Chinese 
type 2 CRSwNP patients a blood eosinophil count of ≥300 cells/mm3 is most closely associated 
with type 2 CRSwNP (21, 22). Given the possible lower prevalence of type 2 CRSwNP in China, 
the study will enrich for this population using blood eosinophils as a surrogate marker for type 2 
CRSwNP. 
The proposed participant selection criteria reflect standard of care in this severe uncontrolled 
participant setting by allowing enrollment of participants that received INCS, with or without SCS 
prior to the run-in period, and/or participants with previous surgeries. 
Dupilumab or matched placebo will be added on top of background treatment of INCS (daily use 
of budesonide nasal spray). By allowing Investigators, at their discretion, to use SCS or surgery as 
a rescue therapy for worsening of CRSwNP, the study will also assess the effect of dupilumab on 
the need for surgery and OCS use over the randomized treatment period.  
The 24-week treatment duration is considered sufficient for efficacy evaluation based on the 
efficacy results from global pivotal CRSwNP studies in which dupilumab 300 mg Q2W 
demonstrated statistically significant and clinically meaningful improvement across all primary and 
multiplicity adjusted secondary outcome measures at Week 24 and Week 52. Early beneficial effect 
was seen from Week 2 to Week 4, followed by a progressive improvement through 24 weeks and 
52 weeks. The 24-week duration is also appropriate to evaluate safety considering the extensive 
safety experience with CRSwNP and the related condition of asthma. The post-treatment 12-week 
follow-up period is based on the expected PK profile of dupilumab after the last dose, ie, the time 
for systemic concentrations to decline to non-detectable levels in most participants. 
Among objective measures of disease burden, radiologic and endoscopic scoring system have 
been the primary foci of outcomes research in rhinology. The presence or absence of polyps is 
confirmed by performing endoscopy. In this study, endoscopic NPS is selected as the primary 
endpoint to evaluate the nasal polyps burden, which was the objective component of co-primary 
endpoints in global pivotal studies (LIBERTY NP SINUS-24, LIBERTY NP SINUS-52). Nasal 
congestion/obstruction is a major clinical symptom in CRSwNP and will be measured by a nasal 
congestion/obstruction score patient-reported outcome (PRO) to evaluate the disease activity as 
secondary endpoint. Other symptoms including rhinorrhea and decreased/loss of sense of smell, 
and participants’ QoL will also be evaluated using the tools similar to the dupilumab CRSwNP 
global program.  
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4.3 
JUSTIFICATION FOR DOSE  
Based on the known clinical PK, efficacy and safety of dupilumab observed in studies conducted 
globally and locally in healthy participants and participants with AD, asthma, and CRSwNP, 
dupilumab 300 mg Q2W was selected as the dosing regimen for this study in Chinese adult 
patients with CRSwNP. 
In the global pivotal studies in CRSwNP participants (LIBERTY NP SINUS-24, LIBERTY NP 
SINUS-52), dupilumab 300 mg Q2W demonstrated statistically significant and clinically 
meaningful improvement across all primary and multiplicity adjusted secondary outcome 
measures at Week 24 and Week 52 and had an acceptable safety profile. The 300 mg Q2W dose 
regimen was approved in EU and US for the treatment of adult participants with inadequately 
controlled CRSwNP. 
In addition to participants with CRSwNP, the 300 mg Q2W dose regimen was also selected for 
adult and adolescent participants with moderate-to-severe AD and moderate-to-severe asthma in 
previous global Phase 3 pivotal studies. In all of these studies, the 300 mg Q2W dose regimen 
achieved concentrations in serum that saturate the target-mediated clearance pathway and has 
been proven to be effective and have an acceptable safety profile. Additionally, 300 mg Q2W was 
studied in Chinese participants with AD in the Phase 3 study EFC15116, showing statistically 
significant and clinically meaningful improvements compared to placebo at Week 16 and an 
acceptable safety profile in Chinese participants with AD.  
As a monoclonal antibody dupilumab PK is insensitive to ethnic factors. In prior global 
population PK analysis with dupilumab for CRSwNP population, race was not identified as the 
significant covariate impacting PK and body weight was the only covariate identified with 
a meaningful impact on dupilumab PK. In global pivotal Phase 3 studies in participants with 
CRSwNP, the trend of slightly higher exposure in Asians/Japanese compared to the 
Caucasians/Non-Japanese is mainly the result of differences in body weight, while there are no 
clinically significant differences in efficacy and safety across race groups or ethnic groups. In 
addition, the safety and efficacy of dupilumab in Chinese adult AD participants was similar to the 
global pivotal studies. 
The insensitivity to ethnic factors of dupilumab with regard to PK, efficacy, and safety has been 
thoroughly demonstrated in participants with AD based on the completed studies conducted 
globally and locally, leading to the approval of AD indication in adults in China with the same 
dose regimen as EU and US. It further supports to select the same regimen 300 mg Q2W as the 
dose regimen approved globally for the CRSwNP development in Chinese participants. Therefore, 
there is no ethnic difference in dupilumab PK that translates to a clinically meaningful difference 
in dupilumab efficacy and safety. It is reasonable to assume that no clinically meaningful 
difference in dupilumab efficacy and safety between Chinese participants with CRSwNP and 
participants enrolled in global CRSwNP studies following 300 mg Q2W treatment will be 
observed. 
The collective PK, clinical efficacy and safety data of dupilumab across diverse disease 
populations suggest that the selected dose regimens 300 mg Q2W for this study will be 
efficacious and safe for the treatment of Chinese adult CRSwNP participants.  
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4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the end of his or her 12-week follow-up period or prematurely discontinues from 
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 of age at the time of signing the informed consent. 
Type of participant and disease characteristics 
Participants with bilateral sino-nasal polyposis that despite prior treatment with SCS anytime 
within the past 2 years; and/or who have a medical contraindication/intolerance to SCS; and/or 
had prior surgery for NP at Visit 1 have: 
I 02. An endoscopic bilateral NPS at Visit 1 of at least 5 out of a maximum score of 8 (with a 
minimum score of 2 in each nasal cavity) as per central assessment (refer to Section 8.1.1) 
I 03. Ongoing symptoms (for at least 8 weeks before Visit 1) of: 
• Nasal congestion/blockade/obstruction with moderate or severe symptom severity (Score 2 
or 3) at Visit 1 and a weekly average severity of greater than 1 at time of randomization 
(Visit 2) 
AND 
• Another symptom such as loss of smell, rhinorrhea (anterior/posterior) 
NOTE: Plan to enroll at least 85% (approximately 52) participants with CRSwNP meeting 
following criterion:  
• Participants with peripheral blood eosinophil count ≥300/mm3 
Sex, contraceptive/barrier method and pregnancy testing requirements/breastfeeding 
I 04. All (Male and/or Female) 
Contraceptive use by women should be consistent with the regulations regarding the 
methods of contraception for those participating in clinical studies (Additional details can 
be found in Appendix 4: Section 10.4). 
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies: 
- 
Is a woman of non-childbearing potential (WONCBP) as defined in Appendix 4 
(Section 10.4 Contraceptive and barrier guidance). 
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OR 
- 
Is a woman of childbearing potential (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 Contraceptive and barrier guidance) during the study intervention period 
and for at least 12 weeks after the last administration of study intervention.  
A WOCBP must have a negative highly sensitive pregnancy test at screening (serum) and on 
Day 1 (urine) before the first administration of study intervention, see Section 8.2.5 Pregnancy 
testing. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from participation if the 
serum pregnancy result is positive. 
Informed Consent 
I 05. Capable of giving signed informed consent as described in Appendix 1 of the protocol 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.  
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Participants with conditions/concomitant diseases making them non-evaluable at Visit 1 or 
for the primary efficacy endpoint (ie, NPS) such as: 
• Antrochoanal polyps. 
• Nasal septal deviation that would occlude at least one nostril. 
• Acute sinusitis, nasal infection or upper respiratory infection (participant can be 
rescreened after resolution of symptoms). 
• Ongoing rhinitis medicamentosa. 
• Eosinophilic granulomatous angiitis (Churg-Strauss syndrome), granulomatosis with 
polyangiitis (Wegener’s granulomatosis), Young’s syndrome, Kartagener’s syndrome or 
other dyskinetic ciliary syndromes, or concomitant cystic fibrosis. 
• Radiologic suspicion, or confirmed invasive or expansive fungal rhinosinusitis. 
E 02. Participants with nasal cavity malignant tumor and benign tumors (eg, papilloma, 
hemangioma, etc). 
E 03. Participant with historical spirometry results which showed 50% or less of predicted 
normal of forced expiratory volume in one second (FEV1).  
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E 04. Diagnosed with; suspected of, or at high risk of endoparasitic infection, and/or use of 
antiparasitic drug within 2 weeks before Visit 1 or during the screening period.  
E 05. History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at 
Visit 1. 
E 06. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, and 
aspergillosis) despite infection resolution, or otherwise recurrent infection of abnormal 
frequency or prolonged duration suggesting an immune-compromised status, as judged by 
the Investigator. 
E 07. Participants with active 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 now start treatment 
with a biologic agent, in the medical judgment of the Investigator and/or infectious disease 
specialist. Tuberculosis testing will be performed according to local guidelines if required 
by regulatory authorities or ethics boards, or if TB is suspected by the investigator. 
E 08. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
or antifungals within 2 weeks before Visit 1 or during the screening period. 
E 09. Active malignancy or history of malignancy within 5 years before the baseline 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 10. Known or suspected alcohol and/or drug abuse. 
E 11. History of systemic hypersensitivity or anaphylaxis to dupilumab including any excipient. 
E 12. Participants meet any contraindications or warning on product labeling for budesonide 
nasal spray. 
E 13. Severe concomitant illness(es) that, in the Investigator’s judgement, would adversely affect 
the participant’s participation in the study. Examples include, but are not limited to 
participants with short life expectancy, participants with uncontrolled diabetes 
(hemoglobin A1c ≥9%), participants with cardiovascular conditions (eg, Class Ⅲ or Ⅳ 
cardiac failure according to the New York Heart Association classification), severe renal 
conditions (eg, participants on dialysis), hepato-biliary conditions (eg, Child-Pugh class B 
or C), neurological conditions (eg, demyelinating disease), autoimmune diseases 
(eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc), other severe 
endocrinological, gastrointestinal, metabolic, pulmonary, psychiatric, or lymphatic 
diseases. The specific justification for participants excluded under this criterion will be 
noted in study documents (chart notes, case report forms [CRFs], etc). 
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E 14. 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, case report form [CRF], etc). 
Prior/concomitant therapy 
E 15. Planned major surgical procedure during the participant’s participation in this study. 
E 16. Participants who have taken: 
• Biologic therapy/systemic immunosuppressant/immunomodulator within 4 weeks before 
Visit 1 or 5 half-lives, whichever is longer. 
• Any investigational monoclonal antibody (mAb) within 5 half-lives or within 6 months 
before Visit 1 if the half-life is unknown. 
• Anti-immunoglobulin E therapy (omalizumab) within 4 months prior to Visit 1. 
E 17. Treatment with a live (attenuated) vaccine within 4 weeks prior to Visit 1. 
NOTE: For participants who have vaccination with live, attenuated vaccines planned 
during the course of the study (based on national vaccination schedule/local guidelines), it 
will be determined, after consultation with a physician, whether the administration of 
vaccine can be postponed until after the end of study (EOS), or preponed to before the start 
of the study without compromising the health of the participant: 
• Participants for whom administration of live (attenuated) vaccine can be safely postponed 
would be eligible to enroll into the study. 
• Participants who have their vaccination preponed can enroll in the study only after a gap 
of 4 weeks following administration of the vaccine. 
E 18. Participants who are receiving leukotriene antagonists/modifiers within 4 weeks before V1 
or 5 half-lives, whichever is longer, unless patient is on a continuous treatment for at least 
4 weeks before Visit 1. 
E 19. Initiation of allergen immunotherapy within 3 months prior to Visit 1 or a plan to begin 
therapy or change its dose during the run-in or randomized treatment period. 
E 20. Participants who have undergone any intranasal and/or sinus surgery (including 
polypectomy) within 6 months prior to Visit 1 or sino-nasal surgery changing the lateral 
wall structure of the nose making the evaluation of NPS impossible. 
E 21. Use of any prohibited medications (Section 6.8.1) and procedures during screening period 
or planned use during screening or study treatment period.  
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E 22. Either intravenous immunoglobulin (IVIG) therapy and/or plasmapheresis within 4 weeks 
before Visit 1. 
Prior/concurrent clinical study experience 
E 23. Current participation in any clinical trial of an investigational drug or device or 
participation within 3 months before V1 or 5 half-lives of the investigational compound, 
whichever is longer. 
E 24. Participation in a prior dupilumab clinical study or have been treated with commercially 
available dupilumab. 
Diagnostic assessments 
E 25.  Patients with any of the following result at the screening visit (Visit 1): 
• Positive (or indeterminate) HBs Ag or, 
• Positive total HBc Ab confirmed by positive HBV DNA or, 
• Positive HCV Ab confirmed by positive HCV RNA. 
Noncompliance to completion of the patient diary or noninvestigational medicinal product 
(NIMP) 
E 26. NIMP noncompliance at Visit 2 (<80%) 
E 27. Any condition that could make the participant noncompliant with the study procedures and 
daily assessment in the e-diary.  
Other exclusions 
E 28. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 29. Participants 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 30. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals 
(in conjunction with Section 1.61 of the ICH-GCP Ordinance E6). 
E 31. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
 
5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable. 
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5.4 
SCREEN FAILURES  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number for every 
screening/rescreening event. Participants who are rescreened are required to sign a new ICF. 
In cases where original screen failure was due to reasons expected to change at rescreening and 
based upon the Investigator’s clinical judgment, the participant can be rescreened one time for this 
study. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Appendix 9 (Section 10.9: Contingency measures for a regional or national emergency that is 
declared by a governmental agency) should be considered for screening, randomization, and 
administration of study intervention. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
A concomitant therapy is any treatment received by the participant concomitantly to any IMP(s) 
or NIMP. This includes medications that were started before the first dose of study intervention 
and are ongoing during the study.
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Participants who satisfy the inclusion and exclusion criteria will be randomized (1:1) to one of the 
following IMP treatment groups: 
• Arm A: dupilumab 300 mg Q2W. 
• Arm B: placebo matching dupilumab Q2W. 
Duration of study intervention: 
• Run-in period: 4 weeks +/-3 days 
• Randomized treatment period: up to 24 weeks +/-3 days 
• Follow-up period: 12 weeks +/-3 days 
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Table 3 - Study intervention(s) administered  
Intervention label 
Dupilumab 
Placebo 
Budesonide nasal spray 
Intervention name 
Dupilumab 300 mg  
Placebo 
Budesonide nasal spray 
Intervention 
description 
Dupilumab 300 mg Q2W via 
SC injection 
Placebo matching dupilumab 
300 mg Q2W via SC injection 
Budesonide nasal spray at 
total daily dose of 256 μg 
Type 
Biological/Vaccine 
Other 
Drug 
Dose formulation 
A 150 mg/mL dupilumab 
solution in a prefilled syringe 
to deliver 300 mg in a 2 mL 
injection 
Identical formulation to the 
active 300 mg formulation 
without dupilumab, in a 
prefilled syringe to deliver 
placebo in a 2 mL injection 
Nasal spray suspension is 
provided in a bottle, that 
contains 120 actuations of 
product formulation 
Unit dose strength(s) 
150 mg/mL 
NA 
64 μg/actuation 
Dosage level(s) 
Dupilumab 300 mg Q2W up to 
24 weeks, the planned last 
administration is at Week 22 
Placebo matching dupilumab 
300 mg Q2W up to 24 
weeks, the planned last 
administration is at Week 22 
Budesonide nasal spray 2 
actuations (64 μg/actuation) 
in each nostril QM or 
1 actuation in each nostril 
BID (total daily dose of 
256 μg). One actuation in 
each nostril once daily 
(total daily dose of 128 μg) 
if the participants are 
unable to tolerate total daily 
dose of 256 μg, in which 
case they can stay on 
a lower dose regimen 
(128 μg) of budesonide 
nasal spray. 
Route of 
administration 
subcutaneous (SC) injection 
subcutaneous (SC) injection 
Nasal spray 
Use 
Experimental  
Placebo  
Background treatment 
IMP and NIMP 
IMP 
IMP 
NIMP 
Packaging and 
labeling 
One prefilled syringe packed 
in a patient kit box. Both the 
prefilled syringe and the box 
will be labeled as required per 
country requirement. 
One prefilled syringe packed 
in a patient kit box. Both the 
prefilled syringe and the box 
will be labeled as required 
per country requirement. 
Nasal spray is provided in 
a bottle. Each container will 
be labeled as required per 
country requirement. 
[Current/former 
name(s) or alias(es)] 
Dupixent® 
NA 
Rhinocort 
Q2W: every 2 weeks; SC: subcutaneous; QM: every morning; BID: twice a day; IMP: investigational medicinal product; NIMP: noninvestigational 
medicinal product. 
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Table 4 - Study arm(s)  
Arm title 
Arm A 
Arm B 
Arm type 
Experimental 
Experimental 
Arm description 
Dupilumab 300 mg Q2W via SC 
injection 
Placebo matching dupilumab 
300 mg Q2W via SC injection 
Associated intervention labels 
Dupilumab  
Placebo 
Q2W: every 2 weeks; SC: subcutaneous. 
6.1.1 Investigational medicinal product(s)  
Regardless of the treatment arm, all randomized participants will receive Q2W SC administrations 
of either dupilumab or placebo starting from Day 1 (V2). Every other week IMP administrations 
must be separated by at least 11 days (See Section 1.2). The planned last IMP administration is at 
Week 22. 
The first IMP administration should be performed at the study center. 
For the doses that are not scheduled to be given at the study site, home administration of IMP is 
allowed after appropriate training of the participant (or caregiver). Investigator or delegate will 
prepare and inject the first dose of IMP at Week 0 (Visit 2), in front of the participant 
(or caregiver). The participant (or caregiver) will prepare and inject the IMP under the supervision 
of the Investigator or delegate at Week 2 (Visit 3). The training must be documented in the 
participant’s study file. In case of emergency (eg, natural disaster, pandemic, etc) different 
training ways (eg, training remotely with instruction provided by phone, etc) can be performed 
(and will be documented in the participant’s study file). 
From Week 4 (except Week 8 [Visit 4] and Week 16 [Visit 5]), every other week home 
administration of IMP is possible if the participant (or the caregiver) has been trained. If the 
participant (or caregiver) is unable or unwilling to prepare and inject IMP, injections can be 
performed at the study site by way of unscheduled visits; or arrangements can be made for 
qualified site personnel and/or health care professionals (eg, visiting nurse service) to administer 
IMP at participant’s home. 
The participant/caregiver should be trained by the site staff to recognize potential signs and 
symptoms of hypersensitivity reaction in order to self-monitor/monitor at home for at least 
30 minutes following injection. In case of hypersensitivity symptoms, the participant should 
contact healthcare provider/emergency. 
When the participant has a study visit, the IMP will be administered after clinical procedures and 
blood collection are performed. 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 among the 4 quadrants of the abdomen (avoiding 
navel and waist areas), the upper thighs or the upper arms, so that the same site is not injected twice 
consecutively. Injection in the upper arms could be done only by a trained person (caregiver trained by 
Investigator or Delegate) or healthcare professional but not the participants themselves. 
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For doses not given at the study site participants will complete a dosing diary to document 
compliance with self-injection (or caregiver) of IMP, location of injection, and any symptoms. 
The diary will be kept as source data in the participant’s study file. 
Detailed instructions for transport, storage, preparation, and administration of IMP are provided to 
the participant. In case of emergency (eg, natural disaster, pandemic, etc), IMP may be supplied 
from the site to the participant via a Sponsor-approved courier company if allowed by regulations 
and approved by the participant. 
6.1.2 Non-investigational medicinal product(s)  
6.1.2.1 Intranasal corticosteroid background therapy  
On a daily basis throughout the study, the participant will use an e-diary to record daily use of 
budesonide nasal spray 64 μg/actuation nasal spray suspension, (refer to the package insert & 
SmPC for a description, administration details and precautions for use). Budesonide nasal spray is 
provided in a bottle that contains 120 actuations of product formulation. 
Non-investigational medicinal products will be supplied by Sponsor’s local affiliate as locally required 
or by sites. Reimbursement will be provided when deemed necessary and as per regulation. 
Detailed instructions for transport, storage, preparation, and administration of non-investigational 
medicinal product (NIMP) are provided to the participant. Participants will complete the e-diary 
to document compliance. The e-diary will be considered as source data. 
Run-In Period 
After V1, once participant eligibility for study entry has been confirmed, all participants will enter 
a run-in period of 4 weeks during which they will receive starting at V1 budesonide nasal spray: 
• Two actuations (64 μg/actuation) in each nostril QM, or 1 actuation in each nostril BID 
(total daily dose of 256 μg). One actuation in each nostril once daily (total daily dose of 
128 μg) if the participants are unable to tolerate total daily dose of 256 μg, in which case 
they can stay on a lower dose regimen (128 μg) of budesonide nasal spray. 
Budesonide nasal spray will be self-administered by the participant, and at each visit the Investigator 
must ensure that the participant has the necessary and sufficient doses up to the next visit. 
Participants who receive rescue medication including INCS drops or systemic (oral, intravenous 
[IV], intramuscular [IM]) steroids between V1 and V2 will not be randomized. They can be 
rescreened as described in Section 5.4. 
Randomized treatment period 
During the randomized treatment period, all participants will continue on the budesonide nasal 
spray stable dose initiated at V1. If they experience an AE during the treatment period, 
participants can reduce the frequency of budesonide nasal spray administration. 
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Follow-up period 
Upon completing the randomized treatment period (or following early discontinuation of IMP or 
discontinuation from the study), participants can continue treatment with the stable dose of 
budesonide nasal spray that was maintained throughout the randomized treatment period until the 
EOS visit, or modify treatment based on medical judgment. 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 9 (Section 10.9: Contingency measures for a regional or national emergency that is 
declared by a governmental agency. 
6.1.3 Devices  
No devices will be used for administration of study drug in this study. 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Any quality issue noticed with the receipt or use of an IMP/NIMP (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/NIMP 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/NIMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party (except for direct-
to-patient [DTP] shipment, for which a courier company has been approved by the Sponsor), 
allow the IMP/NIMP to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP in any other manner. 
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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
The randomized intervention kit number list is generated centrally by Sanofi, and IMPs are 
packaged in accordance with this list. The randomization and intervention allocation are 
performed centrally by IRT. The IRT generates the participant randomization list and allocates the 
intervention number and the corresponding intervention kits to the participants according to it.  
All participants will be centrally assigned to randomized study intervention in a 1:1 ratio using 
an IRT.  
Randomization will be stratified by screening blood eosinophil count (≥300 cells/mm3 or 
<300 cells/mm3). 
Before the study is initiated, the telephone number and call-in directions for the interactive voice 
respond system (IVRS) and/or the log in information and directions for the interactive web 
response system (IWRS) will be provided to each site.  
At Screening (Visit 1), the Investigator or designee will contact the IRT to receive the participant 
number. If a participant who had previously failed screening is approached for re-screening, a new 
ICF must be signed. In such case, a new participant number will be assigned by IRT. 
A randomized participant is defined as a participant who has been allocated to a randomized 
intervention regardless of whether the treatment was administered or not (ie, participant registered 
by the IRT). A participant cannot be randomized more than once in the study. 
Study intervention will be dispensed at the study visits as summarized in the SoA. Returned study 
intervention should not be re-dispensed to the participants. 
Sponsor safety staff may unblind the intervention assignment for any participant with an SAE. If 
the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, 
a copy of the report, identifying the participant’s intervention assignment, may be sent to 
Investigators in accordance with local regulations and/or Sponsor policy. 
Methods of blinding 
Dupilumab 300 mg and placebo matching dupilumab 300 mg will be provided in identically 
matched 2 mL pre-filled syringes that are visually indistinguishable for each dose. Syringes and 
box will be labeled with a treatment kit number. 
Code breaking 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s intervention 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If the Investigator decides that unblinding is warranted, he/she may, at his/her 
discretion, contact the Sponsor to discuss the situation prior to unblinding a participant’s 
intervention assignment unless this could delay emergency treatment of the participant. If 
a participant’s intervention assignment is unblinded, the Sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and eCRF, as applicable. 
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If the code is broken at the site level, the participant must withdraw permanently from IMP 
administration. 
6.4 
STUDY INTERVENTION COMPLIANCE  
The Investigator or his/her delegate must ensure that IMP is administered to each participant 
according to the labeling instructions. 
IMPs/NIMP accountability: 
• Intervention units are returned by the participant at each visit. In case of direct mail to 
participant process, the intervention units can be returned by the carrier (if defined in the 
contract), 
• The Investigator or his/her delegate counts the number of remaining kits/pre-filled 
syringes and fills in the Intervention Log Form, 
• The Investigator or his/her delegate records the dosing information on the appropriate 
source document, 
• The monitor in charge of the study then checks the source document data by comparing 
them with the IMP that he/she has retrieved, and the intervention log forms. 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. All medication treatment kits (whether empty or 
unused) will be returned by the participant at each visit when a treatment dispensing is planned, 
and at the end of treatment (EOT) visit. The completed patient diary (returned to the site at each 
visit), returned IMP treatment and NIMP kit boxes (used and unused) along with any unused 
prefilled syringes will be used for drug accountability purposes. Participants will also return used 
prefilled syringes to the site in a sharps container. Compliance will be assessed by diary, and by 
counting the number of used and unused treatment kits and syringes during the site visits and 
documented in the source documents and relevant form. Deviation(s) from the prescribed dosage 
regimen should be recorded. 
A record of the quantity of IMP and NIMP dispensed to and administered by each participant 
must be maintained and reconciled with study intervention and compliance records. Intervention 
start and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded. 
6.5 
DOSE MODIFICATION  
Dose modification for an individual participant is not allowed. 
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6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
The participants will have no access to study intervention after EOS. 
6.7 
TREATMENT OF OVERDOSE  
Of note, asymptomatic overdose has to be reported as a standard AE. No antidote is available for 
dupilumab. 
For this study, any dose of IMP at least twice the intended dose during an interval of less than 
11 days and any dose of NIMP at least twice the maximum prescribed daily dose, within the 
intended therapeutic interval (≥512 μg; 8 sprays or more) will be considered an overdose. 
Sponsor does not recommend specific treatment for an overdose for IMP or NIMP. 
In the event of an overdose, the Investigator should: 
• Provide symptomatic care. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities (until 
dupilumab can no longer be detected systemically [at least 98 days]). 
• Evaluate the participant to determine whether study intervention should be interrupted. 
• Document appropriately in the CRF. 
• Contact the Sponsor as soon as possible. 
6.8 
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 Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1 Prohibited concomitant medication  
The following concomitant treatments are not permitted during the screening period and the 
treatment period: 
• Treatment with an investigational drug (other than dupilumab) 
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• 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. 
• Use of intranasal decongestants except for preparation of nasal endoscopy (NE). 
• Long term courses (>2 weeks) of systemic steroids. 
• Short term courses (≤2 weeks) of IV, IM, subcutaneous (SC) systemic corticosteroids 
(SCS) except as indicated treatment of NP or to treat other serious coexisting disease 
(such as asthma). 
• Short term courses (≤2 weeks) of systemic corticosteroids (SCS) only between Visit 1 and 
Visit 2. 
• Live (attenuated) vaccine within 4 weeks prior to Visit 1. 
• Other monoclonal antibodies (biological immunomodulators), including but not limited to 
anti-IgE, anti-IL-5 and anti-TNF, etc. 
Participants who between Visit 1 and Visit 2 receive any of the prohibited treatments, treatment 
with systemic (oral, IV, IM) steroids or undergo surgery will not be enrolled. They may however 
be re-screened following the procedures described in the protocol. 
6.8.2 Permitted concomitant medication  
The following treatments are allowed: 
• Budesonide nasal spray during the run-in period and throughout the whole study as 
background treatment (as described in Section 6.1.2). 
• Nasal normal saline lavage (only considered rescue if initiated after V2). 
• Single topical decongestants administration for example oxymetazoline hydrochloride 
(to reduce the swelling and widen the path for the endoscope), as well as a topical 
anesthetic for example lidocaine are allowed before endoscopy. 
• Short term use of antibiotics (<2 weeks) are allowed during the study. 
• Short-acting β2-adrenergic receptor agonists (SABA), long-acting β2-adrenergic receptor 
agonists (LABA), and long-acting muscarinic acetylcholine receptor antagonists (LAMA). 
• Methylxanthines (eg, theophylline, aminophyllines) 
• Inhaled corticosteroids 
• 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 prior to Visit 1 is permitted. 
• Rescue medication including short courses of SCS for treatment of NP as described in 
Section 6.8.1 or short courses of SCS to treat other serious co-existing diseases (such as 
asthma exacerbation) are allowed. 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor if required. 
6.8.3 Rescue medicine  
During the study treatment period and post-treatment follow-up period, based on clinical 
evaluation, in case of worsening of endoscopic/radiological signs and/or clinical symptoms 
requiring medical intervention, the Investigator may consider rescue treatment with: 
• Nasal lavage with saline (only considered rescue if initiated after Visit 2) and/or systemic 
antibiotics (up to 2 weeks in case of acute infection). 
• Short course SCS (oral prednisone, prednisolone or equivalent up to 2 weeks). 
• Surgery for nasal polyps. Based on the observations from previous studies, 8 weeks of 
IMP treatment is recommended prior to surgery to allow onset of treatment effect.  
Participants receiving rescue treatment other than surgery during the study should continue on 
study drug unless the Investigator decides to withdraw the study treatment. Systemic steroids for 
rescue treatment of nasal polyps or for another reason will be provided to the participant by the 
site. Before starting treatment with SCS participants should come to the study site for the clinical 
assessments including endoscopy and SNOT-22.  
Participants scheduled for surgery may continue IMP up to the time of surgery or EOT whichever 
date comes first. At time of surgery participants will be permanently discontinued from study 
treatment and perform as soon as possible the efficacy and safety assessments planned at the EOT 
visit and will be instructed to return to the study site for additional visits as described in 
Section 7.1.1. An AE or SAE page will be completed. 
If the surgery is performed during the post-treatment follow-up period, at the time of surgery the 
participants will be assessed according to the procedures normally planned for the EOS Visit and 
will be instructed to return to the study site for additional visits as described in Section 7.1.1. An 
AE or SAE page will be completed. 
If surgery is scheduled after the planned end of study, EOS visit will not be delayed. A follow up 
contact(s) should be performed around the time of planned surgery to document the surgery date 
and outcome. Surgery data will be collected until electronic case report form (e-CRF) closure of 
the trial. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1 (Section 10.1). 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented. In any case, the participant 
should remain in the study as long as possible. 
7.1.1 Permanent discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for safety. See the SoA 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. 
The participants may withdraw from treatment with the IMP if they decide to do so, at any time 
and irrespective of the reason, or this may be the Investigator’s decision. All efforts should be 
made to document the reasons for treatment discontinuation and this should be documented in the 
eCRF. 
Participants must be withdrawn from the study intervention for the following reasons: 
• At their own request or at the request of their legally authorized representative (legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective participant to the participant’s 
participation in the procedure(s) involved in the research). 
• If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
participant’s well-being. 
• At the specific request of the Sponsor. 
• In the event of a protocol deviation, at the discretion of the investigator or the Sponsor 
• Any code broken at the request of the investigator. 
• Pregnancy. 
• Anaphylactic reactions or systemic hypersensitivity reactions that are related to IMP and 
require treatment (see Section 10.10.3). 
• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or non-
metastatic 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 10.10.4 for list). 
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• Serum ALT >3 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); baseline is defined as the latest value before the first IMP 
administration. 
• If they miss more than 2 consecutive IMP doses. 
• If they are treated with the specific prohibited medications requiring IMP discontinuation 
mentioned in Section 6.8.1. 
• In case of surgery for NP, refer to Section 6.8.3 for details. 
Handling of participants after permanent intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
In any case participants who prematurely discontinued the treatment will be encouraged to return 
to the study site for the efficacy and safety assessments planned at EOT Visit and for additional 
visits. 
Furthermore, all participants will be instructed as follows: 
• Return to the study site for evaluation of NPS, SNOT-22 for all remaining visits 
corresponding to SoA. 
• Continue to complete the patient diary for NC, anterior and posterior rhinorrhea and 
decreased/loss of smell daily symptom evaluation up to Week 36. 
• Continue on budesonide nasal spray stable dose but participants are not required to 
complete the INCS use daily in the e-diary after early treatment discontinuation (ETD). 
• Advise participants with comorbid atopic conditions (such as asthma) not to adjust their 
treatment without consultation with their physicians. 
• Report any AE up to the last scheduled visit (Week 36). 
• Contact the Investigator during the follow-up period up to the EOS visit if the symptoms 
worsen requiring medical attention: 
- The Investigator will record in the corresponding e-CRF pages rescue medication 
prescribed or surgical interventions during the planned study treatment period. Use 
of systemic steroids for rescue treatment of worsening nasal polyps or for another 
reason will be captured by the Investigator on the appropriate page(s) of the e-CRF 
page and the date and dosing information (daily dose, duration, international 
nonproprietary name [INN]) will be informed. Details on planned date for surgery, 
type and outcome (whenever possible) of surgery will be recorded in a specific 
e-CRF page. If surgery is performed during the study treatment period or follow-up 
period, an AE or SAE page will be completed. 
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All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Liver chemistry stopping criteria  
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a participant meets one of the conditions outlined in Appendix 6 (Section 10.6) or in the presence 
of abnormal liver chemistries not meeting protocol-specified stopping rules if the Investigator 
believes that it is in best interest of the participant. 
7.1.3 QTc stopping criteria  
Not applicable. 
7.1.4 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 [Section 10.9: Contingency measures for a regional or 
national emergency that is declared by a governmental agency]). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
e-CRF. 
7.1.5 Rechallenge  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned adverse event 
was unlikely and if the selection criteria for the study are still met (refer to Section 5.1 and 
Section 5.2). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency).  
7.1.5.1 Study intervention restart or rechallenge after liver stopping criteria are met  
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by any 
participant in this study are not allowed. 
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral or 
compliance 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 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 procedures normally planned for the EOS Visit will be performed at early 
discontinuation visit. 
• 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. The Investigator must document this in the site study records and 
inform sponsor in written timely. 
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. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF 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 (treated) in the study. 
Their inclusion and intervention numbers must not be reused. 
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7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, 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. 
• It is recommended that assessments/procedures at a site visit are performed in the 
following order if applicable: 
1) Patient-reported outcomes and other questionnaires: 
- 
Daily symptoms of NC, loss of smell and anterior and posterior rhinorrhoea 
- 
SNOT-22 
2) Procedures. 
3) Safety and laboratory assessments. 
4) IMP administration. 
5) NIMP boxes should be collected at all visits following provision during all study 
periods. 
6) IMP boxes should be collected at all visits following provision for home dosing during 
treatment period. 
• The result of central reading of nasal endoscopy that could unblind the study will not be 
reported to investigative sites or other blinded personnel until the study has been 
unblinded. 
• Blood sampling details including volume for all laboratory assessments will be provided in 
the ICF. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency).  
8.1 
EFFICACY ASSESSMENTS   
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
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8.1.1 Nasal polyps score (NPS)  
Change from baseline in NPS at Week 24 is the primary endpoint of this study. NPS is assessed 
by central video recordings of bilateral nasal endoscopy. The score (NPS) is the sum of the right 
and left nostril scores, as evaluated by means of nasal endoscopy (26, 27, 28). Polyps on each side 
of the nose is graded based on polyp size described in Table 5. 
Table 5 - 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 at the end of the scheduled visits before the administration 
of IMP and preceded by local administration of anesthetic drugs in combination with 
a decongestant. 
Standard video sequences will be downloaded or 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 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 and enter the result in the e-CRF. 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 on each side. The final results of central reading from V2 onward will be made available 
after the study. 
For the analysis of primary endpoint, central reading of V2 will be used for comparison with the 
Week 24 (EOT) reading. The sites will remove patient-identifying information from the imaging 
data header prior to sending the imaging data to the central reader. 
Further details on nasal endoscopy will be available in a separate operational manual provided to 
the sites. 
8.1.2 Nasal congestion/obstruction scores (NCS)  
Change from baseline in NCS at Week 24: NCS is assessed by the participant on a daily basis 
from V1 and throughout the study, using an e-diary using a 0 to 3 categorical scale (where 0 = no 
symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms) (7). 
Nasal congestion/obstruction score is a reflective score of the worst symptom severity over the 
past 24 hours by the participant (see Table 6). 
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Table 6 - Symptom severity score  
Scale  
Symptoms  
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) 
The e-diary is used for daily recording of participant’s answers to the questionnaires. This device 
will be dispensed at the Screening Visit (V1), including instructions for use. Participants will be 
instructed on the use of the device. Recorded information will be downloaded from this device 
daily. At EOS Visit, the e-diary will be downloaded and returned to the site. 
A severity ≥2 on the day of V1 and a weekly average severity greater than 1 at time of 
randomization (V2) is required and will be provided to the site to determine participant 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. 
For the baseline to EOT analysis, 4 weeks average of the symptom scores will be used. 
8.1.3 Proportion of participants during the treatment period who receive SCS rescue or 
are planned to undergo surgery for NP  
SCS rescue 
Systemic steroids for rescue treatment of nasal polyps or for another reason will be prescribed to 
the participant by the site. PROs and a nasal endoscopy should be performed before starting 
treatment with SCS. The Investigator records the date and dosing information (daily dose, 
duration, INN) on the appropriate page(s) of the e-CRF. Indication for SCS use will also be 
captured by selecting one or more of the following categories: 
1. Nasal polyposis 
2. Asthma 
3. Other respiratory disease (specify) 
4. Other ear, nose or throat disease (specify) 
5. Other reason (specify). 
Surgery (actual or planned) for NP 
For participants who have a surgery or have a scheduled date for surgery for NP, the reason 
(worsening signs and/or symptoms during the study), the expected or actual surgery date, the type 
and outcome of surgery will be recorded in a specific e-CRF page. 
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8.1.4 Disease specific daily symptom assessment and total symptom score (TSS)  
On a daily basis from V1 and throughout the study, the participant will use an e-diary to respond 
to the morning individual rhinosinusitis symptom questions using a 0 to 3 categorical scale (where 
0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms) (7): 
• Congestion and/or obstruction. 
• Loss of sense of smell. 
• Anterior rhinorrhea (runny nose). 
• Posterior rhinorrhea (postnasal drip). 
The total symptom score is a composite score (ranging between 0 and 9) consisting of the sum of 
the following symptoms assessed daily in the morning: NC, decreased/loss of sense of smell, 
rhinorrhea (average of anterior/posterior nasal discharge). Higher scores on TSS indicate greater 
overall symptom severity. TSS is a reflective score of the worst symptom severity over the past 
24 hours by the participant. 
The psychometric properties of nasal congestion as an individual item, including validity, reliability 
and ability to detect changes have been demonstrated in adult patients 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. 
8.1.5 Decreased/loss of sense of smell  
The decreased/loss of sense of smell severity is assessed by the participant on a daily basis from 
V1 and throughout the study, using an e-diary and using a 0 to 3 categorical scale (where 0 = no 
symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms). This is 
a reflective score of the worst symptom severity over the past 24 hours by the participant. 
8.1.6 22-Item sino-nasal outcome test (SNOT-22)  
The SNOT-22 is a validated questionnaire to assess the impact of chronic rhinosinusitis on 
HRQoL (Section 10.10.2). The SNOT-22 has 22 items on a 5-category scale applicable to sino-
nasal conditions and surgical treatments. The range of the global score is 0 to 110 with a minimal 
important difference (MID), the smallest difference between clinical trial arms mean change from 
baseline (point estimates) that will be interpreted as important, of 8.9 (30). Lower scores indicate 
less impact and the recall period is the past 2 weeks. There are 5 domains that can be described 
within SNOT-22, including nasal, ear, sleep, general and practical, and emotional. 
8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than adverse events which are presented in 
Section 8.3. 
Planned timepoints for all safety assessments are provided in the SoA. 
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8.2.1 Physical examinations  
• Physical examination will include, at a minimum, assessments of the general appearance, 
skin, eyes, ear/nose/throat, respiratory, cardiovascular, gastrointestinal, neurological, 
lymphatic, and musculoskeletal systems. Height and weight will also be measured and 
recorded. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2 Vital signs  
• Oral temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed in the sitting position using the 
same arm (preferably) at each visit 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 and IMP 
administration) 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. 
8.2.3 Electrocardiograms  
Local single 12-lead ECG will be obtained for screening purpose only. 
8.2.4 Clinical safety laboratory tests  
• 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 hematology testing will be 
performed by central lab. Other clinical laboratory testing will be performed by local or 
central labs. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. Abnormal laboratory findings associated with 
the underlying disease are not considered clinically significant, 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 or within 12 weeks after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator. 
- 
If clinically significant 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 should be notified. 
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- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the SoA (Section 1.3). 
- 
If laboratory values from non-protocol specified laboratory tests 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), then the results 
must be recorded.  
8.2.5 Pregnancy testing  
• Refer to Section 5.1 Inclusion criteria for pregnancy testing criteria; the Investigator is 
responsible for review of medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a woman with an early undetected pregnancy 
• Pregnancy testing (urine or serum) should be conducted every four weeks during 
intervention  
• Pregnancy testing (urine or serum) must be conducted 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 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3 (Section 10.3). The definition of adverse event of special interest (AESI) is provided 
in Section 8.3.6. 
The definitions of unsolicited and solicited adverse events can be found in Appendix 3 
(Section 10.3). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative) 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 or the study (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the informed consent form 
(ICF) until the End of Study (EOS) visit at the timepoints specified in the SoA (Section 1.3). 
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All SAEs and 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 information on AEs or SAEs 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  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs and AEs of 
special interest (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 an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information (IB).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded 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,  
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- 
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor.  
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether 
an event meets the criteria for a SUSAR, and therefore, is expedited to regulatory 
authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants will be collected after the start of study 
intervention and until 12 weeks after the last administration of study intervention. 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the 
pregnancy. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• 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. 
• 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.  
8.3.6 Adverse events of special interest  
• An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific 
and medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and immediate notification by the Investigator to the Sponsor is required. Such 
events may require further investigation in order to characterize and understand them. 
Adverse events of special interest may be added, modified or removed during a study by 
protocol amendment.  
• For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described in Appendix 3 (Section 10.3), even if not fulfilling a seriousness 
criterion, using the corresponding form.  
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• Pregnancy of a female participant entered in a study with IMP;  
- 
Pregnancy occurring in a female participant entered in the clinical trial. It will be 
qualified as an SAE only if it fulfills one of the seriousness criteria (see Appendix 3 
[Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant is mandatory until the outcome has 
been determined (See Section 8.3.5) 
• 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 overdose form. 
- 
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the maximum prescribed daily dose, within the intended therapeutic interval. The 
circumstances (ie, accidental or intentional) should be clearly specified in the overdose 
form. 
• Increase in alanine transaminase (ALT): 
- 
ALT >5 x the upper limit of normal (ULN) in participants with baseline ALT ≤2 x ULN; 
- 
ALT >8 x ULN if baseline ALT >2 x ULN. 
• Other project specific AESI(s) 
- 
Anaphylactic reactions. 
- 
Systemic hypersensitivity reactions. 
- 
Helminthic infections. 
- 
Any severe type of conjunctivitis or blepharitis.  
- 
Keratitis. 
- 
Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms). 
8.3.7 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
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8.3.7.1 Medical device deficiencies  
Not applicable. 
8.4 
PHARMACOKINETICS  
PK parameters are not evaluated in this study. 
8.5 
GENETICS  
Genetics are not evaluated in this study. 
8.6 
BIOMARKERS  
Biomarkers are not evaluated in this study. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Immunogenicity assessments are not performed in this study. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, mechanism of action, or possible toxicity, and can help identify new drug targets or 
biomarkers that predict participant response to treatment. Therefore, data and biological samples 
will be stored and used for future research when consented to by participants (see Section 10.1.3) 
unless prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will 
not be included in the local ICF).  
For participants who consent to the storage and use of their data and remaining (leftover) and/or 
extra (additional) clinical samples, data and samples may be used for future research related either 
to the drug, the mechanism of action, and the disease or its associated conditions. Such research 
may include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites. If future research on genetic material is performed, this will also be limited to the 
purpose of addressing research questions related to the drug, the mechanism of action, the disease 
or its associated conditions. 
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Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct at 
a given timepoint (eg, at randomization visit) as defined in the study protocol. 
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. Data and 
samples will be used in alignment with the information provided to participants in the ICF Part 2 
(future research). For future research projects, all biological samples and relating data to be used 
will be coded such that no participant direct identifiers will be linked to them. These coded data 
and samples may be transferred to a Sponsor site (or a subcontractor site), which may be located 
outside of the country where the study is conducted. The Sponsor adopts safeguards for protecting 
participant confidentiality and personal data (see Section 10.1.4). 
Relating data and biological samples for future research will be stored for up to 25 years after the 
end of the study. Any samples remaining at the end of retention period will be destroyed. If 
a participant requests destruction of his/her samples before the end of the retention period, the 
Investigator must notify the Sponsor (or its contract organization) in writing. In such case, 
samples will be destroyed and related coded data will be anonymized unless otherwise required by 
applicable laws. 
Participant’s coded datasets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
In this China study, samples for storage to support future research will not be collected. All 
biological samples will be disposed of following completion of the CSR. Coded data will be 
stored for up to 25 years after the signature of the final study report and then will be disposed. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined.  
Table 7 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the ICF. 
Randomized 
The randomized population includes all participants with a treatment kit number allocated 
and recorded in the IRT database, regardless of whether the treatment kit was used or not. 
Participants treated without being randomized will not be considered randomized and will 
not be included in any efficacy population. 
Intent-to-treat (ITT) 
All randomized participants analyzed according to the treatment group allocated by 
randomization, regardless of whether the treatment kit was used or not. 
Safety 
All participants randomly assigned to study intervention and who take at least 1 dose of 
study intervention. Participants will be analyzed according to the intervention they actually 
receive.  
Randomized participants for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized.  
For participants who receive a different treatment from the planned one, the participants 
who take at least one dose of dupilumab will be allocated to dupilumab group, otherwise will 
be allocated to placebo group. 
ICF: informed consent form; IRT: interactive response technology, ITT: intent-to-treat. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization will be used in any analysis population. The safety experience associated with any 
later randomization will be reported separately. 
9.2 
STATISTICAL ANALYSES  
The SAP will be finalized prior to the primary analysis at Week 24 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 secondary endpoints. 
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9.2.1 General considerations  
Planned Database lock date 
A primary database lock is currently planned to be performed when all randomized participants 
have completed the 24-week treatment period, including early dropouts. 
The database will be updated at the end of the study for all participants to include the post-
treatment follow-up information and updates for the events previously ongoing at the time of the 
primary lock. Additional data collected between the primary database lock and last participant 
completing last visit will be summarized in a separate CSR addendum, as needed. Details will be 
included in the SAP. 
Analysis considerations 
The baseline value of efficacy parameters is defined as the last available value before 
randomization unless otherwise specified (see below for daily Diary of NCS, TSS and severity of 
decreased/loss of sense of smell). 
The calculation of the baseline for endpoints collected on a daily basis, baseline is defined as the 
average of the scores in the 7 days prior to randomization. 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. 
The baseline value of the other parameters is defined as the last available value prior to the first 
dose of IMP if the participant is treated, or the last available value up to randomization if the 
participant is not exposed to IMP. 
Unless otherwise specified, analyses will be performed by intervention group (and overall for 
baseline and demographics characteristics).  
The observation period will be divided into 4 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. 
• The treatment-emergent (TE) period is defined as the period from the first IMP 
administration to the last IMP administration + 98 days. The treatment-emergent period 
includes the following 2 periods:  
- 
The on-treatment period is defined as the period from the first IMP administration to 
the last administration of the IMP + 14 days  
- 
The residual treatment period is defined as the period from the end of the on-
treatment period to the end of the treatment-emergent period.  
• The post-treatment period is defined as the period from the end of the treatment-
emergent period. 
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9.2.2 Primary endpoint(s) analyses  
The primary endpoint will be analyzed with the primary estimand defined according to the 
following attributes: 
• Endpoint: Change from baseline in NPS at Week 24. 
• Treatment condition: dupilumab 300 mg Q2W will be compared to placebo, on top of 
background therapy. 
• Analysis population: ITT population 
• Intercurrent events (IE):  
- 
Undergoing surgery for CRSwNP or taking SCS for any reason prior to Week 24: data 
after surgery/SCS will be set to missing and the worst post-baseline value on or before 
the time of surgery/SCS will be used to impute missing Week 24 value (WOCF). For 
participants with no post-baseline values, the baseline value will be used (composite 
strategy). 
- 
Taking other prohibited/rescue medications: all data collected after use will be used in 
the analysis (treatment policy strategy). 
- 
Discontinuing the study intervention (but not undergoing surgery for CRSwNP or 
taking SCS for any reason prior to Week 24): all data collected after discontinuation 
will be used in the analysis (treatment policy strategy). 
• Population-level summary: mean change difference between dupilumab 300 mg Q2W and 
placebo from ANCOVA. Model with study intervention and screening blood eosinophil 
count strata, and baseline measurement as covariates is used. Statistical inference obtained 
from all imputed data by ANCOVA model will be combined using Rubin’s rule. Missing 
data at Week 24 will be imputed using the multiple imputation and this multiple 
imputation will use all participants excluding those who have undergone surgery or 
received SCS on or before Week 24. 
In the primary analysis approach for the primary endpoint, for participants who undergo surgery 
for NP or taking SCS for any reason, data collected after surgery or SCS will be set to missing and 
the worst post-baseline value on or before the time of surgery or taking SCS will be used to 
impute missing Week 24 value (ie, WOCF approach). For participants with no post-baseline 
values, the baseline value will be used. For participants taking other prohibited/rescue 
medications, all data collected after use will be used in the analysis. Participants who discontinue 
the study intervention prematurely are encouraged to follow the planned clinical visits and, in 
these participants, who did not undergo surgery or take SCS for any reason, all data collected after 
study intervention discontinuation will be used in the analysis. In case there is missing data, 
a multiple imputation will be used to impute missing Week 24 values, and this multiple 
imputation will use all participants excluding those who have undergone surgery or taking SCS 
for any reason on or before Week 24. Each of the imputed completed data will be analyzed by 
fitting an ANCOVA model with the baseline covariate and factor for study intervention and 
screening blood eosinophil count strata. Statistical inference obtained from all imputed data will 
be combined using Rubin’s rule. Descriptive statistics including number of participants, mean, 
standard error, and LS means will be provided. In addition, difference in LS means and the 
corresponding 95% CI will be provided along with the p-values. 
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Sensitivity/supplementary analyses 
Additional analyses including the following will be performed to confirm robustness of the results 
with respect to intercurrent event and missing data handling strategy: 
• Data collected after initiation SCS for any reason will be included in the analysis. 
• Tipping point analysis. 
Subgroup analysis 
To assess the consistency in treatment effects across different subgroup levels, subgroup analyses 
will be performed for the primary efficacy endpoints with respect to age group, gender, and other 
factors that will be specified in the SAP. 
9.2.3 Secondary endpoint(s) analyses  
The secondary endpoints detailed in this section are as below: 
• Change from baseline in NCS at Week 24 
• Change from baseline in TSS at Week 24 
• Change from baseline in the severity of decreased/loss of smell daily assessed by the 
participant at Week 24 
• Change from baseline in SNOT-22 at Week 24 
• Proportion of participants receiving SCS for any reason or undergo surgery for nasal polyp 
during the study treatment 
The change from baseline in NCS, TSS, severity of decreased/daily loss of smell, and SNOT-22 at 
Week 24 will be analyzed using the same analysis approach as for the primary endpoint. 
Proportion of participants with first SCS rescue for any reason or surgery (actual or planned) for 
NP during the 24-week treatment period will be derived and analyzed using the Cox proportional 
hazards model and log rank test stratified by screening blood eosinophil count, by considering the 
first SCS rescue use for any reason or surgery (actual or planned) for NP as the event. Descriptive 
statistics including number of participants with rescue SCS or surgery and number of participants 
without rescue SCS or surgery (censored) and the corresponding rates will be provided by study 
intervention group. The estimates of the hazard ratio and corresponding 95% CI will be provided 
for the dupilumab group versus the placebo group.  
Other secondary endpoints analyses are defined in Section 9.2.6.1 (AE, SAE), Section 9.2.6.2 
(laboratory abnormalities). 
9.2.4 Tertiary/exploratory endpoint(s) analyses  
Not applicable. 
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9.2.5 Multiplicity adjustment  
A hierarchical procedure is proposed to strongly control the family wise type-I error rate at the 
2-sided 0.05. The primary endpoint will be tested first, followed by selected secondary endpoints. 
The detailed hierarchical testing procedures will be defined in the study statistical analysis plan 
(SAP). 
9.2.6 Other safety analyses  
All safety analyses will be performed on the safety population. 
9.2.6.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
• Treatment-emergent adverse events (TEAEs): AEs that developed, worsened or became 
serious during the treatment-emergent period 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period  
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
Analysis of all adverse events 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment emergent AESI (defined with a PT or a prespecified grouping), all treatment 
emergent SAEs and all TEAEs leading to permanent treatment discontinuation. In addition, 
TEAEs will be described according to maximum intensity and relation to the study intervention. 
Serious AEs and AEs leading to study discontinuation that occur outside the treatment-emergent 
period will be summarized separately. 
The AE summaries will be generated with number (%) of participants experiencing at least 
one event.  
The incidence of each type of AESI and other AE groupings will be tabulated by treatment group. 
For each type of AESI, the following analysis will be generated: 
• A summary of the number (%) of participants with: 
- 
Any TEAE, 
- 
Any SAE (regardless of treatment-emergent status), 
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- 
Any TESAE, 
- 
Any AE leading to death, 
- 
Any TEAE leading permanent study intervention discontinuation, 
- 
Any TEAE related to study intervention reported by the Investigator, 
- 
Any TEAE by maximum intensity, corrective treatment, and final outcome. 
The method to identify AESIs and other AE groupings will be specified in the SAP. 
Deaths will also be analyzed. 
9.2.6.2 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Quantitative analyses 
When relevant, for laboratory variables, vital signs, descriptive statistics for results and changes 
from baseline will be provided for each planned visit, the last value and the worst value 
(minimum and/or maximum value depending on the parameter) during the on-treatment period. 
These analyses will be performed using central measurements only (when available) for 
laboratory variables.  
Analyses according to potentially clinical significant abnormality (PCSA) 
PCSA analyses will be performed based on the PCSA list currently in effect at Sanofi at the time 
of the database lock. 
Analyses according to PCSA will be performed based on the worst value during the treatment-
emergent period, using all measurements (either local or central, either scheduled, nonscheduled 
or repeated). 
For laboratory variables, and vital signs, the incidence of participants with at least one PCSA 
during the treatment-emergent period will be summarized regardless of the baseline level and 
according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
9.2.7 Other analyses  
Data collected regarding the impact of the COVID-19 or other pandemics, on the participants will 
be summarized (eg, discontinuation due to COVID-19). Any additional analyses and methods 
required to investigate the impact of COVID-19 or other pandemics requiring public health 
emergency on the efficacy (eg, missing data due to COVID-19) and safety will be detailed in the 
SAP. 
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For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency). 
9.3 
INTERIM ANALYSES   
No interim analysis will be performed before the final database lock for this study. 
9.4 
SAMPLE SIZE DETERMINATION  
Approximately 62 participants will be randomized to study intervention. 
A total sample size of about 62 participants (randomization ratio [1:1], ie, [31 per intervention 
group]) was determined to demonstrate superiority of dupilumab 300mg Q2W versus placebo 
with 90% power and 2-sided test with 5% significance level based on the following assumptions 
on the primary endpoint: 
• True mean difference of -1.8 between dupilumab 300 mg Q2W and placebo 
• Common SD of 1.83  
• A 25% dropout rate 
Calculations were made based on two sample t-test using nQuery Advisor 7.0. 
Assumptions are based on the following: 
• Mean treatment difference= -1.8 (lowest observed effect size of NPS at Week24 in the 
EFC14146 [SINUS-24] and EFC14280 [SINUS-52])  
• SD=1.83 (highest SD of NPS reduction at Week24 in the EFC14146 [SINUS-24] and 
EFC14280 [SINUS-52]) 
• Dropout rate 25% (higher than 10% due to COVID-19 uncertainties) 
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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 Good Clinical Practice (GCP) guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• The protocol, protocol amendments, ICF, Investigator’s brochure, IDFU, 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. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation 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 (as per Sanofi policy) 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 healthcare 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 
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- 
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. 
- 
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 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (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 , including 
the risks and benefits, to the participants or their legally authorized representative, and 
answer all questions regarding the study, including what happens to the participant when 
his/her participation ends (post-trial access strategy for 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, Privacy and 
Data Protection requirements including those of the Global Data Protection Regulation 
(GDPR) and of the French law, where applicable, and the IRB/IEC or study center.  
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• 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. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative, where applicable.  
Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency).  
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
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Participant race and ethnicity will be collected in this study because they are expected to modify 
the drug response.  
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
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• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering 
an adequate level of protection. Those transfers are safeguarded by Sanofi in accordance 
with the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
No committee will be adopted in this study. 
10.1.6 Dissemination of clinical study data  
Study participants 
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, ClinicalTrialRegister.eu, and sanofi.com, as well as some 
national registries. 
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In addition, results from clinical trials in participants are required to be submitted to peer-
reviewed journals following internal company review for accuracy, fair balance and intellectual 
property. For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/ hospital’s name and location on the China Trial Disclosure website as required 
by the National Medical Products Administration (NMPA) in its guidance “Implementation of 
Drug Clinical Trial Information Registration and Disclosure” (“Notification No. 28”), requesting 
name disclosure of Chinese and foreign investigational sites and Investigators in any eligible 
clinical trial.  
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in CRF Completion Instruction. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These pre-defined parameters 
will be monitored during the study and important deviations from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
• Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in separate study documents. 
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• 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). 
• 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 can be found in source data location list. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The signature of the informed consent by the first participant is considered the first act of 
recruitment and will be the study start date. 
Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
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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 participant and should assure 
appropriate participant 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 tests detailed in Table 8 will be performed by the local or central laboratory except 
that hematology will be performed by central laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
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• Pregnancy testing should be conducted at screening (serum), on Day 1 before the first 
administration of IMP (urine) and every 4 weeks during intervention. 
• Pregnancy testing (urine or serum as required by local regulations) 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 tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 8 - Protocol-required laboratory tests  
 
Laboratory tests 
Parameters 
Hematology 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
Mean corpuscular volume (MCV) 
 
Mean corpuscular hemoglobin (MCH) 
 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose [nonfasting] 
 
Electrolytes (Potassium, Sodium, Chloride) 
 
Uric acid 
 
Total cholesterol 
 
Alkaline phosphatase 
 
Total bilirubinb 
 
Total protein 
 
Albumin 
 
Alanine aminotransferase 
 
Aspartate aminotransferase 
 
Lactate deshydrogenase 
 
Bicarbonate 
 
Creatine phosphokinase 
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Laboratory tests 
Parameters 
Pregnancy testing 
Serum (at screening) or highly sensitive urine (at other timepoints) human chorionic 
gonadotropin (hCG) pregnancy test (as needed for women of childbearing potential)  
Other screening tests 
Serology (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], total 
hepatitis B core antibody [HBcAb], hepatitis C virus antibodies [HCVAb], Human 
Immunodeficiency Virus [HIV] screen [anti-HIV-1 and HIV-2 antibodies] and antinuclear 
antibody [ANA])c 
Follicle-stimulating hormone and estradiol (as needed in women of nonchildbearing 
potential only). 
NOTES : 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.2 (Liver chemistry stopping criteria) 
and Appendix 6 (Section 10.6) (Liver and other safety: Suggested actions and follow-up assessments). All events of ALT >5 ULN if 
baseline ALT is ≤2 ULN or ALT >8 ULN if baseline ALT is >2 ULN which may indicate severe liver injury (possible Hy’s Law) must be 
reported to Sponsor in an expedited manner (excluding studies of hepatic impairment or cirrhosis). 
b In case of values above the normal range, differentiation in conjugated and nonconjugated bilirubin. 
c In case of results showing HBsAg (negative), and HBcAb total or HBcAb IgM (positive), an HBV DNA testing will be performed prior to 
randomization to rule out a false positivity if the Investigator believed the participant is a false positive, or to clarify the serological status if 
the Investigator find it unclear to interpret in absence of known HBV infection. In case of results showing hepatitis C virus antibody 
(HCVAb) (positive), an HCV RNA testing will be performed to rule out a false positivity, if the Investigator believed the participant is a false 
positive. Note: Anti-ds DNA antibody will be tested if ANA was positive (≥1:160 titer). 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: AES AND SAES: 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 adverse event is an adverse event 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 event(s), 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. 
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• 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 
diary. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology or clinical chemistry) 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 
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfill the definition of an AE or SAE. Also, lack of 
efficacy or failure of expected pharmacological action also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
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• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more 
of the criteria listed: 
a) Results in death 
b) Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (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 or significant 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) that 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 by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
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- 
Note: The following list of medically important events is intended to serve as 
a guideline for determining which condition has to be considered as 
a medically important event. The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse  
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic 
ALT increase >10 × ULN  
- 
Suicide attempt or any event suggestive of suicidality  
- 
Syncope, loss of consciousness (except if documented as a consequence of 
blood sampling)  
- 
Bullous cutaneous eruptions  
- 
Cancers diagnosed during the study or aggravated during the study 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated 
during the study 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• 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. 
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Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories: 
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL). Instrumental ADL refers to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
• Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self-care 
ADL. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden 
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. The Investigator will use clinical judgment to determine 
the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• 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 (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’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 with a copy of any postmortem findings 
including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• 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) 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 
offline 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 
offline, 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 site file. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting timeframes. 
• Contacts for SAE reporting can be found in the site file. 
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10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
Woman of childbearing potential (WOCBP)  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range should be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). 
• 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. 
Permanent sterilization methods include: 
• 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, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
Women in the following categories are considered WONCBP: 
1. Any female with permanent infertility due to one 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, gonadal dysgenesis), 
Investigator discretion should be applied to determining study entry. 
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2. Postmenopausal female 
- 
A postmenopausal state is defined as the period of time after a woman has experienced 
no menses for 12 consecutive months without an alternative medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range should 
be used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). 
- 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
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10.4.2 Contraception guidance  
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used 
consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used.  
Highly effective methodsb that are user dependent Failure rate of <1% per year when used 
consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
− oral 
− intravaginal 
− transdermal 
− injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
− oral 
− injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c 
 Male condoms must be used in addition to hormonal contraception 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure from friction). 
 
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10.5 
APPENDIX 5: GENETICS  
Not applicable. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS   
INCREASE IN ALT 
 
Note: 
Normalization is defined as < ULN or baseline value if > ULN. 
As soon as seriousness criterion is met or the event leads to permanent treatment discontinuation, the monitoring team should be notified within 
24 hours. 
* If unable to retest in 72 hours, use original lab results to decide on further monitoring/discontinuation. 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
See Section 8.3.4 for guidance on safety reporting. 
Monitor LFTs every 72 hours
If baseline ≤ 2 ULN & ALT ≤5 ULN, or 
if baseline > 2 ULN & ALT ≤8 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
If baseline ≤2 ULN & ALT > 5 ULN, or 
if baseline > 2 ULN & ALT > 8 ULN
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
COMPLETE the CRF for «ALT Increase» for any permanent discontinuations due to liver injury (See 
protocol/CRF instructions)
3.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
4.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
5.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
6.
CONSIDER consulting with hepatologist
7.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances 
suggesting hepatic encephalopathy
8.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to 
normal/baseline or clinical resolution.
9.
FREEZE serum sample (5ml x 2)
10. In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
Check if special CRF should be 
completed per protocol/CRF 
instructions
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
ALT > 3 ULN
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10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency declared by 
a governmental agency: 
A regional or national emergency declared by a governmental agency (eg, public health emergency, 
natural disaster, pandemic, and terrorist attack) may prevent access to the clinical trial site. 
Contingency procedures are suggested for an emergency that prevents access to the study site, to 
ensure the safety of the participants, to consider continuity of the clinical study conduct, protect 
trial integrity, and assist in maintaining compliance with GCP in Conduct of Clinical Trials 
Guidance. Sponsor agreement MUST be obtained prior to the implementation of these procedures 
for the duration of the emergency. 
The decision for each individual participant to remain and/or start in the study should be made on 
a case-by-case basis based on best Investigator medical judgment. The clinical judgment of the 
treating physician should guide the management plan of each participant based on individual 
benefit/risk assessment and the evolving situation at the site. However, in case new participant is 
eligible for the trial, the PI/site should assess the capacity to maintain these participants into the 
trial before any screening procedures will start. If the site cannot guarantee an accurate follow-up 
in the context of the trial, alternative treatment outside the clinical trial should be proposed. 
When participants are already randomized and/or treated, attempts should be made to perform all 
assessments in accordance with the protocol to the extent possible. 
When possible, the focus should be on IMP administration and safety blood collection 
(eg, biochemistry and hematology). However, all efforts should be made to perform the 
measurements of key parameters for efficacy endpoints (eg, nasal endoscopy) (Section 8.1). The 
deviations from the study protocol (eg, treatment delay, omission, tests not performed…) should 
be documented in the source document and collected in the appropriate pages of the eCRF. 
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc) may be planned for the collection of possible safety and/or efficacy data (eg, safety 
assessments, efficacy assessments). 
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• If onsite 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. 
• The DTP supply of the IMP from the site/sponsor where allowed by local regulations and 
agreed upon by participant. (Section 6.1). 
Contingencies implemented due to emergency will be documented. 
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. 
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) (Section 10.1.3). 
 
10.10 APPENDIX 10: ADDITIONAL APPENDICES  
10.10.1 
List of prohibited live attenuated vaccines  
• Bacillus Chickenpox (Varicella) 
• Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection 
is permitted 
• Measles (Rubeola) 
• Measles-mumps-rubella (MMR) combination 
• Measles-mumps-rubella-varicella (MMRV) combination 
• Mumps 
• Oral polio (Sabin) 
• Oral typhoid 
• Rotavirus 
• Rubella 
• Smallpox (Vaccinia) 
• Varicella Zoster (shingles) 
• Yellow fever 
This list is indicative and not exhaustive. 
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10.10.2 
  
 
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10.10.3 
Definition of anaphylaxis  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death."(31) 
 
10.10.4 
List of opportunistic infections  
• Aspergillosis. 
• Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers).  
• Candidiasis – only systemic or extensive mucosal or cutaneous cases.  
• 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.  
• Nontuberculosis mycobacteria.  
• Pneumocystis pneumonia (PCP).  
This list is indicative and not exhaustive. 
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10.11 APPENDIX 11: ABBREVIATIONS  
 
ABPA: 
allergic bronchopulmonary aspergillosis 
AD: 
atopic dermatitis 
AE: 
adverse events 
AESI: 
adverse event of special interest 
AFRS: 
allergic fungal rhinosinusitis 
ALT: 
alanine transaminase 
AM: 
ante meridiem 
ANA: 
antinuclear antibody 
ANCOVA: 
analysis of covariance 
BID: 
twice a day 
BP: 
bullous pemphigoid 
CI: 
confidence intervals 
CICU: 
chronic inducible cold urticaria 
COPD: 
chronic obstructive pulmonary disease 
COVID-19: 
Coronavirus Disease 2019 
CRF: 
case report form 
CRSsNP: 
chronic rhinosinusitis without nasal polyposis 
CRSwNP: 
chronic rhinosinusitis phenotype with nasal polyps 
CSR: 
clinical study report 
CSU: 
chronic spontaneous urticaria 
CT: 
computed tomography 
D: 
day 
DNA: 
deoxyribonucleic acid 
DTP: 
direct-to-patient 
EC: 
ethic committee 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EoE: 
eosinophilic esophagitis 
EOS: 
end of study 
EOT: 
end of treatment 
FESS: 
functional endoscopic sinus surgery 
FU: 
follow-up 
HBsAb: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HCVAb: 
hepatitis C antibody 
HIV: 
human immunodeficiency virus 
HRQoL: 
health related quality of life 
IB: 
Investigator’s Brochure 
ICF: 
informed consent form 
IEC: 
Independent Ethics Committees 
IgE: 
immunoglobulin E 
IL: 
interleukin 
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IL-4Rα: 
interleukin 4 receptor alpha subunit 
IM: 
intramuscular 
IMP: 
investigational medicinal product 
INCS: 
intranasal corticosteroid 
INN: 
international nonproprietary name 
IRB: 
Institutional Review Boards 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
IV: 
intravenous 
IVRS: 
interactive voice respond system 
IWRS: 
interactive web response system 
LS: 
least squares 
mAb: 
monoclonal antibody 
MRI: 
magnetic resonance imaging 
NC: 
nasal congestion 
NCS: 
nasal congestion/obstruction score 
NE: 
nasal endoscopy 
NIMP: 
noninvestigational medicinal product 
NP: 
nasal polyposis 
NPS: 
nasal polyps score 
PCSA: 
potentially clinical significant abnormality 
PROs: 
patient reported outcomes 
Q2W: 
every 2 weeks 
QM: 
every morning 
QoL: 
quality of life 
RBC: 
red blood cell 
RESS: 
radical endoscopic sinus surgery 
RNA: 
ribonucleic acid 
SAE: 
serious adverse event 
SC: 
subcutaneous 
SCS: 
systemic corticosteroids 
SD: 
standard deviation 
SNOT-22: 
sino-nasal outcome test 
SUSAR: 
suspected unexpected serious adverse reaction 
TEAEs: 
treatment-emergent adverse events 
Th: 
T helper 
TSS: 
total symptom score 
ULN: 
upper limit of normal 
W: 
week 
WBC: 
white blood cell 
WOCBP: 
women of child bearing potential 
WOCF: 
worst observation carried forward 
 
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10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
Not applicable. 
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11 
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