Clinical trial NCT05049122
Conditions: Chronic Rhinosinusitis With Nasal Polyps
Sponsor: Sanofi
Start date: 2021-10-22; Completion date: 2023-07-05
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a Phase 4, open-label, single-arm, multicenter study to evaluate the efficacy and safety of dupilumab subcutaneous (SC) injection monotherapy in Japanese participants aged 18 or older with CRSwNP that is not adequately controlled with existing therapies.

Duration of study period (per participant):

* Screening Period (2 to 4 weeks)
* Intervention Period (up to 52 weeks±3 days)

Detailed description:

Arms: arm 1: Dupilumab every 2 weeks (q2w). Dosing interval may be changed from q2w to q4w at week 24
Interventions: intervention 1: Dupilumab SAR231893
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection Route of administration: subcutaneous (SC)

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
CLINICAL TRIAL PROTOCOL 
Protocol title: 
A single-arm, 52-weeks, Phase 4 study to assess the 
efficacy and safety of dupilumab in patients with chronic 
rhinosinusitis with nasal polyposis (CRSwNP) who are not 
adequately controlled with existing therapies 
Protocol number: 
LPS16872 
Amendment number: Not applicable 
Compound number 
(INN/Trademark): 
SAR231893 
(dupilumab/Dupixent®) 
Brief title: 
Dupilumab in Japanese patients with chronic rhinosinusitis 
with nasal polyp (SINUS-M52) 
Study phase: 
Phase 4 
Sponsor name: 
Sanofi K.K. 
Legal registered 
address: 
3-20-2, Nishi Shinjuku,
Shinjuku-ku, Tokyo 163-1488
Japan
Monitoring team’s 
representative name 
and contact 
information 
Regulatory agency identifier number(s): 
IND: 
Not applicable. 
EudraCT: 
Not applicable. 
NCT: 
Not applicable. 
WHO: 
Not applicable. 
EUDAMED: 
Not applicable. 
Other: 
Not applicable. 
Date: 
11-May-2021
Total number of pages: 97 
NCT05049122


Clinical Trial Protocol 
SAR231893 - LPS16872 - Dupilumab 
11-May-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 2 
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 ........................................................................................................................................ 12 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 13 
2 
INTRODUCTION ............................................................................................................................ 16 
2.1 
STUDY RATIONALE...................................................................................................................... 16 
2.2 
BACKGROUND ............................................................................................................................. 17 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 17 
2.3.1 
Risk assessment ............................................................................................................................ 17 
2.3.2 
Benefit assessment ........................................................................................................................ 18 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 19 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 20 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 21 
4 
STUDY DESIGN ............................................................................................................................ 22 
4.1 
OVERALL DESIGN ........................................................................................................................ 22 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 22 
4.2.1 
Rationale for intervention with dupilumab ...................................................................................... 22 
4.2.2 
Rationale for study design, key study assessments/endpoints ..................................................... 23 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 23 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 23 
5 
STUDY POPULATION .................................................................................................................. 24 
5.1 
INCLUSION CRITERIA .................................................................................................................. 24 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 25 


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5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 29 
5.4 
SCREEN FAILURES...................................................................................................................... 29 
5.5 
CRITERIA FOR TEMPORARILY DELAYING SCREENING ......................................................... 30 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 31 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 31 
6.1.1 
Packaging and labeling .................................................................................................................. 33 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ...................................................... 33 
6.2.1 
Storage and handling ..................................................................................................................... 33 
6.2.2 
Responsibilities .............................................................................................................................. 33 
6.2.3 
Treatment accountability and compliance ..................................................................................... 34 
6.2.4 
Return and/or destruction of treatments ........................................................................................ 34 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 34 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 34 
6.5 
DOSE MODIFICATION .................................................................................................................. 35 
6.5.1 
Retreatment criteria ........................................................................................................................ 35 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 36 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 36 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 36 
6.8.1 
Rescue medicine and procedures ................................................................................................. 38 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 40 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 40 
7.1.1 
Permanent discontinuation ............................................................................................................ 40 
7.1.2 
Liver chemistry stopping criteria .................................................................................................... 41 
7.1.3 
Temporary discontinuation ............................................................................................................. 41 
7.1.4 
Rechallenge ................................................................................................................................... 42 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 42 
7.3 
LOST TO FOLLOW-UP ................................................................................................................. 43 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 44 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 44 
8.1.1 
Nasal endoscopy: nasal polyp score ............................................................................................. 44 


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11-May-2021 
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8.1.2 
Nasal congestion/obstruction symptom severity score .................................................................. 45 
8.1.3 
Computerized tomography scan: Lund Mackay score ................................................................... 46 
8.1.4 
Nasal symptom diary: Disease specific daily symptom assessment and total symptom 
score .............................................................................................................................................. 46 
8.1.5 
Visual analogue scale for rhinosinusitis ......................................................................................... 46 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 47 
8.2.1 
Physical examinations ................................................................................................................... 47 
8.2.2 
Vital signs ....................................................................................................................................... 47 
8.2.3 
Electrocardiograms ........................................................................................................................ 47 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 47 
8.2.5 
Pregnancy testing .......................................................................................................................... 48 
8.2.6 
Suicidal ideation and behavior risk monitoring .............................................................................. 48 
8.2.7 
Hypersensitivity monitoring ............................................................................................................ 48 
8.2.8 
Injection site reaction assessments ............................................................................................... 49 
8.3 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND OTHER SAFETY REPORTING ...... 49 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 50 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 50 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 50 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 50 
8.3.5 
Pregnancy ...................................................................................................................................... 51 
8.3.6 
Adverse event of special interest ................................................................................................... 51 
8.3.7 
Guidelines for management of specific laboratory abnormalities .................................................. 53 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 53 
8.4 
PHARMACOKINETICS .................................................................................................................. 53 
8.5 
GENETICS ..................................................................................................................................... 53 
8.6 
BIOMARKERS ............................................................................................................................... 53 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 53 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 54 
8.9 
USE OF DATA FOR FUTURE RESEARCH .................................................................................. 54 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 55 
9.1 
SAMPLE SIZE DETERMINATION ................................................................................................. 55 
9.2 
POPULATIONS FOR ANALYSES ................................................................................................. 55 


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9.3 
STATISTICAL ANALYSES ............................................................................................................ 57 
9.3.1 
General considerations .................................................................................................................. 57 
9.3.2 
Primary efficacy endpoint ............................................................................................................... 57 
9.3.3 
Key secondary efficacy endpoints ................................................................................................. 58 
9.3.4 
Exploratory efficacy endpoints ....................................................................................................... 59 
9.3.5 
Safety analysis ............................................................................................................................... 59 
9.3.5.1 
Adverse events .............................................................................................................................. 59 
9.3.5.2 
Laboratory variables and vital signs ............................................................................................... 60 
9.3.5.3 
Product complaints......................................................................................................................... 60 
9.3.6 
Other analysis ................................................................................................................................ 60 
9.4 
INTERIM ANALYSES .................................................................................................................... 60 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 61 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 61 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 61 
10.1.2 
Financial disclosure........................................................................................................................ 62 
10.1.3 
Informed consent process .............................................................................................................. 62 
10.1.4 
Data protection ............................................................................................................................... 63 
10.1.5 
Dissemination of clinical study data ............................................................................................... 65 
10.1.6 
Data quality assurance .................................................................................................................. 65 
10.1.7 
Source documents ......................................................................................................................... 66 
10.1.8 
Definition of source data ................................................................................................................ 67 
10.1.9 
Study and site start and closure ..................................................................................................... 67 
10.1.10 Publication policy ........................................................................................................................... 68 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 69 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 71 
10.3.1 
Definition of AE .............................................................................................................................. 71 
10.3.2 
Definition of SAE ............................................................................................................................ 72 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 74 
10.3.4 
Reporting of SAEs .......................................................................................................................... 75 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION ...................................................................................................... 76 
10.4.1 
Definitions ...................................................................................................................................... 76 
10.4.2 
Contraception guidance ................................................................................................................. 78 
10.4.3 
Collection of pregnancy information ............................................................................................... 79 


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10.5 
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS AND STUDY INTERVENTION RECHALLENGE GUIDELINES ....................... 80 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 85 
10.7 
APPENDIX 7: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 86 
10.8 
APPENDIX 8: LIST OF PROHIBITED LIVE ATTENUATED VACCINES ...................................... 88 
10.9 
APPENDIX 9: LIST OF OPPORTUNISTIC INFECTIONS ............................................................. 89 
10.10 
APPENDIX 10: VISUAL ANALOGUE SCALE ............................................................................... 90 
10.11 
APPENDIX 11: QUESTIONS FOR PARTICIPANTS WITH CRSWNP TO ASSIST 
DETERMINATION OF NERD DIAGNOSIS ................................................................................... 91 
10.12 
APPENDIX 12: DEFINITION OF ANAPHYLAXIS ......................................................................... 92 
10.13 
APPENDIX 13: ABBREVIATIONS ................................................................................................. 93 
10.14 
APPENDIX 14: PROTOCOL AMENDMENT HISTORY ................................................................ 95 
11 
REFERENCES ............................................................................................................................... 96 
 


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SAR231893 - LPS16872 - Dupilumab 
11-May-2021 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 20 
Table 2 - Overview of study interventions administered ............................................................................... 32 
Table 3 - Endoscopic nasal polyp score ....................................................................................................... 44 
Table 4 - Nasal congestion/obstruction symptom severity score .................................................................. 45 
Table 5 - Populations for analyses ................................................................................................................ 56 
Table 6 - Protocol-required laboratory tests .................................................................................................. 69 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 12 
 
 


Clinical Trial Protocol 
SAR231893 - LPS16872 - Dupilumab 
11-May-2021 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: 
A single-arm, 52-weeks, Phase 4 study to assess the efficacy and safety of dupilumab in patients 
with chronic rhinosinusitis with nasal polyposis (CRSwNP) who are not adequately controlled 
with existing therapies 
Brief title: Dupilumab in Japanese patients with chronic rhinosinusitis with nasal polyp 
(SINUS-M52) 
Rationale: 
Dupilumab blockade of interleukin-4 (IL-4) and IL-13 signaling has demonstrated a favorable 
efficacy and safety profile for the treatment of a variety of atopic disease states, including atopic 
dermatitis (AD), asthma, and CRSwNP, where type-2 inflammation is a key driver of the 
underlying disease process. This study will assess the efficacy and safety profile of dupilumab 
administered as monotherapy to Japanese CRSwNP participants whose disease is not adequately 
controlled with existing therapies (systemic corticosteroids [SCS] and surgery). 
Dupilumab has been approved for the treatment of CRSwNP that is not adequately controlled with 
existing therapies by the health authority in Japan on the condition that the efficacy and safety of 
dupilumab monotherapy will be assessed after approval; the efficacy and safety data in the global 
program were developed with intranasal corticosteroid (INCS) concomitantly administered with 
dupilumab. Intranasal corticosteroid is not approved for CRSwNP in Japan. Their use for 
CRSwNP is an off-label use in Japan. The objective of this Phase 4 study is to assess the efficacy 
and safety of dupilumab as monotherapy (without concomitant INCS) in participants with 
CRSwNP. 


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Objectives and endpoints: 
Objectives 
Endpoints 
Primary 
• 
To assess the efficacy of 24-week treatment with 
dupilumab 300 mg every 2 weeks (q2w) to reduce 
nasal polyp score (NPS) in participants with chronic 
rhinosinusitis with nasal polyposis (CRSwNP) who do 
not use concomitant intranasal corticosteroid (INCS) 
• 
Proportion of participants with NPS improvement 
from baseline ≥1 at Week 24  
Secondary 
 
• 
To assess the efficacy of 24-week treatment with 
dupilumab 300 mg q2w on other efficacy endpoints in 
participants with CRSwNP who do not use 
concomitant INCS 
Key secondary efficacy endpoints: 
• 
Change from baseline to Week 24 in bilateral NPS 
• 
Change from baseline to Week 24 in nasal 
congestion/obstruction (NC) symptom severity score 
using the CRSwNP nasal symptom diary 
• 
Change from baseline to Week 24 in opacification of 
sinuses assessed by computerized tomography (CT) 
scan using the Lund Mackay (LMK) score  
Other secondary efficacy endpoints: 
• 
Change from baseline to Week 24: 
- 
Total symptom score (TSS), a composite score 
derived from the nasal symptom diary (includes 
nasal congestion, loss of sense of smell, 
anterior and posterior rhinorrhea) 
- 
Loss of smell symptom severity score using the 
nasal symptom diary 
- 
Visual analogue scale for rhinosinusitis 
• 
To evaluate the safety of 24-week treatment with 
dupilumab in participants with CRSwNP 
• 
Incidence of treatment-emergent adverse events 
(TEAEs), treatment-emergent serious adverse events 
(TESAEs), and TEAEs leading to treatment 
discontinuation 
Tertiary/exploratory 
 
• 
To assess the efficacy of 52-week treatment with 
dupilumab under different dosing regimens to 
participants with CRSwNP who do not use 
concomitant INCS 
• 
Proportion of participants with NPS improvement 
from baseline ≥1 at Week 52 
• 
Change from baseline to Week 52 in bilateral NPS 
• 
Change from baseline to Week 52 in NC symptom 
severity score using the CRSwNP nasal symptom 
diary 
• 
Change from baseline to Week 52 in opacification of 
sinuses assessed by CT scan using the LMK score 
• 
Change from baseline to Week 52 in TSS 
• 
To evaluate the safety of 52-week treatment with 
dupilumab in participants with CRSwNP 
• 
Incidence of TEAEs, TESAEs, and TEAEs leading to 
treatment discontinuation 
Abbreviations: CRSwNP: chronic rhinosinusitis with nasal polyposis; CT: computerized tomography; INCS: intranasal corticosteroid; LMK: Lund 
Mackay; NC: nasal congestion/obstruction; NPS: nasal polyp score; q2w: every 2 weeks; TEAE: treatment-emergent adverse event; TESAE: 
treatment-emergent serious adverse events, TSS: total symptom score. 


Clinical Trial Protocol 
SAR231893 - LPS16872 - Dupilumab 
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Overall design: 
This is a Phase 4, open-label, single-arm, multicenter, efficacy and safety study of dupilumab 
monotherapy in participants with CRSwNP that is not adequately controlled with existing 
therapies.  
This study will investigate the efficacy and safety of dupilumab 300 mg every 2 weeks (q2w) at 
Week 24, without concomitant administration of INCS.  
In addition, in line with Japan label, the study is designed to assess the long-term (52 weeks) 
efficacy and safety of an initial treatment regimen of dupilumab 300 mg q2w for 24 weeks 
without INCS, followed by a less frequent dosing regimen (300 mg every 4 weeks [q4w]) up to 
Week 48 for those participants who demonstrate stable disease* at Week 24. Other participants 
will receive the q2w regimen up to Week 50. 
*Stable disease definition: nasal polyp score (NPS) improvement from baseline to both Weeks 16 
and 24 is ≥ 2 points. 
During the study, participants who report deterioration requiring medical or surgical intervention 
may go to the study site for 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 6.8.1. 
Brief summary:  
This is a Phase 4, open-label, single-arm, multicenter study to evaluate the efficacy and safety of 
dupilumab monotherapy in participants aged 18 or older with CRSwNP that is not adequately 
controlled with existing therapies. 
Number of participants: 
Approximately 25 participants will be enrolled. 
Intervention groups and duration: 
Study intervention(s) 
• Dupilumab 300 mg q2w  
• Dupilumab 300 mg q4w 
For participants who have stable disease, the dosing interval can be changed from q2w to q4w at 
the discretion of the Investigator at Week 24. Participants who change from q2w to q4w will not 
be permitted to return to the q2w regimen during this study and will receive the q4w regimen until 
Week 48. Other participants will receive the q2w regimen up to Week 50. The participants will be 
followed up to Week 52. 


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Duration of study period (per participant): 
• Screening Period (2 to 4 weeks): between Screening Visit (Visit 1) and the first dose of 
investigational medicinal product (IMP) (Visit 2) 
• Intervention Period (up to 52 weeks±3 days) 
Investigational medicinal product(s): 
• Dupilumab 300 mg 
Formulation: 
• Dupilumab 300 mg: a 150 mg/mL dupilumab solution in a prefilled syringe to deliver 
300 mg in a 2-mL injection 
Route of administration: subcutaneous (SC) injection 
Dose regimen: 
• One injection of 300 mg q2w up to Week 24 (all participants) 
• One injection of 300 mg q4w after Week 24 (participants who have stable disease at 
Week 24) 
• One injection of 300 mg q2w after Week 24 (participants who cannot achieve stable 
disease) 
Post-trial access to study medication will not be provided. 
Statistical considerations: 
This postmarketing study is to assess whether dupilumab used without INCS will show similar 
efficacy to that of dupilumab used with INCS in EFC14280, using the point estimates of the 
proportion of responders (NPS improvement from baseline ≥1) at Week 24. Formal statistical 
tests for hypotheses (null/alternative) will not be performed. 
• Primary endpoint:  
- 
The proportion of responders (NPS improvement from baseline ≥1) at Week 24.  
• Key secondary endpoints: 
- 
Change from baseline to Week 24 in bilateral NPS  
- 
Change from baseline to Week 24 in nasal congestion/obstruction (NC) symptom 
severity score using the CRSwNP nasal symptom diary 
- 
Change from baseline to Week 24 in opacification of sinuses assessed by computerized 
tomography (CT) scan using the Lund Mackay (LMK) score 
Data Monitoring/Other committee: No 


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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
 
Abbreviations: D: day; EOS: end of study, EOT: end of treatment; q2w: every 2 weeks; q4w: every 4 weeks; V: visit. 


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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Procedure 
D-28 to 
D­14 
Intervention Period 
W0 
D1 
W2 
D15 
(±3 days) 
W4 
D29 
(±3 days) 
W8 
D57 
(±3 days) 
W16 
D113 
(±3 days) 
W24 
D169 
(±3 days) 
W40 
D281 
(±3 days) 
W52 
D364 
(±3 days)  
EOT/EOS 
Visit 
V1 
(Screening) 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
Patient demographics  
X 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
 
X  
 
X 
Medical/surgical/medication 
historya 
X 
 
 
 
 
 
 
 
 
Record planned surgery for 
NP, SCS use, and other 
rescue medication use 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Call IVRS (IWRS)b 
X 
  
IMP administrationc 
 
 
All participants: q2w up to W24 
Participants with stable disease at W24: q4w from W24 up to W48 
Participants who cannot achieve stable disease at W24: q2w from W24 up to W50 
Nasal endoscopyd 
X 
X 
 
X 
X 
X 
X 
X 
X 


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Procedure 
D-28 to 
D­14 
Intervention Period 
W0 
D1 
W2 
D15 
(±3 days) 
W4 
D29 
(±3 days) 
W8 
D57 
(±3 days) 
W16 
D113 
(±3 days) 
W24 
D169 
(±3 days) 
W40 
D281 
(±3 days) 
W52 
D364 
(±3 days)  
EOT/EOS 
Visit 
V1 
(Screening) 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
CT scan 
Xe 
 
 
 
 
 
X 
 
X 
Nasal Symptom Diaryf 
(includes nasal congestion, 
loss of smell, anterior and 
posterior rhinorrhea; TSS 
derived from these 4 items) 
 
 
daily diary 
VAS for rhinosinusitis  
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsg 
X 
X 
 
 
X 
X 
X 
X 
X 
12-Lead ECG (local 
reading) 
X 
 
 
 
 
 
 
 
 
AE review 
 
 
SAE review 
 
 
Laboratory assessments 
(including hematology, 
biochemistry, and 
urinalysis)h 
X 
X 
 
 
X 
 
X 
 
X 
Hepatitis B and C; HIV 
testing; TB testingi 
X 
 
 
 
 
Xj 
Xj 
Xj 
Xj 
Pregnancy test (WOCBP 
only)k 
X 
X 
 
X 
X 
  
X (W12, 16) 
  
X 
(W20, 24) 
X 
(W28, 32, 36, 
40) 
X 
(W44, 48, 52) 


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Abbreviations: AE: adverse event; CT: computerized tomography; D: day; e-CRF: electronic case report form; ECG: electrocardiogram; EOS: end of study; EOT: end of treatment; HBcAb: hepatitis B core antibody; 
HBsAb: hepatitis B surface antibody; HBsAg: hepatitis B surface antigen; HCV Ab: hepatitis C virus antibody; HIV: human immunodeficiency virus; IgM: immunoglobulin M; IGAR: Interferon-gamma release assay; IMP: 
investigational medicinal product; IVRS/IWRS: interactive voice/web response system; MRI: magnetic resonance image; NE: nasal endoscopy; NERD: non-steroid anti-inflammatory drug exacerbated respiratory 
disease; NP: nasal polyposis; NPS: nasal polyp score; q2w: every 2 weeks; q4w: every 4 weeks; SAE: serious adverse event; SCS: systemic corticosteroids; TB: tuberculosis; TSS: total symptom score; V: visit; VAS: 
visual analogue scale; W: week; WOCBP: women of childbearing potential.  
a Past medical history, including allergic comorbidities (asthma, aspirin sensitivity, allergic rhinitis, etc.). Surgeries for NP, including number, type and dates of sinonasal surgeries, and polypectomies, in the past will 
be recorded. Systemic corticosteroid use (number of courses, doses, route 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 e-CRF. NERD will be assessed through a specific questionnaire (Appendix 11 [Section 10.11]). 
b Call IVRS/IWRS to register visit and obtain next IMP kit numbers assignment or report potential definitive IMP stop. 
c Investigational medicinal product will be administered q2w (after Week 24, some participants can be administered q4w). Between visits, at site or home administration is allowed after the second dose. 
Investigational medicinal product will be administered after the completion of all scheduled clinical assessments at the visit or at home. The planned last dose is at Week 48 or 50. 
For participants who have stable disease at Week 24, the dosing interval can be changed from q2w to q4w at the discretion of the Investigator; the reason for the change in dosing regimen should be recorded in 
the e-CRF. Other participants will receive the q2w regimen until Week 50. Stable disease is defined as NPS improvement from baseline to both Weeks 16 and 24 of ≥2 points. 
d Nasal endoscopy: endoscopy (including use of decongestants before the procedure) will be performed after all other efficacy assessments have been completed for each visit. Standard video sequences will be 
downloaded by the Investigator to the central reader’s secured internet site. For eligibility, central reading of V1 will be used. At V2, the Investigator will review the V1 results from the central reader to confirm entry 
criteria and reconfirm eligibility based on a review of the 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 will be 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. 
e Computerized tomography scan to be done during the Screening Period. 
f 
Captured daily. 
g Vital signs, including systolic and diastolic blood pressures (mmHg), pulse rate (beats per minute), respiratory rate (breaths per minute), and body temperature (forehead [temporal] temperature; degrees Celsius), 
and body weight (kg) will be measured at V1 and V2 and subsequent visits prespecified in the SoA. Height (cm) will be measured at V1 only. Vital signs will be measured prior to receiving IMP at the clinic visits in 
the sitting position, preferably using the same arm at each visit. 
h Hematology: platelet count, red blood cell count, hemoglobin, hematocrit, and total white blood cell count with five-part differential count. Clinical chemistry: blood urea nitrogen, creatinine, glucose (indicate if 
fasting or 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), and creatine phosphokinase. Routine urinalysis: specific gravity, pH, glucose, protein, blood, 
ketones, urobilinogen, nitrite by dipstick, and microscopic examination (if blood or protein is abnormal). 
i 
Hepatitis screen: HBsAg, HBsAb, HBcAb or HBcAb IgM and total; HCV Ab. HIV screen: anti-HIV-1 and HIV-2 antibodies. TB blood testing: IGRA.  
In case of results showing HBsAg (negative) and HBcAb total or HBcAb IgM (positive), HBV DNA testing may be performed prior to enrollment to rule out a false positive if the Investigator believes the participant is 
a false positive or to clarify the serological status if the Investigator finds it unclear to interpret in the absence of known HBV infection.  
In case of results showing HCV Ab (positive), HCV RNA testing may be performed to rule out a false positive, if the Investigator believes the participant is a false positive.  
An IGRA will be performed for diagnosis of both latent and active TB only for participants without a history of active/latent TB.  
j 
Participant who are HBcAb (positive) and HBV DNA (negative) at Visit 1 will require HBV DNA monitoring at Visits 6, 7, and 8 and the EOT/EOS Visit. If the HBV DNA result becomes positive during the study, the 
participant will be temporarily discontinued from IMP administration and should be referred to a hepatologist. Investigational medicinal product may be restarted under careful consideration of participant’s risks and 
benefits based on hepatologist evaluation and current treatment guidelines and after consultation with the Medical Monitor. 
k Serum pregnancy test at V1 and urine pregnancy tests q4w thereafter. A negative result must be obtained during the Screening Period before IMP administration. Urinary pregnancy test could be performed at 
home as part of visit with or without the assistance of a home care provider. In the case of a positive urine pregnancy test, the study intervention will be withheld, and a serum pregnancy test to confirm the 
pregnancy should be performed as soon as possible. Pregnancy will lead to definitive treatment discontinuation in all cases. 
 


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2 
INTRODUCTION  
Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor alpha subunit 
(IL-4Rα), which is a component of IL-4 receptors Type I and Type II, as well as the IL-13 Type II 
receptor. The binding of dupilumab to IL-4Rα results in the blockade of IL-4 and IL-13 
intracellular signaling.  
As a targeted/specific immunomodulatory agent, dupilumab is expected to selectively inhibit 
type-2 inflammation and is designed to achieve the desired therapeutic effect without the side 
effects typically associated with the use of less selective immunosuppressants.  
Both the 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, and asthma. 
2.1 
STUDY RATIONALE  
This is a Phase 4, open-label, single-arm, multicenter, efficacy and safety study of dupilumab 
monotherapy in participants with CRSwNP whose disease is not adequately controlled with 
existing therapies (SCS and surgery). 
Dupilumab has been approved for the treatment of CRSwNP that is not adequately controlled with 
existing therapies by the health authority in Japan on the condition that the efficacy and safety of 
dupilumab monotherapy will be assessed after approval; the efficacy and safety data in the global 
program were developed with INCS concomitantly administered with dupilumab; no efficacy and 
safety data for dupilumab used as monotherapy were collected in the pivotal Phase 3 studies. 
Intranasal corticosteroid is not approved for CRSwNP in Japan. Their use for CRSwNP is an off-
label use in Japan. The objective of this Phase 4 study is to assess the efficacy and safety of 
dupilumab as monotherapy (without concomitant INCS) in participants with CRSwNP. 
This study will primarily investigate the efficacy of dupilumab 300 mg q2w at Week 24, without 
concomitant administration of INCS in CRSwNP participants. The safety of 24-week treatment 
with dupilumab will also be investigated. 
In addition, in line with the Japan label, the study is designed to assess the long-term (52 weeks) 
efficacy and safety of an initial treatment regimen of dupilumab 300 mg q2w for 24 weeks, 
followed by a less frequent dosing regimen (300 mg q4w) up to Week 48 for those participants 
who demonstrate stable disease* at Week 24. Other participants will receive the q2w regimen 
until Week 50.  
*Stable disease definition: nasal polyp score (NPS) improvement from baseline to both Weeks 16 and 24 is ≥ 2 points. 


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2.2 
BACKGROUND  
The study background is described in Section 2.1. 
2.3 
BENEFIT/RISK ASSESSMENT  
Dupilumab has shown clinically relevant benefit in several type 2-driven immunological disorders 
such as AD, asthma, and CRSwNP. A satisfactory safety profile has been observed so far in 
completed and currently ongoing studies. 
More detailed information about the known and expected benefits and risks and adverse events 
(AEs) considered as expected of dupilumab may be found in the Package Insert.  
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 September 2020, 10 773 participants had 
been enrolled into the development program for dupilumab and are included in the safety 
population. The estimated number of participants exposed to dupilumab in clinical studies was 
9110 (356 in healthy volunteer studies, 4130 in AD studies, 3319 in asthma studies, 470 in 
CRSwNP studies, 226 in eosinophilic esophagitis studies, 176 in the grass/peanut allergy studies, 
355 in the chronic obstructive pulmonary disease (COPD) studies, 36 in prurigo nodularis (PN) 
studies, and 42 in the chronic spontaneous urticaria (CSU) study).  
Based on the sales figures and the World Health Organization defined daily dose of 21.4 mg/day, 
the cumulative postmarketing exposure to dupilumab could be estimated to be 249 341 patient 
years from 01 January 2017 through 30 September 2020. 
Dupilumab was generally well tolerated in all populations tested in clinical development programs, 
consistent with a favorable 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, pyrexia, headache, 
arthralgia, anaphylaxis, serum sickness-like reaction, and serum sickness. These ADRs were 
generally mild or moderate, transient, and manageable. These ADRs were not observed 
consistently in all indications. More significant serious allergic reactions were very rare. 
Importantly, no increased overall risk of serious infection was observed in participants treated 
with dupilumab. 
Systemic hypersensitivity is established as an important identified risk with dupilumab. As protein 
therapeutics, all monoclonal antibodies are potentially immunogenic. Rare serious and systemic 
hypersensitivity reactions have been observed in the dupilumab program, including serum 
sickness or serum sickness-like reaction in the adult AD program and anaphylaxis related to 
dupilumab in the adult asthma clinical studies.  


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Participants 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, participants with pre-existing helminth infections should be treated for 
their helminth infection before initiating therapy with dupilumab. 
Other potential risks based on the safety profile in particular indications such as eosinophilia in 
asthma participants treated with dupilumab monotherapy were reported in 2 asthma studies. 
However, eosinophil counts declined to near baseline levels during study treatment. It is 
anticipated that dupilumab used as monotherapy in Japanese participants with CRSwNP will have 
a favorable safety profile, as observed in the Phase 3 global clinical program for this disease (with 
concomitant INCS administration) and across other type 2-driven immunological disorders. 
2.3.2 Benefit assessment  
Dupilumab solution for injection is currently authorized: 
• In over 40 countries worldwide, including the United States (US) for use in adults with 
inadequately controlled CRSwNP, the European Union (EU) as an add-on therapy with 
INCS for the treatment of adults with severe CRSwNP for whom therapy with SCS and/or 
surgery does not provide adequate disease control, and in Japan for use in adults with 
CRSwNP (only participants whose disease is not adequately controlled with existing 
therapies). Review of this indication is ongoing in several other countries worldwide. 
• In over 60 countries worldwide including the US, EU (Centralised Procedure), and Japan 
for the treatment of adults with inadequately controlled moderate-to-severe AD. In the US 
and EU, it has also been authorized for use in adolescent patients (≥12 years of age) with 
inadequately controlled moderate-to-severe AD. Further, in the US and EU as well as 
some additional countries, dupilumab is approved for the treatment of children aged 6 to 
<12 years with AD. 
• In over 40 countries worldwide for the asthma indication. In the US for use in adults and 
adolescents (≥12 years of age) with moderate-to-severe eosinophilic or oral steroid 
dependent asthma, in the EU for use in adults and adolescents with severe asthma with 
type-2 inflammation characterized by raised blood eosinophils and/or raised fractional 
exhaled nitric oxide, and in Japan for use in adults and adolescents with severe or 
refractory bronchial asthma. The review of dupilumab for this indication is ongoing in 
several other countries worldwide. 
As part of the dupilumab CRSwNP clinical development program, two Phase 3 studies in 
participants with severe CRSwNP have demonstrated that dupilumab 300 mg q2w coadministered 
with INCS is significantly better than placebo for the reduction of polyp size, sinus opacification, 
and severity of symptoms and that it is generally well tolerated.  
However, in previous Phase 3 studies, the placebo group to which only INCS was administered 
showed a trend of slight improvement in NC symptom severity but no trend of improvement in 
NPS and LMK score. The change in NPS and NC symptom severity during the screening period 
(4 weeks) in which only INCS was administered was small in both the group of participants who 
had used INCS prior to screening and the participants who started INCS during the screening 


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period. Since the efficacy of INCS in participants with CRSwNP in these Phase 3 studies was 
extremely limited, the efficacy observed was most likely attributed to dupilumab. Therefore, 
dupilumab administered as monotherapy, without INCS, is expected to have similar efficacy. 
2.3.3 Overall benefit: risk conclusion  
The target population of this study is patients with uncontrolled CRSwNP without concomitant 
INCS. These patients have failed medical therapies and/or surgical intervention and have active 
disease that causes significant impairment in function and quality of life. Therefore, these patients 
have a high unmet medical need for novel effective treatment. Participation in the study will 
provide an opportunity for these patients to be treated with a novel therapy that has proven 
efficacy in other disease states (eg, AD, asthma) and more importantly in two large Phase 
3 studies in CRSwNP.  
The Sponsor recognizes that the “Coronavirus Disease 2019” (COVID-19) pandemic is having an 
impact on the conduct of clinical studies. The Sponsor is monitoring the situation closely and may 
suspend study screening activities until the impact of the COVID-19 pandemic is deemed 
manageable and no longer interfering with the conduct of studies at individual sites and 
participants can safely participate in this study. To ensure the integrity of the studies and safety of 
the participants, there is a contingency plan in place to address any potential impact of COVID-19 
that may arise during the conduct of the study (refer to Appendix 7 [Section 10.7]).  
Based on the aforementioned potential benefits to patients participating in this study and the 
appropriate precautions and mitigations that have been instituted to manage any potential impact 
of COVID-19 on the conduct of the study and the safety of the participants, the Sponsor assesses 
that the overall benefit-risk balance is positive for the conduct of and patient participation in this 
study. 


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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To assess the efficacy of 24-week treatment with 
dupilumab 300 mg every 2 weeks (q2w) to reduce 
nasal polyp score (NPS) in participants with chronic 
rhinosinusitis with nasal polyposis (CRSwNP) who do 
not use concomitant intranasal corticosteroid (INCS) 
• 
Proportion of participants with NPS improvement 
from baseline ≥1 at Week 24 
Secondary 
• 
To assess the efficacy of 24-week treatment with 
dupilumab 300 mg q2w on other efficacy endpoints in 
participants with CRSwNP who do not use 
concomitant INCS 
Key secondary efficacy endpoints: 
• 
Change from baseline to Week 24 in bilateral NPS 
• 
Change from baseline to Week 24 in in nasal 
congestion/obstruction (NC) symptom severity score 
using the CRSwNP nasal symptom diary 
• 
Change from baseline to Week 24 in opacification of 
sinuses assessed by computerized tomography (CT) 
scan using the Lund Mackay (LMK) score 
Other secondary efficacy endpoints: 
• 
Change from baseline to Week 24: 
- 
Total symptom score (TSS), a composite score 
derived from the nasal symptom diary (includes 
nasal congestion, loss of sense of smell, 
anterior and posterior rhinorrhea) 
- 
Loss of smell symptom severity score using the 
nasal symptom diary 
- 
Visual analogue scale for rhinosinusitis 
• 
To evaluate the safety of 24-week treatment with 
dupilumab in participants with CRSwNP  
• 
Incidence of treatment-emergent adverse events 
(TEAEs), treatment-emergent serious adverse events 
(TESAEs), and TEAEs leading to treatment 
discontinuation 
Tertiary/exploratory 
 
• 
To assess the efficacy of 52-week treatment with 
dupilumab under different dosing regimens to 
participants with CRSwNP who do not use 
concomitant INCS 
• 
Proportion of participants with NPS improvement 
from baseline ≥1 at Week 52 
• 
Change from baseline to Week 52 in bilateral NPS 
• 
Change from baseline to Week 52 in NC symptom 
severity score using the CRSwNP nasal symptom 
diary 
• 
Change from baseline to Week 52 in opacification of 
sinuses assessed by CT scan using the LMK score 
• 
Change from baseline to Week 52 in TSS 
• 
To evaluate the safety of 52-week treatment with 
• 
Incidence of TEAEs, TESAEs, and TEAEs leading to 


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Objectives 
Endpoints 
dupilumab in participants with CRSwNP 
treatment discontinuation 
Abbreviations: CRSwNP: chronic rhinosinusitis with nasal polyposis; CT: computerized tomography; INCS: intranasal corticosteroid; LMK: Lund 
Mackay; NC: nasal congestion/obstruction; NPS: nasal polyp score; q2w: every 2 weeks; TEAE: treatment-emergent adverse event; TESAE: 
treatment-emergent serious adverse events, TSS: total symptom score. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Refer to Section 4.2.2 for the rationale for the endpoints. The primary objective of this study is to 
assess the efficacy of dupilumab monotherapy in CRSwNP participants. The primary efficacy 
endpoint is the proportion of participants with improvement in NPS improvement (≥1 point) at 
Week 24. A 1-point improvement in NPS was defined as a clinically meaningful difference based 
on the results of the pivotal Phase 3 study (EFC14280). The secondary objectives of this study are 
to assess the efficacy and safety of dupilumab monotherapy in CRSwNP participants. The 
secondary efficacy endpoints, the change from baseline in the NPS, LMK score, and NC symptom 
severity scores to Week 24, were primary endpoints in EFC14280. These endpoints are to be 
evaluated to show the similar efficacy of dupilumab monotherapy compared to dupilumab with 
INCS coadministration.  


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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 4, open-label, single-arm, multicenter, efficacy and safety study of dupilumab 
monotherapy in participants with CRSwNP that is not adequately controlled with existing 
therapies. 
This study will investigate the efficacy and safety of dupilumab 300 mg q2w at Week 24, without 
concomitant administration of INCS.  
In addition, in line with Japan label, the study is designed to assess the long-term efficacy 
(52 weeks) and safety of an initial treatment regimen of dupilumab 300 mg q2w for 24 weeks 
without INCS, followed by a less frequent dosing regimen (300 mg q4w) up to Week 48 for those 
participants who demonstrate stable disease (NPS improvement from baseline to both Weeks 16 
and 24 ≥2 points) at Week 24. Other participants will receive the q2w regimen until Week 50. 
During the study, participants who report deterioration requiring medical or surgical intervention 
may go to the study site for 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 6.8.1. 
Study duration for each participant will be a total of up to 56 weeks. 
The study includes 2 study periods: 
• Screening Period (2 to 4 weeks): between the Screening Visit (Visit 1) and the first dose of 
IMP (Visit 2); to determine a participant’s eligibility 
• Intervention Period (up to 52 weeks ±3 days): to treat participants with dupilumab starting 
at baseline (Visit 2) 
Patients who fulfill the inclusion criteria and do not meet any of the exclusion criteria will be 
enrolled to receive the IMP (Section 5). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
4.2.1 Rationale for intervention with dupilumab  
Dupilumab blockade of IL-4 and IL-13 signaling has demonstrated a favorable efficacy and 
acceptable safety profile for the treatment of a variety of atopic disease states, including AD (1), 
asthma (2), and CRSwNP (3), where type-2 inflammation is a key driver of the underlying disease 
process. Notably, in the dupilumab CRSwNP clinical development program, two Phase 3 studies 
in participants with severe CRSwNP have demonstrated that dupilumab 300 mg q2w, when used 


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concomitantly with INCS, is significantly better than placebo for the reduction of polyp size, sinus 
opacification, and severity of symptoms and is generally well tolerated.  
The primary objective of this study is to assess the efficacy of dupilumab without INCS 
administered to CRSwNP participants whose disease is not adequately controlled with existing 
therapies. The safety of dupilumab monotherapy will also be investigated. 
4.2.2 Rationale for study design, key study assessments/endpoints  
Efficacy will be determined using the primary endpoint of the proportion of participants with 
improvement in NPS (≥1 point) at Week 24. A 1-point improvement in NPS is defined as a 
clinically meaningful difference based on the results of the Phase 3 study (EFC14280). 
Additionally, as key secondary efficacy endpoints, the change from baseline in the NPS, LMK, 
and NC symptom severity scores up to Week 24 will be measured. These secondary endpoints 
were primary endpoints in EFC14280. These endpoints should be evaluated to show the similar 
efficacy of dupilumab alone compared to dupilumab with INCS coadministration. 
This study will collect data on the primary and secondary efficacy endpoints at Week 52 as well 
for both the q2w and q4w (after Week 24) dosing regimens. 
4.3 
JUSTIFICATION FOR DOSE  
Dupilumab will be administered in accordance with the approved dose in Japan. 
The recommended dose of dupilumab for adult CRSwNP patients is 300 mg given q2w; however, 
after the disease condition is stable, 300 mg given q4w could be used. 
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 phases of the 
study, including the last visit or the last scheduled procedure shown in the Schedule of Activities 
(SoA ; Section 1.3). 


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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 who is at least 18 years of age at the time of signing the informed consent 
Type of participant and disease characteristics 
I 02. Participant who has bilateral sinonasal polyposis despite prior treatment with SCS anytime 
within the past 2 years; and/or has a medical contraindication/intolerance to SCS; and/or 
has had prior surgery for nasal polyposis at Screening Visit (Visit 1) and has: 
- 
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) 
- 
Ongoing symptoms of: 
Nasal congestion/blockade/obstruction for at least 8 weeks before Visit 1 that is 
moderate or severe (NC symptom severity score 2 or 3) at Visit 1 and a weekly 
average severity of greater than 1 (based on the average of the assessments 1 week 
before Visit 1) at the time of enrollment (Visit 2) 
AND 
Loss of smell or rhinorrhea (anterior/posterior) for at least 8 weeks before Visit 1 
Weight 
I 03. Participant whose body weight is >30 kg at the time of screening 
Sex, contraceptive/barrier method, and pregnancy testing requirements 
I 04.  Participant who is male or female 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
• Female participants 
- 
A female participant is eligible to participate if she is not pregnant or breastfeeding and 
at least 1 of the following conditions applies: 


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- 
Is not a woman of childbearing potential (WOCBP) 
OR 
- 
Is a WOCBP and agrees to use an acceptable contraceptive method as described in 
Appendix 4 (Section 10.4) of the protocol during the study (at a minimum until 
12 weeks after the last dose of IMP). 
- 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations; refer to Section 8.2.5) at both Visit 1 and Visit 2 before 
the first dose of IMP. 
- 
If a urine test on Day 1 cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. The participant must be excluded from participation 
if the serum pregnancy result is positive. Additional details can be found in 
Appendix 4 (Section 10.4) of the protocol. 
- 
The Investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed consent 
I 05. Participant who is capable of giving signed informed consent as described in Appendix 1 
(Section 10.1) of the protocol, which includes compliance with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. If the participant 
is less than 20 years of age, a specific ICF must also be signed by the participant's 
parent/legally authorized representative (LAR). 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Participant with conditions/concomitant diseases making them nonevaluable at Visit 1 or 
for the primary efficacy endpoint such as:  
- 
Antrochoanal polyps 
- 
Nasal septal deviation that would occlude at least 1 nostril  
- 
Acute sinusitis, nasal infection, or upper respiratory infection within 2 weeks prior to 
Visit 1 (participant can be rescreened after resolution of symptoms) 
- 
Ongoing rhinitis medicamentosa 
- 
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), 
granulomatosis with polyangiitis (Wegener’s granulomatosis), Young’s syndrome, 
Kartagener’s syndrome or other dyskinetic ciliary syndromes, or concomitant cystic 
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- 
Radiologic suspicion or confirmed invasive or expansive fungal rhinosinusitis 
- 
Clinically significant/active underlying hepatobiliary disease 
- 
Alanine aminotransferase (ALT) >3 × upper limit of normal (ULN) 
- 
Creatine phosphokinase (CPK) >10 × ULN 
- 
Platelets <100 000 cells/mm3 
- 
Neutrophils <1500 cells/mm3 
- 
Serum creatinine >1.7 × ULN 
E 02. Participant with nasal cavity malignant tumor and benign tumors (eg, papilloma, blood boil) 
E 03. Participants 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 04.  Participant who has history of human immunodeficiency virus (HIV) infection or positive 
HIV screen (anti-HIV-1 and HIV-2 antibodies) serology at Visit 1 
E 05. Participant who has severe concomitant illness(es) that, in the Investigator’s judgment, 
would adversely affect the participant’s participation in the study. Examples include, but 
are not limited to, participants with short life expectancy, participants with uncontrolled 
diabetes (hemoglobin A1c ≥9%), participants with cardiovascular conditions (eg, Class III 
or IV cardiac failure according to the New York Heart Association classification), severe 
renal conditions (eg, participants on dialysis), hepato-biliary conditions (eg, Child-Pugh 
class B or C), neurological conditions (eg, demyelinating diseases), active major 
autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis), and 
other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic 
diseases. The specific justification for participants excluded under this criterion will be 
noted in study documents (chart notes, electronic case report forms [e-CRFs], etc). 
E 06. Participant who has known or suspected immunodeficiency, including history of invasive 
opportunistic infections (eg, tuberculosis [TB], histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystosis, and aspergillosis), despite infection resolution, or 
otherwise recurrent infections of abnormal frequency or prolonged duration suggesting an 
immune compromised status, as judged by the Investigator 
E 07.  Participant who has current diagnosis of active or latent TB, nontuberculous mycobacterial 
infection, or a history of incompletely treated TB 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 
E 08.  Participant who has active chronic or acute infection requiring treatment with systemic 
antibiotics, antivirals, or antifungals within 2 weeks before Visit 1 or during Screening 
Period 


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E 09.  Participant who has history of malignancy without complete remission (ie, participant who 
required treatment of malignancy within 5 years before Visit 1), except completely treated 
in situ carcinoma of the cervix, completely treated and resolved nonmetastatic squamous 
or basal cell carcinoma of the skin 
E 10.  Participant who has known or suspected alcohol and/or drug abuse 
E 11. Participant who has history of systemic hypersensitivity or anaphylaxis to dupilumab or 
any of its excipients 
E 12. Participant who has a planned major surgical procedure during the participant’s 
participation in this study 
E 13. Participant who has undergone any and/or sinus intranasal surgery (including polypectomy) 
within 6 months before Visit 1 
E 14. Participant who has had a sinonasal surgery changing the lateral wall structure of the nose 
making impossible the evaluation of NPS 
E 15. Participant who has any other medical or psychological condition including relevant 
laboratory or cardiovascular 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 
study, may make participant's participation unreliable, or may interfere with study 
assessments. The specific justification for participants excluded under this criterion will be 
noted in study documents (chart notes, e-CRF, etc.). 
Prior/concomitant therapy 
E 16. Participants who have participated in a prior dupilumab clinical study or have been treated 
with commercially available dupilumab 
E 17. Participants who have taken: 
- 
Biologic therapy/systemic immunosuppressant to treat inflammatory disease or 
autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary 
biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis) within 4 weeks 
before Visit 1 or 5 half-lives, whichever is longer 
- 
Any investigational monoclonal antibody within 5 half-lives or within 6 months before 
Visit 1 if the half-life is unknown 
- 
Anti-IgE therapy (omalizumab) within 4 months before Visit 1 
E 18. Participant who received treatment with a live (attenuated) vaccine within 4 weeks before 
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 


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will be determined, after consultation with a physician, whether the administration of 
vaccine can be postponed until after the end of treatment (EOT) or end of study (EOS) or 
moved 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 moved to before the start of the study can be 
enrolled into the study only after a gap of 4 weeks following administration of the vaccine. 
E 19. Participant who has received leukotriene antagonists/modifiers within 4 weeks before Visit 
1, unless participant is on a continuous treatment for at least 30 days  
E 20. Participant who has initiated allergen immunotherapy within 3 months before Visit 1 or 
has planned to begin therapy or change its dose during the screening or intervention period 
E 21. Participant who receives concomitant treatment prohibited in the study (see Section 6.8) 
E 22. Participant who has received either intravenous immunoglobulin therapy and/or 
plasmapheresis within 30 days before Visit 1 
Diagnostic assessments 
E 23. Participants with any of the following results at Visit 1: 
a) Positive (or indeterminate) hepatitis B surface antigen (HBsAg), or  
b) Positive total hepatitis B core antibody (HBcAb) and a negative HBsAg with positive 
hepatitis B virus (HBV) DNA, or 
c) Positive hepatitis C virus (HCV) antibody with positive HCV RNA. 
Noncompliance with diary completion 
E 24. Participants who do not demonstrate the following for acceptable compliance: completing 
the diary for any 4 mornings in the 7 days immediately preceding the Baseline Visit 
(Visit 2) 
Other exclusions 
E 25. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized 
E 26. Participant not suitable for participation, whatever the reason, as judged by the Investigator, 
including medical or clinical conditions or participants potentially at risk of noncompliance 
with study procedures 
E 27. Participants who are employees of the clinical study site, other individuals directly 
involved in the conduct of the study, or immediate family members of such individuals (in 


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conjunction with Section 1.61 of International Council for Harmonisation - Good Clinical 
Practice [ICH-GCP] Ordinance E6) 
E 28. Any specific situation during study impleentation/course that may lead to ethical concerns 
E 29. Participant who has 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  
No restrictions are required in this study. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled. 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 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. 
There is no requirement for a waiting period between the screen failure date and the rescreening 
date. The interactive voice/web response system (IVRS/IWRS) report will flag rescreened 
participants. The Investigator will obtain information about subsequent scheduled visits via the 
IVRS/IWRS, which will be available 24 hours a day. 
Participants who fail screening during the Screening Period may be rescreened for study 
eligibility only once for the following criteria: 
• They do not meet the inclusion criterion of having a weekly average NC symptom severity 
score >1 at Visit 2. 
• They have an acute illness such as acute sinusitis, nasal infection, or upper respiratory 
infection (E 01). These participants can be rescreened only after complete resolution of 
symptoms. 
• They have taken one of the prohibited treatments listed in Section 6.8 during the Screening 
Period.  
Participants who are rescreened must sign a new consent form, and all of the Visit 1 procedures 
must be repeated (refer to Section 10.1.3 for further instructions related to rescreening) unless a 
prior assessment is performed within the time frame permitted prior to study entry or the Visit 1 


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baseline CT scan of sinuses is performed. Participants with positive test results for HIV or 
hepatitis will not be allowed to rescreen. 
All participants must fulfill all eligibility criteria before enrollment into the study; no waiver will 
be allowed for enrollment. 
If certain dynamic laboratory tests do not meet the eligibility criteria, these laboratory assessments 
may be repeated, at the discretion of the Investigator, if the results are judged to be likely to return 
to acceptable range for study inclusion within the Screening Visit window. 
For participants who do not fulfill other exclusion criteria, rescreening should be discussed with 
the Sponsor. In all cases, a given participant can only be rescreened once. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING SCREENING  
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 7: Contingency measures for a regional or national emergency that is declared by a 
governmental agency (Section 10.7) should be considered for screening. 


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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. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Approximately 25 participants will be enrolled and will be assigned to study intervention as 
described below:  
• Dupilumab 300 mg q2w up to Week 24 (all participants) 
• Dupilumab 300 mg q4w after Week 24 (participants who have stable disease at Week 24) 
• One injection of 300 mg q2w after Week 24 (participants who cannot achieve stable 
disease) 
For participants who have stable disease (NPS improvement from baseline to both Weeks 16 and 
24 ≥2 points), the dosing interval can be changed from q2w to q4w at the discretion of the 
Investigator at Week 24. Participants who proceed from the q2w regimen to the q4w regimen will 
receive the q4w regimen up to Week 48 and will not be permitted to return to the q2w regimen 
during this study. Other participants will receive q2w regimen up to Week 50. All participants 
will be followed up to Week 52. 
At Visit 2, the Investigator (or designee) will prepare and perform the first IMP injection in front 
of the participant (or parent/LAR/caregiver). The IMP will be administered following clinic 
procedures. Participants will be monitored at the study site for at least 30 minutes after the 
injection for signs of hypersensitivity reaction. 
After the second dose of IMP, home administration of IMP q2w (by participant, caregiver, or 
health care professional) is possible if the participant (or caregiver) has been appropriately trained 
at the study site. Training must be documented when it is completed successfully, and training 
injections must be recorded in the participant’s study file. In case of emergency (eg, natural 
disaster, pandemic), different training methods (eg, training remotely with instruction provided by 
phone) can be performed (and will be documented in the participant’s study file). When IMP is 
administered at home, the participants must be advised by the site staff to self-monitor for 
potential signs and symptoms that may suggest a hypersensitivity reaction for at least 30 minutes 
after administration.  
If the participant (or caregiver) is unable or unwilling to administer IMP, arrangements must be 
made for qualified site personnel and/or healthcare professionals to administer IMP for the doses 
that are not scheduled to be given at the study site. If the participant or caregiver(s) do not become 
comfortable with injecting the IMP at home or if the Investigator determines that participant (or 
caregiver) administering an injection at home is not appropriate, injections can be performed at 
the site by way of unscheduled visits. 


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Subcutaneous injection sites should be alternated among the 4 quadrants of the abdomen 
(avoiding the navel and waist areas), the upper thighs. and the upper arms, such that the same site 
is not injected twice consecutively. Injection in the upper arms can be done only by a trained 
person (caregiver trained by Investigator or designee) or health care professional but not the 
participants themselves. 
Post-trial access to IMP will not be provided. 
Table 2 - Overview of study interventions administered  
Arm name 
Dupilumab 
Intervention name 
Dupilumab 300 mg 
Type  
Biological 
Dose formulation 
A 150 mg/mL dupilumab solution in a prefilled syringe to deliver 
300 mg in 2 mL 
Unit dose strength(s) 
300 mg 
Dosage level(s) 
300 mg q2w or q4w ±3 days 
Route of administration 
Subcutaneous 
Use 
Experimental 
IMP or NIMP 
IMP 
Packaging and labeling 
One glass prefilled syringe packed in a participant kit box. Both 
the glass prefilled syringe and the box will be labeled as 
required per country requirement. 
Former names 
Dupixent 
Abbreviation: IMP: investigational medicinal product; NIMP: noninvestigational medicinal product; q2w: every 2 weeks; q4w: every 4 weeks 
The IMP may be supplied at the site or from the Investigator, site, or Sponsor to the participant 
via a Sponsor-approved courier company where allowed by local regulations and agreed upon by 
the participant.  
Detailed instructions for transport, storage, preparation, and administration of IMP are provided to 
the participants. For doses that are not given at the study site, participants will complete a paper 
dosing diary to document compliance with self-injection (or caregiver injection) of IMP, location 
of injection, and any symptoms. The diary will be kept as source data in the participant’s study 
file. 
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 7: Contingency measures for a regional or national emergency that is declared by a 
governmental agency (Section 10.7). 


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6.1.1 Packaging and labeling  
Dupilumab 300 mg will be supplied at each visit as glass prefilled syringes packed in one 
participant kit box. The number of kits to be supplied to each participant at each visit is based on 
the Investigator’s instruction.  
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 Storage and handling  
1. The Investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all study intervention received and that 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 it. At site, all study interventions 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). 
It is the responsibility of the Investigators to inform the participants regarding the mandatory 
storage requirements for the IMP. No temperature monitoring will be performed at the 
participants’ homes. 
6.2.2 Responsibilities  
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.8). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for 
direct-to-patient [DTP] shipment, for which a courier company has been approved by the 
Sponsor), allow the IMP to be used other than as directed by this clinical study protocol, or 
dispose of IMP in any other manner. 


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6.2.3 Treatment accountability and compliance  
The Investigator or designee will keep accurate records of the quantities of the IMP dispensed and 
returned, used and unused by each participant.  
• Proper recording of treatment kit numbers as required on the appropriate e-CRF page for 
accounting purposes. 
• All medication treatment kits (whether empty or unused) are returned by the participant at 
each visit when a treatment dispensing is planned and at the EOT/EOS Visit.  
• The completed patient diary (returned to the site at each visit), returned IMP treatment 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. 
• The Investigator (or designee) will track treatment accountability/compliance by diary and 
by counting the number of used and unused treatment kits and syringes and will complete 
the appropriate page of the patient treatment log.  
• The monitor in charge of the study will then check the data entered on the IMP 
administration page by comparing them with the IMPs that have been retrieved and the 
patient treatment log forms. Reconciliation will occur with the paper diary as appropriate 
depending on the study visit/period. 
6.2.4 Return and/or destruction of treatments  
Whenever possible, all partially used, used, or unused IMP provided by the Sponsor will be 
destroyed on-site according to the standard practices of the site. A detailed treatment log of the 
destroyed IMP supplied by the Sponsor will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will 
not destroy any IMP supplied by the Sponsor unless the Sponsor provides written authorization. 
When destruction at the site cannot be performed, all IMP supplied by the Sponsor will be 
retrieved by the Sponsor. A detailed treatment log of the returned IMP supplied by the Sponsor 
will be established with the Investigator (or the pharmacist) and countersigned by the Investigator 
and the monitoring team. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
This is an open-label, single-arm study; randomization and blinding will not be implemented. 
6.4 
STUDY INTERVENTION COMPLIANCE  
• Methods used by the Investigator or his/her delegate to ensure that the IMP was 
administered 


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• IMP accountability: 
- 
Intervention units are returned by the participant at each visit. In case of DTP process, 
the intervention units can be returned by the carrier (if defined in the contract). 
- 
The Investigator counts the number of prefilled syringes remaining in the returned 
packs and fills in the intervention log form. 
- 
The Investigator records the dosing information on the appropriate page(s) of the 
e-CRF. 
- 
The monitor in charge of the study then checks the e-CRF data by comparing them 
with the IMP that he/she has retrieved and the intervention log forms. 
- 
Proper placement of tear-off label for accounting purposes. 
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 and recorded. 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. Compliance will be assessed by patient diary (returned 
to the site at each visit) and by returned IMP treatment kit boxes, both used and unused, along 
with any unused prefilled syringes during the site visits and documented in the source documents 
and relevant form. Deviation(s) from the prescribed dosage regimen should be recorded (refer to 
Section 6.2.3 for details). 
A record of the quantity of IMP 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  
For participants who have stable disease (NPS improvement from baseline to both Weeks 16 
and 24 is ≥2 points), the dosing interval can be changed from q2w to q4w at the discretion of the 
Investigator at Week 24. Participants who proceed to the dosing interval from q2w to q4w will not 
be permitted to return to the q2w regimen during this study. The maximum dose will not exceed 
dupilumab 300 mg q2w. 
However, any dose reduction is not allowed other than above. 
6.5.1 Retreatment criteria  
Not applicable. 


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6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
Post-trial access to study medication will not be provided. 
6.7 
TREATMENT OF OVERDOSE  
For this study, any dose of dupilumab greater than twice the intended dose during an interval of 
less than 11 days will be considered an overdose.  
No antidote is available for dupilumab. The Sponsor does not recommend specific treatment for 
an overdose. Symptomatic overdoses (serious or nonserious) are required to be reported as AE of 
special interests (AESI) (refer to Section 8.3.6).  
In the event of an overdose, the Investigator should: 
• Contact the Sponsor immediately. 
• Evaluate the participant to determine, in consultation with the Sponsor, whether study 
intervention should be interrupted. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
dupilumab can no longer be detected systemically. 
• Document appropriately in the e-CRF. 
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) or procedures 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. 
Prohibited medications 
The following concomitant treatments are not permitted during the Screening Period and 
throughout the study unless otherwise specified:  
• Intranasal corticosteroids within 5 half-lives or at least 30 days, whichever is longer, 
before Visit 1, during the Screening Period, and up to Week 52 (however, INCS can be 
used for other coexisting diseases [eg, allergic rhinitis] after Week 24, as needed, to keep 
more participants for the assessment of exploratory endpoints with 52-week treatment) 


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• Any systemic immunosuppressive treatment, including but not limited to methotrexate, 
cyclosporine, mycophenolate, tacrolimus, gold, penicillamine, sulfasalazine, 
hydroxychloroquine, azathioprine, and cyclophosphamide, within 4 weeks before Visit 1 
or 5 half-lives, whichever is longer, during the Screening Period, and up to Week 52 
• Anti-IgE therapy (omalizumab) within 4 months before Visit 1, during the Screening 
Period, and up to Week 52 and other biologics for immuno-inflammatory conditions 
within 4 weeks before Visit 1 or 5 half-lives, whichever is longer, and up to Week 52 
• Allergen immunotherapy during the Screening Period and up to Week 52 (except if 
initiated more than 3 months prior to Visit 1 and dose stable for 1 month prior to Visit 1)  
• Long-term courses (>2 weeks) of SCS are prohibited from Visit 1 onward 
• Short-term courses (≤2 weeks) of SCS are prohibited only during the Screening Period, 
and they are allowed as rescue medication after Visit 2 
• Live, attenuated vaccines within 4 weeks before Visit 1, during the Screening Period, and 
up to Week 52 (Appendix 8 [Section 10.8])  
• Systemic antibiotic for >2 weeks during the study 
• Use of intranasal decongestants, except for preparation of nasal endoscopy (NE) 
Participants who receive any of the prohibited treatments or undergo surgery during the Screening 
Period will not start the intervention period. They may, however, be rescreened following the 
procedures described in the SoA (Section 1.3). 
Participants who use INCS between Visit 2 and Week 24 for whatever reason will discontinue the 
IMP administration. 
Permitted concomitant medication 
The following treatments are allowed throughout the study unless otherwise specified:  
• Intranasal corticosteroids to treat other coexisting diseases (such as allergic rhinitis) are 
allowed after Week 24 as needed. 
• Nasal normal saline. 
• Single topical decongestant administration such as oxymetazoline hydrochloride (to 
reduce swelling and widen the path for the endoscope) and topical anesthetics such as 
lidocaine are allowed before endoscopy. 
• Short-acting β2-adrenergic receptor agonists, long-acting β2-adrenergic receptor agonists, 
and long-acting muscarinic acetylcholine receptor antagonists. 
• Methylxanthines (eg, theophylline, aminophyllines). 
• Inhaled corticosteroids. 
• Systemic antihistamines. 


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• Leukotriene antagonists/modifiers are permitted during the study, only for participants 
who were on a continuous treatment for ≥30 days before Visit 1. 
• Allergen immunotherapy in place for ≥3 months before Visit 1 is permitted. 
• Paracetamol/Acetaminophen, at doses of ≤2 g/day, is permitted for use any time during the 
study.  
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor if required. 
Rescue medication including antibiotics, short courses of SCS for treatment of CRSwNP as 
described in Section 6.8.1, or short courses of SCS to treat other serious coexisting diseases (such 
as asthma exacerbation) or for AEs is allowed.  
6.8.1 Rescue medicine and procedures  
During the study intervention period, based on clinical evaluation, in case of worsening of signs 
and/or symptoms requiring medical intervention, the following rescue medications/procedures 
may be employed as per Investigator’s judgment: 
1. Systemic (eg, oral) corticosteroids up to 2 weeks 
2. Antibiotics for the treatment of acute sinusitis less than 2 weeks after Visit 2 
3. Sinonasal surgery 
Participants receiving rescue treatment other than surgery during the study should continue on 
IMP unless the Investigator decides to withdraw the study intervention. Before starting treatment 
with SCS, participants should come to the study site for the clinical assessments including 
endoscopy. 
For participants who undergo or plan to have surgery for NP, the Investigator may decide to 
continue IMP up to the time of surgery or EOT, whichever date comes first. At the time of surgery, 
participants will be permanently discontinued from study intervention and assessed as soon as 
possible using the procedures normally planned for the EOT/EOS Visit as described in the SoA 
(Section 1.3).  
If the surgery is to be performed during the intervention period, an AE or SAE page will be 
completed. If surgery is scheduled after the planned EOS, the EOT/EOS Visit will not be delayed. 
The surgery will be followed up by the Investigator or the participant’s physician with general 
medical practice. 
In any case, participants who prematurely discontinue the treatment will be encouraged to return 
to the study site for the efficacy and safety assessments planned at the EOT/EOS Visit (refer to 
SoA [Section 1.3]). 
The date and time of rescue medication administration as well as the name and dosage regimen of 
the rescue medication must be recorded. For participants who undergo sinonasal surgery for NP, 
the reason (worsening signs and/or symptoms during the study), the expected and real surgery 


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dates, and the type and outcome of surgery will be recorded. For participants who plan to have 
sinonasal surgery for NP, the reason (worsening signs and/or symptoms during the study), the 
expected and real surgery dates, and the type of surgery will also be recorded in the e-CRF. 


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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
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 the e-CRF. 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 the assessments planned for the EOT/EOS Visit, with the exception of 
the CT scan. See the SoA (Section 1.3) for data to be collected at the time of discontinuation of 
study intervention and follow-up and for any further evaluations that need to be completed. 
Participants must be withdrawn from the study (ie, from any further IMP or study procedure) for 
the following reasons: 
• At their own request or at the request of their LAR (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 procedures involved in the research) 
• If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
participant’s well-being 
• In case of surgery for NP 
• At the specific request of the Sponsor 
• In the event of a critical protocol deviation, at the request of the Investigator or the 
Sponsor 
• In the event of an anaphylactic systemic allergic reaction that is related to IMP and that 
requires treatment 
• In the event that the participant is diagnosed with a malignancy during the study, 
excluding carcinoma in situ of the cervix or squamous or basal cell 
• Pregnancy 
• Any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (refer to Appendix 9 [Section 10.9]) 
• Met liver chemistry stopping criteria (Section 7.1.2) 


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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. 
If possible, and after the permanent discontinuation of intervention, the participants will be 
assessed as soon as possible using the procedures normally planned for the EOT/EOS Visit (refer 
to SoA [Section 1.3]). 
All cases of permanent intervention discontinuation must be recorded by the Investigator on the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Liver chemistry stopping criteria  
Details of the liver chemistry stopping criteria are provided in Appendix 5 (Section 10.5). 
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a participant meets one of the conditions outlined in the algorithm (ie, ALT >3 × ULN) 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 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical study due to a regional or national emergency declared 
by a governmental agency (Appendix 7: Contingency measures for a regional or national 
emergency that is declared by a governmental agency [Section 10.7]). For all temporary 
intervention discontinuations, the duration should be recorded by the Investigator on the 
appropriate pages of the e-CRF.  
In addition, any of the following conditions will be a cause for temporary treatment 
discontinuation: 
• Infections or infestations that do not respond to medical treatment should have IMP 
discontinued until the infection is resolved 
• Any laboratory abnormality that meets the temporary treatment discontinuation criteria as 
per Appendix 5 (Section 10.5) 
For a participant who requires HBV DNA monitoring, if the HBV DNA result becomes positive 
during the study, the participant will temporarily discontinue IMP and should be referred to a 
hepatologist. Investigational medicinal product may be restarted under careful consideration of the 
participant’s risks and benefits based on hepatologist evaluation and current treatment guidelines 
and after consultation with Medical Monitor (refer to footnote j in the SoA [Section 1.3]). 


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Temporary intervention discontinuation decided by the Investigator corresponds to more than 
1 dose not being administered to the participant. If the IMP is interrupted for more than 2 doses, 
then the participant should permanently discontinue the study intervention. 
7.1.4 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator has considered, according to his/her best medical 
judgment, that the IMP was unlikely to have been responsible for the AE in question and that the 
selection criteria for the study are still met (refer to Section 5). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 7: Contingency measures for a regional or national emergency that is 
declared by a governmental agency (Section 10.7).  
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. See the SoA (Section 1.3) for data to be collected at the time of 
EOT/EOS and for any further evaluations that need to be completed. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants 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 


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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 retreated in the study. Their inclusion 
and intervention numbers must not be reused.  
7.3 
LOST TO FOLLOW-UP  
A participant will be considered lost to follow-up if he/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 study site for a required 
study visit: 
• The site must attempt to contact the participant, reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 documented attempts 
via 2 different methods [phone, text, e-mail, certified letter, etc] should be done). 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.  
• Site personnel or an independent third party will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants enrolled, including those 
who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 


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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count, urine tests) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes, provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
• 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 7: Contingency measures for a regional or national emergency that is 
declared by a governmental agency (Section 10.7).  
8.1 
EFFICACY ASSESSMENTS  
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1 Nasal endoscopy: nasal polyp score  
The NPS (4, 5, 6) is assessed by central video recordings of NE. The NPS is the sum of the right 
and left nostril scores, as evaluated by means of NE. Nasal polyp is graded based on polyp size 
described in Table 3. 
Table 3 - Endoscopic nasal polyp score  
Polyp Score 
Polyp Size 
0 
No polyps 
1 
Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate 
2 
Polyps reaching below the lower border of the middle turbinate  
3 
Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate 
4 
Large polyps causing complete obstruction of the inferior nasal cavity 


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Nasal endoscopy should be performed at the end of the scheduled visits before the administration 
of IMP and should be preceded by local administration of anesthetic drugs in combination with a 
decongestant. 
Standard video sequences will be downloaded or sent to a centralized reader. Centralized imaging 
data assessments and scoring by independent physician reviewer(s) for the imaging data will be 
performed for all endoscopies. To confirm eligibility at Visit 2, only the Visit 1 central reading 
will be made available to the site. In addition, at Visit 2, the Investigator will perform the NE to 
confirm the eligibility score and enter the result in the e-CRF. Thus, the participant will be 
considered eligible based on a Visit 1 central reading followed by a Visit 2 local reading NPS 
score of 5 or more and at least 2 on each side. 
For the analysis of the primary endpoint, the central reading of Visit 2 will be used for comparison 
with the Week 24 reading. The sites will remove participant-identifying information from the 
imaging data header prior to sending the imaging data to the central reader. 
Nasal endoscopy will be conducted at the Screening Visit (Visit 1), Visit 2, and Visits 4 to 9. 
Further details on NE will be available in a separate operational manual provided to the sites. 
8.1.2 Nasal congestion/obstruction symptom severity score  
Nasal congestion/obstruction will be assessed by the participant using a diary on a daily basis 
from Visit 1 and throughout the study, on a 0 to 3 categorical scale (where 0 = no symptoms, 
1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms) (7):  
Nasal congestion/obstruction will be scored as a reflective score (evaluation of symptom severity 
over the past 24 hours) by the participants (Table 4). 
Table 4 - Nasal congestion/obstruction 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 diary will be dispensed at Visit 1, and the diary will be checked by the study site at each visit.  
A NC symptom severity score ≥2 at Visit 1 and a weekly average severity greater than 1 at the 
time of enrollment (Visit 2) are required and will be provided to the site to determine participant 
eligibility. The participant must have 4 or more measurements collected within 7 days prior to 
enrollment; the baseline will be the average of these measurements (E 24). 
For the baseline to EOT/EOS analysis, the average of the symptom severity scores from the most 
recent 4 weeks before a scheduled visit will be used. 


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8.1.3 Computerized tomography scan: Lund Mackay score  
The LMK system is based on localization with points given for degree of opacification: 
0 = normal, 1 = partial opacification, 2 = total opacification. These points are then applied to the 
maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinus on each side. The 
osteomeatal complex (OC) is graded as 0 = not occluded or 2 = occluded. Adding the scores of 
these 6 parameters will derive a maximum score of 12 per side (left and right). The total score of 
the 2 sides will be used for analysis. This scoring system has been validated in several studies (8, 
9, 10). 
For participants in whom the OC is missing (because of a previous surgery), the reader should 
consider the location of the previous OC and provide a score (as if the OC were there). 
Computerized tomography scan should be performed anytime during the Screening Period before 
the first administration of IMP and at Visits 7 and 9 (Weeks 24 and 52). Whenever possible, a 
cone beam CT scan should be utilized. 
Details for CT will be available in a separate operational manual provided to the sites. 
8.1.4 Nasal symptom diary: Disease specific daily symptom assessment and total 
symptom score  
On a daily basis from Visit 1 and throughout the study, the participant will use a 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) (11):  
- 
Congestion and/or obstruction 
- 
Loss of sense of smell 
- 
Anterior rhinorrhea (runny nose) 
- 
Posterior rhinorrhea (postnasal drip) 
The total symptom score (TSS) is a composite score (ranging between 0 and 9) consisting of the 
sum of the following symptoms assessed daily in the morning: nasal congestion/obstruction, 
decreased/loss of sense of smell, and rhinorrhea (average of anterior/posterior nasal discharge). 
8.1.5 Visual analogue scale for rhinosinusitis  
The visual analogue scale (VAS) for rhinosinusitis is used to evaluate the total severity (7). 
Rhinosinusitis disease can be divided into MILD, MODERATE, and SEVERE based on total 
severity VAS score (0 to 10 cm): 
• MILD = VAS 0 to 3 
• MODERATE = VAS >3 to 7 
• SEVERE = VAS >7 to 10 


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The participant will be asked to indicate on a VAS the answer to the question below:  
“How troublesome are your symptoms of your rhinosinusitis?” 
The VAS ranges from 0 (Not troublesome) to 10 (Worst thinkable troublesome) (Appendix 10 
[Section 10.10]). 
8.2 
SAFETY ASSESSMENTS  
This section presents safety assessments other than AEs, which are presented in Section 8.3.  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
Physical examinations will include an assessment of general appearance, skin, eyes, 
ear/nose/throat, heart, chest, abdomen, reflexes, lymph nodes, spine, and extremities. All 
deviations from normal will be recorded, including those attributable to the participant’s disease. 
Physical examinations will be performed at Visits 1, 7, and 9. 
8.2.2 Vital signs  
Vital signs including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), 
respiratory rate (breaths per minute), and body temperature (forehead [temporal] temperature; 
degrees Celsius); and body weight (kg) will be measured at Visit 1, Visit 2, and Visits 5 to 9. 
Height (cm) will be measured at screening (Visit 1) only. Vital signs will be measured in the 
sitting position at each visit and will be measured prior to receiving IMP using preferably the 
same arm at each visit. 
8.2.3 Electrocardiograms  
A standard 12-lead electrocardiogram (ECG) will be performed at the sites at the Screening Visit 
(Visit 1). In case of an abnormal ECG finding, the Investigator should enter details into the e-CRF. 
At Visit 2, the Investigator should use his/her medical judgment to consider whether the 
participant is eligible for the study. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
the SoA (Section 1.3) for their timing and frequency.  
• The Investigator must review the laboratory report 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. 


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• All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator. 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
- 
If laboratory values from non-protocol-specified laboratory 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 or dose 
modification), then the results must be recorded in the e-CRF. 
8.2.5 Pregnancy testing  
A serum pregnancy test will be performed at Visit 1, and urine pregnancy tests will be performed 
at Visit 2 and q4w thereafter. A negative result must be obtained at both Visit 1 and Visit 2 prior 
to the first administration of IMP. A urinary 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 
intervention will be withheld and a serum pregnancy test to confirm the pregnancy should be 
performed as soon as possible. Pregnancy will lead to definitive treatment discontinuation in all 
cases. 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria; the Investigator 
is responsible for the review of medical history, menstrual history, and recent sexual 
activity to decrease the risk for including a woman with an early undetected pregnancy. 
• 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. 
8.2.6 Suicidal ideation and behavior risk monitoring  
Not applicable. 
8.2.7 Hypersensitivity monitoring  
Allergic reaction is a potential risk associated with the administration of most therapeutic 
monoclonal antibody treatments. 
Allergic reactions may be defined as allergic reaction-mediated signs and symptoms experienced 
by participants during or shortly after a pharmacologic or biologic agent is given. These reactions 
may present in a variety of ways, including dizziness, headache, anxiety, dyspnea, hypotension, 
tachycardia, pruritus, rash, urticaria/angioedema, flushing, nausea or vomiting, and joint pain with 
fever. Allergic reactions may begin within a few hours and persist up to 24 hours after dosing. 


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Refer to Appendix 12 (Section 10.12), which describes the clinical criteria for the diagnosis of 
anaphylaxis. 
Participants should be monitored for at least 30 minutes after each study site IMP administration 
for any signs or symptoms of a hypersensitivity reaction. Any instance of allergic reaction should 
be reported as an AESI (Section 8.3.6). Any anaphylactic reactions or acute allergic reactions that 
require immediate treatment will be an AESI with immediate reporting (within 24 hours), and 
study medication must be permanently discontinued. Trained personnel and medications should 
be available to treat anaphylaxis or any severe allergic reaction if it occurs. Furthermore, the study 
participants will be advised, when the IMP is administered at home, to self-monitor for potential 
signs and symptoms that may suggest a hypersensitivity reaction for at least 30 minutes after 
administration. 
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require treatment 
must be reported as an AESI (within 24 hours; for further details, see AESI definition in 
Section 8.3.6), and study medication must be permanently discontinued.  
8.2.8 Injection site reaction assessments  
Based on the SC mode of administration of high doses of protein and on a higher incidence of 
local injection site reactions observed at the highest dose level (300 mg weekly) in dupilumab 
studies, severe injection site reactions are considered a potential risk. Participants who experience 
an injection site reaction must be closely monitored for the possibility of a more intense injection 
site reaction with a future injection. Any severe injection reaction that lasts over 24 hours will be 
reported as an AESI (Section 8.3.6) with immediate notification. 
Prophylactic treatment/premedication for an injection site reaction is not permitted. 
8.3 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND OTHER SAFETY 
REPORTING  
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). The definition of 
AESI is provided in Section 8.3.6. 
The definitions of unsolicited and solicited AEs can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s LAR).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs that are considered related to the study intervention or study procedures or that cause 
the participant to discontinue the study intervention (see Section 7).  
The method of recording, evaluating, and assessing the causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3).  


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8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until the EOT/EOS 
Visit at the time points specified in the SoA (Section 1.3). 
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 the data 
being available. 
The Investigator should take appropriate measures to follow all AEs until clinical recovery is 
complete and laboratory results have returned to normal, until progression has been stabilized, or 
until death, in order to ensure the safety of the participants. This may imply that observations will 
continue beyond the last planned visit per protocol and that additional investigations may be 
requested by the monitoring team up to the time as noticed by the Sponsor. 
The 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 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.  
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the prespecified study end-date, all SAEs and AESIs 
(as defined in Section 8.3.6) will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further information 
on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of 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 (IRBs), 
and the Investigators. 


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• Serious adverse events that are considered expected will be specified in the Package Insert.  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• 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 Package Insert and will notify the IRB, if 
appropriate according to local requirements. It is the responsibility of the Sponsor to assess 
whether an event meets the criteria for a SUSAR and, therefore, is expedited to regulatory 
authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until EOT/EOS. 
• 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 female 
participant’s pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant or pregnant female partner will be followed to determine the outcome of 
the pregnancy. The Investigator will collect follow-up information on the participant or 
pregnant female partner and the neonate, and the information will be forwarded to the 
Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 10.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants or pregnant female partners, he/she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue the study intervention. 
8.3.6 Adverse event of special interest  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor are 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 the SAE 
notification described in Section 10.3.4, even if it does not fulfill a seriousness criterion. 


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Adverse event of special interests for this study include the following: 
• Anaphylactic or systemic allergic reactions that are related to IMP and that require 
treatment (refer to Appendix 12 [Section 10.12] for the definition of anaphylaxis) 
• Severe injection site reactions that last longer than 24 hours 
• Conjunctivitis, blepharitis, or keratitis 
• Serum sickness or serum sickness-like reaction 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms) 
• Any infection meeting at least 1 of the following criteria: 
- 
Any SAE of serious infection 
- 
Requires parenteral (intravenous, intramuscular, SC) antimicrobial therapy 
- 
Requires oral antimicrobial therapy for longer than 2 weeks 
- 
Is a parasitic infection 
- 
Is an opportunistic infection (refer to Appendix 9 [Section 10.9]) 
Note: Antimicrobial therapy refers to antibiotic, antiviral, and antifungal agents. 
• Significant elevation of alanine aminotransferase (ALT) 
- 
ALT >5 × ULN in participants with baseline ALT ≤2 × ULN 
or 
- 
ALT >8 × ULN if baseline ALT >2 × ULN 
• Pregnancy of a female participant as well as pregnancy occurring in a female partner of a 
male participant entered in a study with IMP  
- 
Pregnancy occurring in a female participant entered in the clinical study or in a female 
partner of a male participant entered in the clinical study. It will be qualified as an 
SAE only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]). 
• Symptomatic overdose (serious or nonserious) with IMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the intended dose during an interval of less than 11 days. The circumstances (ie, 
accidental or intentional) should be clearly specified in the verbatim and symptoms, if 
any, entered on separate AE forms. 
Of note, asymptomatic overdose has to be reported as a standard AE. 


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8.3.7 Guidelines for management of specific laboratory abnormalities  
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix 5 (Section 10.5). 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• Neutropenia 
• Thrombocytopenia 
• Increase in ALT 
• Increase in serum creatinine 
• Increase in creatine phosphokinase (CPK) 
8.3.8 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team, which will complete a product complaint form within the required timelines. 
Appropriate information (eg, samples, labels or documents like pictures, or photocopies) related 
to product identification and to the potential deficiencies may need to be gathered. The 
Investigator will assess whether or not the quality issue has to be reported together with an AE or 
SAE. 
8.4 
PHARMACOKINETICS  
Pharmacokinetics 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 is not evaluated in this study. 


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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 DATA FOR FUTURE RESEARCH  
Not applicable. 


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9 
STATISTICAL CONSIDERATIONS  
This postmarketing study is to assess whether dupilumab used without INCS will show similar 
efficacy to that of dupilumab used with INCS in EFC14280, using the point estimates of the 
proportion of responders (NPS improvement from baseline ≥1) at Week 24. Formal statistical 
analysis for hypothesis (null/alternative) will not be performed. 
9.1 
SAMPLE SIZE DETERMINATION  
In EFC14280, the proportion of responders (NPS improvement from baseline ≥1) at Week 24 was 
62.0% in the dupilumab group. Based on this result, the proportion of responders (NPS 
improvement from baseline ≥1) at Week 24 in this postmarketing study will be at least 50.0% to 
justify the similar effect size between EFC14280 and this study. 
It is necessary for 20 participants to achieve this similar responder rate (at least 50%) with a 90% 
probability of success. The sample size was adjusted up to 25 to account for a 20% drop-out rate.  
9.2 
POPULATIONS FOR ANALYSES  
The populations for analyses are defined in Table 5. 


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Table 5 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the informed consent form (ICF) 
Enrolled 
The enrolled population includes all participants with a treatment kit number allocated 
and recorded in the interactive response technology (IRT) database, regardless of 
whether the treatment kit was used or not. 
Participants treated without a treatment kit number being allocated will not be 
considered enrolled and will not be included in any efficacy population. 
Intent-to-treat (ITT)  
Enrolled population with chronic rhinosinusitis with nasal polyp (CRSwNP) 
Modified intent-to-treat (mITT) 
All participants in ITT allocated to study intervention administered at least 1 dose of 
study intervention 
Per protocol (PP) 
All participants in mITT allocated to study intervention administered at least 1 dose of 
study intervention, and who did not receive intranasal corticosteroids (INCS) up to 
Week 24 
Per protocol with extension term (PPE) 
All participants in mITT allocated to study intervention administered at least 1 dose of 
study intervention during the intervention period after Week 24, and who did not receive 
INCS throughout the study 
Safety (SAF) 
All participants allocated to study intervention administered at least 1 dose of study 
intervention before Week 24 
Safety for extension term (SAFE) 
All participants allocated to study intervention administered at least 1 dose of study 
intervention during the intervention period after Week 24 
Abbreviations: CRSwNP: chronic rhinosinusitis with nasal polyp; ICF: informed consent form; INCS: intranasal corticosteroids; IRT: interactive 
response technology; ITT: intent-to-treat; mITT: modified ITT; PP: per protocol; PPE: per protocol with extension term; SAF: safety; SAFE: safety 
for extension term 
Efficacy analyses for the treatment period up to Week 24 will be performed using the per protocol 
(PP) population. Efficacy analyses for the treatment period after Week 24 will be performed using 
the per protocol with extension term (PPE) population. Additionally, supportive efficacy analyses 
will be performed using the modified intent-to-treat (mITT) population. 
Safety data up to Week 24 will be reported for the safety (SAF) population. Safety data collected 
after Week 24 will be reported for the safety for extension term (SAFE) population. 
Participants exposed to study intervention before or without being enrolled will not be considered 
enrolled and will not be included in any efficacy or safety populations. The safety experience of 
these participants will be reported separately. 
Enrolled participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety populations. 
For any participant enrolled more than once, only the data associated with the first enrollment will 
be used in any efficacy or safety population. The safety experience associated with any later 
enrollment will be reported separately. 


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9.3 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will be finalized prior to database lock and will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints. 
A primary database lock will be performed when all participants have completed their treatment 
phase. Final analyses in the clinical study report will be based on all data collected up to this 
database lock. 
9.3.1 General considerations  
The baseline value is defined generally as the last available value before first IMP administration. 
The observation period will be divided into 2 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. 
• The treatment-emergent period is defined as the period from the first IMP 
administration to the last visit in the study.  
Dose regimen groups in the extension term after Week 24 will be defined as follows: 
• 300 mg q2w group: participants who were administered at least 1 dose of the 300 mg q2w 
regimen and never experienced q4w administration during the extension term after 
Week 24 
• 300 mg q4w group: participants who were administered at least 1 dose of the 300 mg q4w 
regimen during the extension term after Week 24 
During the treatment term, including efficacy variable after Week 24, continuous variables and 
binary variables for efficacy by each visit will be summarized using descriptive statistics and 
frequency table in both the PP and mITT populations. 
9.3.2 Primary efficacy endpoint  
• The proportion of responders (NPS improvement from baseline ≥1) at Week 24. 
The number of participants and percentage with the 95% confidence interval (CI) for the primary 
endpoint will be provided at Week 24 in the PP population. 
Participants who undergo surgery for NP or receive SCS for any reason will be considered 
nonresponders for time points after undergoing surgery or receiving SCS. Participants who have 
missing data at Week 24 will be considered nonresponders. 
Details of supportive analyses will be provided in the SAP. 


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9.3.3 Key secondary efficacy endpoints  
• Change from baseline to Week 24 in bilateral NPS  
• Change from baseline to Week 24 in NC symptom severity score using the CRSwNP nasal 
symptom diary (refer to Section 8.1.2 for the details of NC symptom severity score 
assessment) 
• Change from baseline to Week 24 in opacification of sinuses assessed by CT scan using 
the LMK score (refer to Section 8.1.3 for the details of LMK score) 
Handling of missing data 
Each of the 3 key secondary efficacy endpoints will be analyzed using a hybrid method of 
worst-observation carried forward (WOCF) and multiple imputation. For participants taking 
selected prohibited medications and/or rescue medications or who undergo surgery (details of 
selection will be specified in the SAP, refer to Section 6.8.1), their data after the medication usage 
or surgery will be set to missing, and the worst postbaseline value on or before the time of the 
medication usage or surgery will be used to impute the missing Week 24 value (for participants 
whose postbaseline values are all missing, the baseline will be used to impute). Participants who 
discontinue the treatment prematurely are encouraged to follow the planned clinical visits, and in 
those participants who did not take the selected prohibited medications and/or rescue medications 
or undergo surgery, all data collected after treatment discontinuation will be used in the analysis. 
For these participants, missing data may still happen despite all efforts to collect the data after 
treatment discontinuation. For participants who discontinue due to lack of efficacy, all data 
collected after discontinuation will be used in the analysis, and a WOCF approach will be used to 
impute the missing Week 24 value if needed. For participants who discontinue not due to lack of 
efficacy, a multiple imputation approach assuming missing at random will be used to impute the 
missing Week 24 value, and this multiple imputation will use all participants, excluding 
participants who have taken the selected prohibited medications and/or rescue medications or 
undergone surgery on or before Week 24 and excluding participants who discontinue due to lack 
of efficacy on or before Week 24. All of the imputed complete data will be analyzed by 
descriptive statistics with the 95% CI. The summarized mean changes obtained from each 
imputed dataset will be combined using Rubin’s rule for a single estimate. 
Other secondary efficacy endpoints 
• Change from baseline to Week 24 in TSS  
• Change from baseline to Week 24 in loss of smell severity score  
• Change from baseline to Week 24 in VAS for rhinosinusitis  
The other secondary efficacy endpoints will be analyzed using the same hybrid approach as the 
3 key secondary efficacy endpoints. 


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9.3.4 Exploratory efficacy endpoints  
Descriptive statistics for the exploratory efficacy endpoints (NPS, NC symptom severity score, 
LMK score, and TSS) will be presented by dose regimen group and overall for the extension term 
after Week 24. 
Details of exploratory efficacy analyses will be provided in the SAP. 
9.3.5 Safety analysis  
All safety analyses up to Week 24 will be analyzed for the SAF. Safety data collected during the 
extension term after Week 24 up to Week 52 will be reported for the SAFE. Safety analyses for 
the extension term will be presented by dose regimen group and overall. 
The number and percentage of participants with at least 1 treatment-emergent AE (TEAE), 
treatment-emergent serious AE (TESAE), and TEAE leading to treatment discontinuation will be 
tabulated. Multiple occurrences of the same event in the same participant will be counted once in 
the tables. The denominator for computing percentages will be the safety populations. Serious 
AEs and AEs leading to withdrawal from the withdrawal that occur before or after the "treatment-
emergent period" will be summarized separately. Definitions for AESI and the method to identify 
AESIs will be specified in the SAP. 
Descriptive statistics of values and change from baseline values for each laboratory and vital signs 
parameters will be summarized at each time point. The number and percentage of participants 
with at least 1 incidence of potentially clinically significant abnormality (PCSA) at any time 
during the treatment-emergent period will be summarized. 
9.3.5.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 2 categories: 
• Pre-treatment AEs: AEs that developed, worsened, or became serious during the 
pre-treatment period. 
• Treatment-emergent AEs: AEs that developed, worsened, or became serious during the 
treatment-emergent period. 
Similarly, the deaths will be analyzed in the pre-treatment and treatment-emergent periods.  
Analysis of all adverse events 
An AE incidence table will be provided for all types of TEAEs: all TEAEs, all 
treatment-emergent AESIs (defined with a preferred term [PT] or a prespecified grouping), all 
treatment-emergent SAEs, and all TEAEs leading to permanent treatment discontinuation. 


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The AE summaries will be generated with the number (%) of participants experiencing at least 
one event. Participants who die during the study will also be listed. 
9.3.5.2 Laboratory variables and vital signs  
Quantitative analyses 
For laboratory variables, vital signs, descriptive statistics for results, and changes from baseline 
will be provided for each planned visit, with the last value and the worst value (minimum and/or 
maximum value depending on the parameter) during the treatment-emergent period. These 
analyses will be performed using central measurements (when available) or local measurements 
for laboratory variables. 
Analyses according to PCSA  
Potentially clinically significant abnormality analyses will be performed based on the PCSA list 
currently in effect at Sanofi at the time of 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, and 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, according to the following baseline 
status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
9.3.5.3 Product complaints  
Product complaints will be summarized in the safety population.  
9.3.6 Other analysis  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 7: Contingency measures for a regional or national emergency that is 
declared by a governmental agency (Section 10.7).  
9.4 
INTERIM ANALYSES  
No interim analysis is planned. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH-GCP Guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
- 
Good Postmarketing Study Practice (GPSP) 
• The protocol, protocol amendments, ICF, and other relevant documents (eg, 
advertisements) must be submitted to an IRB by the Investigator and reviewed and 
approved by the IRB before the study is initiated.  
• Any amendments to the protocol will require IRB 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 annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
- 
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 of SAEs or other significant safety findings as required by IRB 
procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, 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 study 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 study participants or on the scientific value of the study) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participants or their LAR, and answer all questions regarding the study, including what 
happens to the participant when his/her participation ends.  
• Participants must be informed that their participation is voluntary. Participants or their 
LAR 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 GDPR and of the French law, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• In case of ICF amendment while the participants are still included in the study, they must 
be reconsented to the most current version of the ICF(s).Where participants are not in the 


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study anymore, teams in charge of the amendment must define if those participants must 
or not reconsent 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 LAR, where applicable.  
Participants who are rescreened are required to sign a new ICF. 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency (Appendix 7: Contingency measures for a 
regional or national emergency that is declared by a governmental agency [Section 10.7]). The 
participants or their LAR 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).  
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. The study Sponsor is the Sanofi company responsible for ensuring compliance with this 
matter, when processing data from any individual who may be included in the Sanofi databases, 
including Investigators, nurses, experts, service providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant, and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because they are expected to modify 
the drug response/because they are required by regulatory agencies (eg, on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan).  
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers 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 members, and by inspectors from regulatory authorities. 


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• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this study 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 
precontractual 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 
• 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 intragroup transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to 30 years, unless further 
retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators’ personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 


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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 
e-mail, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical studies and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical studies in 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 studies. 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 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”. 
10.1.6 Data quality assurance  
• All participant data relating to the study will be recorded on e-CRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is 


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responsible for verifying that data entries are accurate and correct by electronically signing 
the CRF.  
• Guidance on completion of e-CRFs will be provided in CRF Completion Guideline. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the e-CRF. 
• The Investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be predefined in the Centralized Monitoring Plan to 
identify systematic issues that can impact participant safety and/or reliability of study 
results. These predefined 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 (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• 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.  
10.1.7 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 entered in the e-CRF 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 Section 10.1.8. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the e-CRF. 


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• Study monitors will perform ongoing source data verification to confirm that data entered 
into the e-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. 
10.1.8 Definition of source data  
Source data is all information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study. Source data are contained in source documents. Source documents are 
original documents, data and records such as hospital records, clinic and office charts, laboratory 
notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, etc. 
All the data collected in the e-CRF should be transcribed directly from source documents. Data 
collected from the study-associated laboratories, endoscopy, CT scan, and patient diary will be 
considered source data. 
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 first act of recruitment is the first site open 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. 
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: 


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- 
Failure of the Investigator to comply with the protocol, the requirements of the IRB 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 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. 


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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 6 will be performed by the local laboratories.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator.  
Table 6 - Protocol-required laboratory tests  
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
RBC count 
 
Hemoglobin 
 
Hematocrit 
 
Total WBC count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
 
 
BUN 
 
Creatinine 
 
Glucose (Indicate if fasting, or nonfasting) 
 
Uric acid 
 
Total cholesterol 
 
Total protein 
 
Albumin 
 
Total bilirubin (in case of values above the normal range, differentiation in conjugated and 
nonconjugated bilirubin) 
 
ALT/SGPT 
 
AST/SGOT 
 
Alkaline phosphataseb 
 
Lactate dehydrogenase 
 
Sodium 
 
Potassium 
 
Chloride 
 
Creatine phosphokinase 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, urobilinogen, nitrite by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy testing 
• 
Serum and urine hCG pregnancy test (as needed for women of childbearing 


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Laboratory tests 
Parameters 
potential)  
Other screening tests 
• 
Serology:  
- 
HBsAg, HBcAb or HBcAb IgM and totalc 
- 
HBsAb 
- 
HCVAbd 
- 
HIV screen (anti-HIV-1 and HIV-2 antibodies) 
- 
TB blood testing (IGRA)e 
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; HBcAb: hepatitis B core antibody; 
HBsAb: hepatitis B surface antibody; HBsAg: hepatitis B surface antigen; HBV: hepatitis B; hCG: human chorionic gonadotropin; HCVAb: 
hepatitis C virus antibody; HIV: human immunodeficiency virus; IgM: immunoglobulin M; IGRA: interferon-gamma release assay; RBC: red 
blood cell, SAE: serious adverse event; SGOT: serum glutamic-oxaloacetic transaminase; SGPT: Serum glutamic-pyruvic transaminase; TB: 
tuberculosis; WBC: white blood cell. 
NOTES : 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.2 and Appendix 5 (Section 10.5). All 
events of ALT or bilirubin which may indicate severe liver injury (possible Hy’s Law) must be reported as an SAE. 
b If alkaline phosphatase is elevated, consider fractionating.  
c In case of results showing HBsAg (negative), and HBcAb total or HBcAb IgM (positive), an HBV DNA testing will be performed and should 
be confirmed prior to enrollment. Participants who are HBcAb (positive) and HBV DNA (negative) at Visit 1 will require HBV DNA 
monitoring at Visits 6, 7, and 8 and at the participant’s last visit (refer to SoA [Section 1.3]). 
d In case of results showing HCV Ab (positive), HCV RNA testing will be performed and should be confirmed prior to enrollment. 
e An IGRA is required only for participants without history of active/latent TB. 
Investigators must document their review of each laboratory safety report. 


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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 participant or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of unsolicited and solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant, participant’s parent, or LAR 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 
hospitalization, or emergency room visit, or visit to/by a health care provider). The 
participant, participant’s parent, or LAR 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, participant’s parent, or LAR’s concern. Detailed 
information about reported unsolicited AEs will be collected by qualified site personnel 
and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by participant, 
participant’s parent, or LAR will be collected during interview with the participant, 
participant’s parent, or LAR and by review of available medical records at the next visit. 
• Solicited AEs are predefined local 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, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital sign 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  


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- 
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 conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 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 AE that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 


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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. 
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:  
o Allergic bronchospasm 
o Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc.) 
o 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 


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- 
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. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 


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• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Package Insert for marketed products, in his/her 
assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representatives. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representatives. 
• 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. 
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, the Investigator will provide the 
Sponsor’s representatives 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  
Serious adverse event 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. 


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• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representative by telephone. 
• Contacts for SAE reporting are: 
FAX: 0120-305-260/03-6301-3052 
E-mail: jp.adamsSAE@sanofi.com 
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 time frames. 
• Contacts for SAE reporting are: 
FAX: 0120-305-260/03-6301-3052 
E-mail: jp.adamsSAE@sanofi.com 
For AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE notification 
described above, even if not fulfilling a seriousness criterion. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION  
10.4.1 Definitions  
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 may 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 nonestrogen hormonal highly effective contraception methods if they wish to 


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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. 


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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.  
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
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.) 
Effective methodsd that are not considered highly effective Failure rate of ≥1% per year when used 
consistently and correctly. 
• 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action 
• 
Male or female condom with or without spermicide 
• 
Cervical cap, diaphragm, or sponge with spermicide 
• 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-
barrier methods) c 
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 


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and correctly. 
c Male condoms must be used in addition to hormonal contraception. 
d Considered effective, but not highly effective - failure rate of ≥1% per year. 
NOTE: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM) are not acceptable methods of contraception.  
Male condom and female condom should not be used together (due to risk of failure from friction). 
10.4.3 Collection of pregnancy information  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy-related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.5 of the protocol. While the Investigator is not obligated to actively seek this 
information in former study participants, he/she may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 


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10.5
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS AND STUDY INTERVENTION RECHALLENGE GUIDELINES  
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.3 is met.


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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.3 are met.


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INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or episode of 
arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances suggesting hepatic 
encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to normal/baseline or clinical 
resolution.
8.
FREEZE serum sample (5ml x 2)
9.   In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
“Baseline” refers to ALT sampled at Baseline Visit; or if baseline value unavailable, to the latest ALT sampled before the Baseline Visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.3 for guidance on safety reporting. 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 


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Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting AEs in Section 10.3 are met.


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Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting AEs in Section 10.3 are met.


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10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 


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10.7 
APPENDIX 7: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical study 
site. 
Contingency procedures are suggested below and in other sections (Section 5.5, Section 6.1, 
Section 7.1.3, Section 7.1.4, Section 8, Section 9.3.6, and Section 10.1.3) for an emergency that 
prevents access to the study site to ensure the safety of the participants and to consider continuity 
of the clinical study conduct, protect study 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. 
During the emergency, if the site will be unable to adequately follow protocol-mandated 
procedures, screening may be temporarily delayed (see also Section 5.5). 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to those assessments that are necessary to ensure the safety of 
participants and those that are important to preserving the main scientific value of the study. 
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If on-site visits are not possible, visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely (eg, nasal endoscopy, CT scan, vital 
signs, laboratory assessments, serum pregnancy test) and should be documented in the 
participant’s study file. 
• Use of local clinic or laboratory locations may be allowed. 
• Arrangements can be made for qualified site personnel and/or health care professionals (eg, 
visiting nurse service) for vital signs, blood sample collection, and IMP administration, if 
allowed by local regulations and approved by the participant. 
As an alternative to on-site IMP dispensing, IMP may be supplied from the site to the participant 
via a Sponsor-approved courier company where allowed by local regulations and approved by the 
participant. 
During a regional or national emergency declared by a governmental agency, reinitiation of IMP 
can only occur once the Investigator has determined, according to his/her best judgment, that the 
contribution of the IMP to the occurrence of the epidemic event (eg, COVID-19) was unlikely. 
The participants or their LAR should be verbally informed prior to initiating any changes that are 
to be implemented for the duration of the emergency (eg, study visit delays/treatment extension, 
use of local labs). 


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Contingencies implemented due to emergency will be documented and a sensitivity analysis may 
be conducted (details will be specified in the SAP).  


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10.8 
APPENDIX 8: LIST OF PROHIBITED LIVE ATTENUATED VACCINES  
The list below is indicative and not exhaustive. 
• 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 


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10.9 
APPENDIX 9: LIST OF OPPORTUNISTIC INFECTIONS  
The list below is indicative and not exhaustive. 
• Aspergillosis 
• Blastomyces dermatitidis (endemic in the south-eastern and south-central states of the 
USA, along the 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 in tropical areas and the 
Tennessee-Ohio-Mississippi river basins) 
• Listeriosis 
• Mycobacterium avium 
• Nontuberculosis mycobacteria 
• Pneumocystis pneumonia 


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10.10 APPENDIX 10: VISUAL ANALOGUE SCALE  
 


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10.11 APPENDIX 11: QUESTIONS FOR PARTICIPANTS WITH CRSWNP TO ASSIST 
DETERMINATION OF NERD DIAGNOSIS  
The following questions are to assist the determination of nonsteroid anti-inflammatory drug 
exacerbated respiratory disease (NERD) diagnosis in participants with CRSwNP (12, 13, 14, 15): 
QUESTION 1 - Have you ever had respiratory, nasal and/or bronchial, symptoms following 
the intake of aspirin or/and non-steroidal anti-inflammatory drugs (NSAID)? 
• NO, I usually take aspirin or NSAID drugs  the patient has not NERD. 
• NO, I don’t take aspirin or NSAID drugs  the patient unlikely has NERD but cannot be 
totally ruled out. 
• YES, only to one drug  the patient likely has NERD. However, a potential IgE-mediated 
allergy to a specific NSAID should be further investigated 
• YES, to 2 or more drugs  the patient most likely has NERD. 
QUESTION 2 - While having a positive clinical history of NERD, have you ever undergone an 
aspirin provocation test, either nasal, bronchial, or oral? 
• NO  conclusion can be only obtained from clinical history. 
• YES, negative  the patient unlikely has NERD but cannot be totally ruled out. 
• YES, positive  confirms the patient has NERD. 
DIAGNOSIS OF NERD: 
• Conditional: only based on clinical history (question 1). 
• Strong: based in both clinical history and provocation test (questions 1 and 2). 


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10.12 APPENDIX 12: DEFINITION OF ANAPHYLAXIS  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.” 
(Adapted from Second symposium on the definition and management of anaphylaxis: Summary 
report— Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium [16]) 
 
 


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10.13 APPENDIX 13: ABBREVIATIONS  
 
AD: 
atopic dermatitis 
ADR: 
adverse drug reaction 
AE: 
adverse event 
AESI: 
adverse event of special interests 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
BUN: 
blood urea nitrogen 
CI: 
confidence interval 
CIOMS: 
Council for International Organizations of Medical Sciences 
COPD: 
chronic obstructive pulmonary disease 
COVID-19: 
Coronavirus Disease 2019 
CPK: 
creatine phosphokinase, creatine phosphokinase 
CRSwNP: 
chronic rhinosinusitis with nasal polyposis 
CSU: 
chronic spontaneous urticaria 
CT: 
computerized tomography 
DTP: 
direct to patient 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EOS: 
end of study 
EOT: 
end of treatment 
EU: 
European Union 
FSH: 
follicle-stimulating hormone 
GDPR: 
General Data Protection Regulation 
GPSP: 
Good Postmarketing Study Practice 
HBcAb: 
hepatitis B core antibody 
HBsAb: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
hCG: 
human chorionic gonadotropin 
HCV: 
hepatitis C virus 
HCVAb: 
hepatitis C virus antibody 
HIV: 
human immunodeficiency virus 
HRT: 
hormonal replacement therapy 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IGAR: 
interferon-gamma release assay 
IgM: 
immunoglobulin M 
IL: 
interleukin 
IL-4Rα: 
interleukin-4 receptor alpha subunit 
IMP: 
investigational medicinal product 
INCS: 
intranasal corticosteroid 
IRB: 
Institutional Review Board 


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IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LAR: 
legally authorized representative 
LMK: 
Lund Mackay 
mITT: 
modified intention-to-treat 
NC: 
nasal congestion obstruction 
NE: 
nasal endoscopy 
NERD: 
nonsteroid anti-inflammatory drug exacerbated respiratory disease 
NIMP: 
noninvestigational medicinal product 
NPS: 
nasal polyp score 
NSAID: 
nonsteroid anti-inflammatory drug 
OC: 
osteomeatal complex 
PCSA: 
potentially clinically significant abnormality 
PN: 
prurigo nodularis 
PP: 
per protocol 
PPE: 
per protocol with extension term 
PT: 
preferred term 
q2w: 
every 2 weeks 
q4w: 
every 4 weeks 
QTL: 
quality tolerance limit 
SAE: 
serious adverse event 
SAF: 
safety population 
SAFE: 
safety population for extension term 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SCS: 
systemic corticosteroid 
SGOT: 
serum glutamic-oxaloacetic transaminase 
SGPT: 
serum glutamic-pyruvic transaminase 
SoA: 
Schedule of Activities 
SUSAR: 
suspected unexpected serious adverse reaction 
TB: 
tuberculosis 
TEAE: 
treatment-emergent adverse event 
TESAE: 
treatment-emergent serious adverse event 
TSS: 
total symptom score 
ULN: 
upper limit of normal 
US: 
United States 
VAS: 
visual analogue scale 
WBC: 
white blood cell 
WOCBP: 
woman of childbearing potential 
WOCF: 
worst-observation carried forward 
 


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10.14 APPENDIX 14: PROTOCOL AMENDMENT HISTORY  
Not applicable. 


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11 
REFERENCES  
1. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two phase 3 
trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335-48. 
2. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe K, et al. Dupilumab efficacy and 
safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378:2486-96. 
3. Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. Efficacy and safety of 
dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP 
SINUS-24 and LIBERTY NP SINUS-52): results from two nulticentre, randomised, double-
blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019;394(10209):1638-50. 
4. Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, et al. Omalizumab is 
effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin 
Immunol. 2013;131:110-6. 
5. Gevaert P, Van Bruaene N, Cattaert T, Van Steen K., Van Zele T, Acke F, et al. Mepolizumab, 
a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin 
Immunol. 2011;128:989-95. 
6. Van Zele T, Gevaert P, Holtappels G, Beule A, Wormald PJ, Mayr S, et al. Oral steroids and 
doxycycline: two different approaches to treat nasal polyps. J Allergy Clin Immunol. 
2010;125:1069-76. 
7. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European 
position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. 
Rhinology. 2012;50:1-12. 
8. Lund VJ, Mackay IS. Staging in Rhinosinusitis. Rhinology. 1993;31:183-4. 
9. Metson R, Gliklich RE, Stankiewicz JA, Kennedy DW, Duncavage JA, Hoffman SR, et al. 
Comparison of sinus computed tomography staging systems. Otolaryngol Head Neck Surg. 
1997;117:372-9. 
10. Oluwole M, Russell N, Tan L, Gardiner Q, White P. A comparison of computerized 
tomographic staging systems in chronic sinusitis. Clin Otolaryngol Allied Sci. 1996;21:91-5. 
11. Bryson JM, Tasca RA, Rowe-Jones JM. Local and systemic eosinophilia in patients 
undergoing endoscopic sinus surgery for chronic rhinosinusitis with and without polyposis. 
Clin Otolaryngol Allied Sci. 2003;28:55-8. 
12. Kowalski ML, Asero R, Bavbek S, Blanca M, Blanca-Lopez N, Bochenek G, et al. 
Classification and practical approach to the diagnosis and manage-ment of hypersensitivity to 
non-steroidal anti-inflammatory drugs. Allergy. 2013;68:1219-32. 


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13. Mullol J, Picado C. Rhinosinusitis and nasal polyps in aspirin-exacerbated respiratory disease. 
Immunol Allergy Clin North Am. 2013;33:163-76. 
14. Nissen CV, Bindslev-Jensen C, Mortz CG. Hypersensitivity to non-steroidal anti-
inflammatory drugs (NSAIDs): classification of a Danish patient cohort according to 
EAACI/ENDA guidelines. Clin Trans Allergy. 2015;5:10. 
15. Nizankowska-Mogilnicka E, Bochenek G, Mastalerz L, Swierczyńska M, Picado C, Scadding 
G, et al. EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin 
hypersensitivity. Allergy. 2007;62:1111-8. 
16. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report— 
second national institute of allergy and infectious disease/food allergy and anaphylaxis 
network symposium. J Allergy Clin Immunol. 2006;117:391-7.  

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
property of Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the 
recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated 
company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication 
or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ 
meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, 
partnership or other entity 
According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Protocol title: 
A single-arm, 52-weeks, phase 4 study to assess the 
efficacy and safety of dupilumab in patients with 
chronic rhinosinusitis with nasal polyposis 
(CRSwNP) who are not adequately controlled with 
existing therapies 
Protocol number: 
LPS16872 
Compound number 
(INN/Trademark): 
SAR231893 
(dupilumab/Dupixent®) 
Study phase: 
Phase 4 
Short title: 
Dupilumab in Japanese patients with chronic 
rhinosinusitis with nasal polyposis (SINUS-M52) 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
16-JAN-2023
Regulatory agency identifier number(s): 
IND: 
Not applicable. 
EudraCT: 
Not applicable. 
NCT: 
Not applicable. 
WHO: 
Not applicable. 
EUDAMED: 
Not applicable. 
Other: 
Not applicable. 
Total number of pages: 47 
NCT05049122


Statistical Analysis Plan  
16-JAN-2023 
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Version number: 1.0 
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
LIST OF FIGURES .......................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 7 
1.2.1 
Estimands ........................................................................................................................................ 8 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 14 
3 
ANALYSIS POPULATIONS .......................................................................................................... 15 
4 
STATISTICAL ANALYSES ........................................................................................................... 17 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 17 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 18 
4.3 
PRIMARY ENDPOINT ANALYSIS ................................................................................................ 19 
4.3.1 
Definition of endpoints ................................................................................................................... 19 
4.3.2 
Main analytical approach ............................................................................................................... 20 
4.3.3 
Sensitivity analysis ......................................................................................................................... 20 
4.3.4 
Supplementary analyses ................................................................................................................ 20 
4.3.5 
Subgroup analyses ........................................................................................................................ 20 
4.4 
SECONDARY ENDPOINTS ANALYSIS ....................................................................................... 20 
4.4.1 
Key secondary endpoints ............................................................................................................... 20 
4.4.1.1 
Definition of endpoints ................................................................................................................... 21 
4.4.1.2 
Main analytical approach ............................................................................................................... 22 
4.4.1.3 
Supplementary analyses ................................................................................................................ 23 
4.4.2 
Supportive secondary endpoints .................................................................................................... 23 
4.4.2.1 
Definition of endpoints ................................................................................................................... 23 
4.4.2.2 
Main analytic approach .................................................................................................................. 24 
4.5 
TERTIARY/EXPLORATORY ENDPOINTS ANALYSIS ................................................................ 24 


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4.5.1 
Tertiary/Exploratory Endpoints ....................................................................................................... 24 
4.5.2 
Main Analytical approach ............................................................................................................... 25 
4.5.2.1 
Proportion of participants with NPS improvement from baseline ≥1 at Week 52 .......................... 25 
4.5.2.2 
Change from baseline to Week 52 ................................................................................................. 25 
4.5.2.3 
Same as primary and secondary endpoints .................................................................................. 25 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 25 
4.7 
SAFETY ANALYSES ..................................................................................................................... 25 
4.7.1 
Extent of exposure ......................................................................................................................... 25 
4.7.2 
Adverse events .............................................................................................................................. 26 
4.7.3 
Additional safety assessments ....................................................................................................... 30 
4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 30 
4.8 
OTHER ANALYSES ....................................................................................................................... 31 
4.9 
INTERIM ANALYSES .................................................................................................................... 32 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 33 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 33 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 33 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 34 
5.3.1 
Protocol deviations ......................................................................................................................... 34 
5.3.2 
Demographics and baseline characteristics .................................................................................. 34 
5.3.3 
Medical or surgical history ............................................................................................................. 35 
5.3.4 
Disease characteristics at baseline ................................................................................................ 35 
5.3.5 
Prior and concomitant medications ................................................................................................ 36 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 37 
5.4.1 
Demographic formulas ................................................................................................................... 37 
5.4.2 
Disease characteristics formulas ................................................................................................... 38 
5.4.3 
Reference dates ............................................................................................................................. 38 
5.4.4 
Missing Data .................................................................................................................................. 38 
5.4.5 
Timepoint assessment ................................................................................................................... 40 
5.5 
APPENDIX 5 POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA .......... 41 
5.6 
APPENDIX 6 SELECTION CRITERIA FOR AE/MEDICATION GROUPINGS ............................. 45 
6 
REFERENCES ............................................................................................................................... 47 
 


Statistical Analysis Plan  
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Page 4 
LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 5 
Table 2 - Objectives and endpoints ................................................................................................................. 7 
Table 3 - Summary of primary estimand for main endpoints .......................................................................... 9 
Table 4 - Populations for analyses ................................................................................................................ 15 
Table 5 - Endoscopic nasal polyp score ....................................................................................................... 19 
Table 6 - Symptom severity score ................................................................................................................. 21 
Table 7 - Sorting of AE tables ....................................................................................................................... 27 
Table 8 - Analyses of adverse events ........................................................................................................... 28 
Table 9 - Selections for AESIs and other AEs of interest .............................................................................. 29 
Table 10 - Analysis window definition ........................................................................................................... 40 
Table 11 - Criteria for Potentially Significant Abnormalities – for Phase 2/3 studies .................................... 41 
Table 12 - List of PTs or Medications for CMQs/CDGs ................................................................................ 45 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................... 6 
 
 


Statistical Analysis Plan  
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Page 5 
VERSION HISTORY  
This statistical analysis plan (SAP) for study LPS16872 is based on the protocol version 1 dated 
11-May-2021. There are no major changes to the statistical analysis features in this SAP 
compared to those in the protocol. 
This SAP will be finalized before efficacy review. 
Table 1 - Major changes in statistical analysis plan  
SAP Version 
Approval Date 
Changes 
Rationale 
1.0 
22NOV2022 
Not Applicable 
Original version 


Statistical Analysis Plan  
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Page 6 
1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a 52-week, Phase 4, open-label, single-arm, multicenter study to assess the efficacy and 
safety of dupilumab as monotherapy without concomitant intranasal corticosteroid (INCS) in 
approximately 25 participants 18 years and older with chronic rhinosinusitis with nasal  polyposis 
(CRSwNP) not adequately controlled with existing therapies. 
After a screening phase of 2 to 4 weeks, participants will be treated with dupilumab 300 mg q2w 
without concomitant administration of INCS for approximately 24 weeks. For participants who 
have stable disease, the dosing interval can be changed from q2w to q4w at the discretion of the 
Investigator at Week 24. Participants who change from q2w to q4w will not be permitted to return 
to the q2w regimen during this study and will receive the q4w regimen until Week 48. Other 
participants will receive the q2w regimen up to Week 50. The participants will be followed up to 
Week 52. 
Figure 1 - Graphical study design  
 
Study analysis will be conducted after study completion. 


Statistical Analysis Plan  
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Page 7 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To assess the efficacy of 24-week treatment 
with dupilumab 300 mg every 2 weeks (q2w) to 
reduce nasal polyp score (NPS) in participants 
with chronic rhinosinusitis with nasal polyposis 
(CRSwNP) who do not use concomitant 
intranasal corticosteroid (INCS) 
• 
Proportion of participants with NPS improvement from 
baseline ≥1 at Week 24 
Secondary 
 
• 
To assess the efficacy of 24-week treatment 
with dupilumab 300 mg q2w on other efficacy 
endpoints in participants with CRSwNP who do 
not use concomitant INCS 
Key secondary efficacy endpoints: 
• 
Change from baseline to Week 24 in bilateral NPS 
• 
Change from baseline to Week 24 in nasal 
congestion/obstruction (NC) symptom severity score using 
the CRSwNP nasal symptom diary 
• 
Change from baseline to Week 24 in opacification of 
sinuses assessed by computerized tomography (CT) scan 
using the Lund Mackay (LMK) score  
Other secondary efficacy endpoints: 
• 
Change from baseline to Week 24: 
- 
Total symptom score (TSS), a composite score 
derived from the nasal symptom diary (includes nasal 
congestion, loss of sense of smell, anterior and 
posterior rhinorrhea) 
- 
Loss of smell symptom severity score using the nasal 
symptom diary 
- 
Visual analogue scale for rhinosinusitis 
• 
To evaluate the safety of 24-week treatment with 
dupilumab in participants with CRSwNP 
• 
Incidence of treatment-emergent adverse events (TEAEs), 
treatment-emergent serious adverse events (TESAEs), 
and TEAEs leading to treatment discontinuation 
Tertiary/Exploratory 
 
• 
To assess the efficacy of 52-week treatment with 
dupilumab under different dosing regimens to 
participants with CRSwNP who do not use 
concomitant INCS 
• 
Proportion of participants with NPS improvement from 
baseline ≥1 at Week 52 
• 
Change from baseline to Week 52 in bilateral NPS 
• 
Change from baseline to Week 52 in NC symptom severity 
score using the CRSwNP nasal symptom diary 
• 
Change from baseline to Week 52 in opacification of 
sinuses assessed by CT scan using the LMK score 
• 
Change from baseline to Week 52 in TSS 
• 
To evaluate the safety of 52-week treatment with 
dupilumab in participants with CRSwNP 
• 
Incidence of TEAEs, TESAEs, and TEAEs leading to 
treatment discontinuation 
Abbreviations: CRSwNP: chronic rhinosinusitis with nasal polyposis; CT: computerized tomography; INCS: intranasal 
corticosteroid; LMK: Lund Mackay; NC: nasal congestion/obstruction; NPS: nasal polyp score; q2w: every 2 weeks; TEAE: 
treatment-emergent adverse event; TESAE: treatment-emergent serious adverse events, TSS: total symptom score 


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1.2.1 Estimands  
Primary estimand definitions for main endpoints are summarized below in Table 3. More details 
are provided in Section 4. 


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Table 3 - Summary of primary estimand for main endpoints  
Endpoint 
Category  
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
(The missing data handling) 
Population-level summary  
(Analysis method) 
Primary objective: To assess the efficacy of 24-week treatment with dupilumab 300 mg every 2 weeks (q2w) to reduce nasal polyp score (NPS) in participants with chronic 
rhinosinusitis with nasal polyposis (CRSwNP) who do not use concomitant intranasal corticosteroid (INCS) 
Primary endpoint: 
 
Proportion of participants with 
NPS improvement from 
baseline ≥1 at Week 24 
PP 
The intercurrent events will be handled as follows: 
• 
Undergoing surgery for NP or receiving SCS 
for any reason will be considered 
nonresponders for time points after 
undergoing surgery or receiving SCS. 
(composite strategy) 
In addition, the missing data imputation rules are as 
follows: 
Patients having missing data at Week 24 will be 
considered nonresponders.. 
The number of participants and percentage with 95% 
continuity corrected Wilson confidence interval (CI). 
No additional imputation necessary. 
Primary endpoint 
(Supplymentary 
analysis) 
Proportion of participants with 
NPS improvement from 
baseline ≥1 at Week 24 
mITT 
The intercurrent events will be handled as follows: 
• 
Undergoing surgery for NP or receiving SCS 
for any reason for CRSwNP will be 
considered nonresponders for time points 
after undergoing surgery or receiving SCS. 
• 
Receiving intranasal corticosteroids (INCS) 
for CRSwNP up to Week 24 : Participants 
will be considered as non-responders 
(composite strategy). 
In addition, the missing data imputation rules are as 
follows: 
Patients having missing data at Week 24 will be 
considered nonresponders. 
The number of participants and percentage with 95% 
continuity corrected Wilson confidence interval (CI). 
No additional imputation necessary. 
Secondary objective: To assess the efficacy of 24-week treatment with dupilumab 300 mg q2w on other efficacy endpoints in participants with CRSwNP who do not use 
concomitant INCS 


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Endpoint 
Category  
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
(The missing data handling) 
Population-level summary  
(Analysis method) 
Key secondary 
endpoints 
 
Change from baseline to 
Week 24: 
• Bilateral NPS 
• NC symptom severity score 
• LMK score 
PP 
The intercurrent events will be handled as follows: 
• 
Taking rescue medications or undergo 
surgery prior to Week 24: data will be set to 
missing after the medication usage, and the 
participant’s worst postbaseline value on or 
before the time of the medication usage or 
surgery will be used to impute the missing 
Week 24 value (for participants whose 
postbaseline values are all missing, the 
baseline will be used to impute) (hypothetical 
strategy) 
• 
Discontinuing the treatment prematurely 
(Participants who did not take rescue 
medications or undergo surgery): all data 
collected after treatment discontinuation will 
be used in the analysis (treatment policy 
strategy).  
All imputed, complete data will be analyzed by 
descriptive statistics and 95% CI. The summarized 
mean changes obtained from each imputed dataset 
will be combined using Rubin’s rule for a single 
estimate. 


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Endpoint 
Category  
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
(The missing data handling) 
Population-level summary  
(Analysis method) 
Other secondary 
efficacy endpoints 
• 
Change from baseline 
to Week 24: 
• Total symptom score 
• Loss of smell symptom 
severity score 
Visual analogue scale for 
rhinosinusitis 
In addition, the missing data imputation rules are as 
follows: 
• 
After treatment discontinuation due to lack of 
efficacy prior to Week 24: WOCF approach 
will be used to impute the missing Week 24 
value if needed 
• 
After treatment discontinuation due to 
reasons other than lack of efficacy prior to 
Week 24: multiple imputation approach 
assuming missing at random will be used to 
impute the missing Week 24 value, and this 
multiple imputation will use all participants, 
excluding participants who have taken 
rescue medications or undergone surgery on 
or before Week 24 and excluding 
participants who discontinue due to lack of 
efficacy on or before Week 24. 


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Endpoint 
Category  
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
(The missing data handling) 
Population-level summary  
(Analysis method) 
Key secondary 
(Supplymentary 
analysis) 
Change from baseline to 
Week 24: 
• 
Bilateral NPS 
• 
NC symptom 
severity score 
• 
LMK score 
mITT 
The intercurrent events will be handled as follows: 
• 
Taking rescue medications or undergo 
surgery for CRSwNP prior to Week 24: data 
will be set to missing after the medication 
usage, and the participant’s worst 
postbaseline value on or before the time of 
the medication usage or surgery will be used 
to impute the missing Week 24 value (for 
participants whose postbaseline values are 
all missing, the baseline will be used to 
impute) (hypothetical strategy) 
• 
Discontinuing the treatment prematurely 
(Participants who did not take rescue 
medications or undergo surgery): all data 
collected after treatment discontinuation will 
be used in the analysis (composite policy 
strategy).  
In addition, the missing data imputation rules are as 
follows: 
• 
After treatment discontinuation due to lack of 
efficacy prior to Week 24: WOCF approach 
will be used to impute the missing Week 24 
value if needed 
After treatment discontinuation due to reasons other 
than lack of efficacy prior to Week 24: multiple 
imputation approach assuming missing at random will 
be used to impute the missing Week 24 value, and this 
multiple imputation will use all participants, excluding 
participants who have taken rescue medications or 
undergone surgery on or before Week 24 and 
excluding participants who discontinue due to lack of 
efficacy on or before Week 24. 
 


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Endpoint 
Category  
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
(The missing data handling) 
Population-level summary  
(Analysis method) 
 
 
 
 
 
Tertiary/exploratory objective: To assess the efficacy of 52-week treatment with dupilumab under different dosing regimens to participants with CRSwNP who do not use 
concomitant INCS 
 
Proportion of participants with 
NPS improvement from 
baseline ≥1 at Week 52 
PPE 
The intercurrent events will be handled as follows: 
• 
Undergoing surgery for NP or receiving SCS 
for any reason will be considered 
nonresponders for time points after 
undergoing surgery or receiving SCS. 
(composite strategy) 
In addition, the missing data imputation rules are as 
follows: 
Patients having missing data at Week 52 will be 
considered nonresponders.. 
Descriptive statistics 
 
Change from baseline to 
Week 52 in: 
• 
Bilateral NPS 
• 
NC symptom 
severity score 
• 
LMK score 
• 
TSS score 
 
The intercurrent events will be handled as follows: 
• 
Taking rescue medications or undergo 
surgery for NP prior to Week 52: data will be 
set to missing after the medication usage, 
and the participant’s worst postbaseline 
value on or before the time of the medication 
usage or surgery will be used to impute the 
missing Week 52 value (for participants 
whose postbaseline values are all missing, 
the baseline will be used to impute) 
(hypothetical strategy) 
• 
Discontinuing the treatment(Participants who 
did not take rescue medications or undergo 
surgery): all data collected after treatment 
discontinuation will be used in the analysis 
(treatment policy strategy). 
Descriptive statistics 
. 


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2 
SAMPLE SIZE DETERMINATION  
The EFC14280 study, which was conducted as a pivotal study for Nasal Polyposis, the proportion 
of responders (NPS improvement from baseline ≥1) at Week 24 was 62.0% in the dupilumab 
group. Based on this result, the target proportion of responders (NPS improvement from baseline 
≥1) at Week 24 in this postmarketing study is at least 50.0% to reflect the similar effect size 
between EFC14280 and this study. 
It is necessary for 20 participants to achieve this response rate (at least 50%) with a 90% 
probability of success. The sample size was adjusted up to 25 to account for a 20% drop-out rate.  


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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined in Table 4. 
Table 4 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the informed consent form (ICF). 
Enrolled 
The enrolled population includes all participants with a treatment kit number allocated 
and recorded in the interactive response technology (IRT) database, regardless of 
whether the treatment kit was used or not. 
Participants treated without a treatment kit number being allocated will not be 
considered enrolled and will not be included in any efficacy population. 
Intent-to-treat (ITT) 
Enrolled population with chronic rhinosinusitis with nasal polyposis (CRSwNP) 
Modified ITT (mITT) 
All participants in ITT allocated to study intervention administered at least 1 dose of 
study intervention 
Per-protocol (PP) 
All participants in mITT allocated to study intervention administered at least 1 dose of 
study intervention, and who did not receive intranasal corticosteroids (INCS) up to 
Week 24 
Per protocol with extension term (PPE) 
All participants in mITT allocated to study intervention administered at least 1 dose of 
study intervention during the intervention period after Week 24, and who did not 
receive INCS throughout the study 
Safety (SAF) 
All participants allocated to study intervention administered at least 1 dose of study 
intervention before Week 24 
Safety for extension term (SAFE) 
All participants allocated to study intervention administered at least 1 dose of study 
intervention during the intervention period after Week 24 
Population without trial impact 
(disruption) due to COVID-19 
A Population without trial impact (disruption) due to COVID-19 is defined as any 
participant in randomized population: 
- without any critical or major deviation related to COVID-19  
- and who didn’t permanently discontinue treatment due to COVID-19  
- and who didn’t permanently discontinue study due to COVID-19. 
Abbreviations: CRSwNP: chronic rhinosinusitis with nasal polyposis; ICF: informed consent form; INCS: intranasal corticosteroids; IRT: 
interactive response technology; ITT: intent-to-treat; mITT: modified ITT; PP: per protocol; PPE: per protocol with extension term; SAF: safety; 
SAFE: safety for extension term 
Efficacy analyses for the treatment period up to Week 24 will be performed using the per protocol 
(PP) population. Efficacy analyses for the treatment period after Week 24 will be performed using 
the per protocol with extension term (PPE) population. Additionally, supportive efficacy analyses 
will be performed using the modified intent-to-treat (mITT) population. 
Safety analyses for the treatment period up to Week 24 will be performed using the Safety 
population, including all participants allocated to study intervention and administered at least one 
dose of study medication prior to Week 24. Safety analyses for the treatment period after Week 24 
will be performed using the Safety for extension term population, including all participants 
allocated to study intervention administered at least 1 dose of study intervention after Week 24. 


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Participants exposed to study intervention before or without being enrolled will not be considered 
enrolled and will not be included in any analysis population. The safety experience of these 
participants will be reported separately. 
Enrolled participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety populations. 
For any participant enrolled more than once, only the data associated with the first enrollment will 
be used in any analysis population. The safety experience associated with any later enrollment 
will be reported separately. 
Regarding the COVID-19 pandemic, additional summaries by COVID-19 subgroups will be 
provided to assess the impact of the COVID-19 on treatment effect. Participants impacted by the 
COVID-19 pandemic are defined as randomized participants with any critical or major deviation 
related to COVID-19 or who permanently discontinued study intervention or study due to 
COVID-19. 


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4 
STATISTICAL ANALYSES  
The database lock will be performed when all participants have completed their treatment phase. 
Final analyses in the clinical study report will be based on all data collected up to this database 
lock. 
4.1 
GENERAL CONSIDERATIONS  
The baseline value of efficacy parameters is defined as the last available value up to 
enrollment(Visit 2) but prior to the first dose of study medication unless otherwise specified. The 
baseline value of safety parameters is defined as the last available value prior to the first dose of 
investigational medicinal product (IMP). The baseline value of the other parameters is defined as 
the last available value prior to the first dose of IMP if the patient is treated, or the last available 
value up to enrollment if the patient is not exposed to IMP. 
During the treatment term, including efficacy variables after Week 24, continuous variables and 
binary variables for efficacy by each visit will be summarized using descriptive statistics and 
frequency tables in the PP and mITT populations. Analyses up to Week 52 will be run using the 
PPE population, including data through Week 24. 
All safety analyses up to Week 24 will be analyzed for the SAF analysis population. Safety data 
collected during the extension term after Week 24 up to Week 52 will be reported for the SAFE 
analysis population. Safety analyses for the extension term will be presented by dose regimen 
group and overall. 
Observation period  
The observation period will be divided into 2 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. 
• The treatment-emergent period is defined as the period from the first IMP 
administration to the last visit in the study or the date of treatment discontinuation if 
discontinued from the study, whichever is earlier. 
Dose regimen groups  
Dose regimen groups in the extension term after Week 24 will be defined as follows: 
• 300 mg q2w group: participants who were administered at least 1 dose of the 300 mg q2w 
regimen and never experienced q4w administration during the extension term after 
Week 24 
• 300 mg q4w group: participants with stable disease who were administered at least 1 dose 
of the 300 mg q4w regimen during the extension term after Week 24 
 


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Rescue 
Participants who have undergone surgery or received SCS for any reasons are considered rescued. 
NP surgery and SCS use will be determined by the corresponding eCRF pages.  
The date of rescue will be the earliest date of having undergone surgery or received SCS for any 
reason.  
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 4 will 
be summarized. 
Screened patients are defined as any patients who signed the informed consent. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently enrolled. The number (%) of screen failures and reasons for screen failures will be 
provided in the Screened population. 
The number (%) of participants in the following categories will be provided:  
• Screened participants 
• Enrolled participants 
• Enrolled but not exposed participants 
• Enrolled and exposed participants 
• Participants who completed the Week 24 study treatment period as per protocol 
• Participants who did not complete the Week 24 study treatment period as per protocol and 
main reason for permanent treatment discontinuation including due to COVID-19 
• Participants with nasal polyp score (NPS) improvement from baseline to both Weeks 16 
and 24 is ≥ 2 points. 
•  
• Participants who decreased treatment to the q4w regimen 
- 
Participants who completed the Week 52 study treatment period as per protocol 
- 
Participants who did not complete the Week 52 study treatment period as per protocol 
and the main reasons for permanent treatment discontinuation including due to 
COVID-19 
- 
Participants rescued prior to Week 52 by type of rescue 
• Participants who continued the q2w regimen 
- 
Participants who completed the Week 52 study treatment period as per protocol 


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- 
Participants who did not complete the Week 52 study treatment period as per protocol 
and the main reasons for permanent treatment discontinuation including due to 
COVID-19 
- 
Participants rescued prior to Week 52 by type of rescue 
For all categories of participants (except for the screened categories), percentages will be 
calculated using the number of enrolled participants as the denominator.  
4.3 
PRIMARY ENDPOINT ANALYSIS  
4.3.1 Definition of endpoints  
The primary endpoint is the proportion of responders, defined as the proportion of participants 
with a nasal polyp score (NPS) improvement from baseline ≥1, at Week 24. Baseline will be the 
central reading at Visit 2. If a Visit 2 reading is missing, the central reading at Visit 1 will be used. 
The NPS is assessed by central video recordings of nasal endoscopy (NE). The NPS is the sum of 
the right and left nostril scores and is graded based on polyp size as described below 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 should be preceded by local administration of anesthetic drugs in combination with a 
decongestant. NE will be conducted at the Screening Visit (Visit 1), Visit 2, and Visits 4 to 9. 
Standard video sequences will be downloaded or sent to a centralized reader. Centralized imaging 
data assessments and scoring by independent physician reviewer(s) for the imaging data will be 
performed for all endoscopies. To confirm eligibility at Visit 2, only the Visit 1 central reading 
will be made available to the site. In addition, at Visit 2, the Investigator will perform the NE to 
confirm the eligibility score and enter the result in the e-CRF. Thus, the participant will be 
considered eligible based on a Visit 1 central reading followed by a Visit 2 local reading NPS 
score of 5 or more and at least 2 on each side. 
Further details on NE is available in a separate operational manual provided to the sites. 


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4.3.2 Main analytical approach  
The number of participants and percentage with the 95% continuity corrected Wilson confidence 
interval (CI) will be provided at Week 24 using the PP population. 
The main strategy for handling intercurrent events will be a Composite approach, where 
participants who are rescued (undergo surgery for NP or receive SCS for any reason) will be 
considered nonresponders for time points after rescue. Participants who have missing data at 
Week 24 will be considered nonresponders. 
The date of rescue will be the earliest date of any intercurrent events that occur. 
4.3.3 Sensitivity analysis  
There are no sensitivity analyses planned. 
4.3.4 Supplementary analyses  
The primary endpoint, the proportion of responders, defined as the proportion of participants 
with a nasal polyp score (NPS) improvement from baseline ≥1, at Week 24 will be analyzed using 
the mITT population and the following methodologies for intercurrent events: 
• Composite strategy: Censor participants with INCS use, SCS, and surgery for CRSwNP 
prior to Week 24 at the earliest date of all intercurrent events. These participants will be 
categorized as nonresponders at timepoints after the censoring date.  
Missing data related to the primary endpoint will be tabulated including by relation to the 
COVID-19 pandemic. If necessary, additional supplementary analyses will be presented. 
4.3.5 Subgroup analyses  
The number and percent of responders with NPS improvement from baseline ≥1 at Week 24 will 
be presented by the following subgroups within the PP analysis population: 
• Age group (18-64, 65-74, ≥75 years) 
• Gender (Male, Female). 
Intercurrent events and missing data will be handled using the same methodology as Estimand 1 
Participants who receive INCS are excluded from the PP analysis population. Participants who 
undergo surgery for NP, receive SCS for any reason, or have missing data will be considered 
nonresponders for time points after the earliest date of all intercurrent events that occur. 
4.4 
SECONDARY ENDPOINTS ANALYSIS  
4.4.1 Key secondary endpoints  
• Change from baseline to Week 24 in bilateral NPS 


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• Change from baseline to Week 24 in NC symptom severity score using the CRSwNP nasal 
symptom diary 
• Change from baseline to Week 24 in opacification of sinuses assessed by CT scan using 
the LMK score  
4.4.1.1 Definition of endpoints  
Change from baseline to Week 24 in bilateral NPS is defined as the difference between the central 
reading NPS at Week 24 and the central reading NPS at Visit 2. If the central reading value at 
Visit 2 is missing, the central reading value from Visit 1 will be used. 
See Section 4.3.1 for additional details regarding NE. 
Change from baseline to Week 24 in NC symptom severity score: 
On a daily basis from Visit 1 and throughout the study, the participant will use a diary to respond 
to the morning individual rhinosinusitis symptom questions evaluating symptom severity over the 
past 24 hours using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = 
moderate symptoms, and 3 = severe symptoms) as described in Table 6 below. 
Table 6 - Symptom severity score  
Scale 
Symptom severity description 
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) 
A NC symptom severity score ≥2 at Visit 1 and a weekly average severity >1 at the time of 
enrollment (Visit 2) are required and will be provided to the site to determine participant 
eligibility. The participant must have 4 or more measurements collected within 7 days prior to 
enrollment; the baseline will be the average of the non-missing measurements. 
. 
For the baseline to EOT/EOS analysis, the average of the symptom severity scores from the most 
recent 4 weeks before a scheduled visit will be used. 
Change from baseline to Week 24 in LMK score 
Computerized tomography (CT) scan should be performed anytime during the Screening Period 
before the first administration of IMP and at Visits 7 and 9 (Weeks 24 and 52). Whenever 
possible, a cone beam CT scan should be utilized. 
Details for CT are available in a separate operational manual provided to the sites. 


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The LMK system is based on localization with points given for degree of opacification: 0 = 
normal, 1 = partial opacification, 2 = total opacification. These points are then applied to the 
maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinus on each side. The 
osteomeatal complex (OC) is graded as 0 = not occluded or 2 = occluded. Adding the scores of 
these 6 parameters will derive a maximum score of 12 per side (left and right). The total score of 
the 2 sides will be used for analysis. This scoring system has been validated in several 
studies(1)(2)(3). 
For participants in whom the OC is missing (because of a previous surgery), the reader should 
consider the location of the previous OC and provide a score (as if the OC were there). 
4.4.1.2 Main analytical approach  
Handling of missing data 
Each of the 3 key secondary efficacy endpoints will be analyzed using the PP population and a 
hybrid method of worst observation carried forward (WOCF) and multiple imputation. For 
participants taking rescue medications or who undergo surgery, their data after the medication 
usage or surgery will be set to missing, and the worst postbaseline value on or before the time of 
the medication usage or surgery will be used to impute the missing Week 24 value. Participants 
who discontinue the treatment prematurely are encouraged to follow the planned clinical visits, 
and in those participants who did not take rescue medications or undergo surgery, all data 
collected after treatment discontinuation will be used in the analysis. For these participants, 
missing data may still happen despite all efforts to collect the data after treatment discontinuation. 
For participants who discontinue due to lack of efficacy, all data collected after discontinuation 
will be used in the analysis, and a WOCF approach will be used to impute the missing Week 24 
value if needed. For participants who discontinue not due to lack of efficacy, a multiple 
imputation approach assuming missing at random will be used to impute the missing Week 24 
value, and this multiple imputation will use all participants, excluding participants who have taken 
rescue medications or undergone surgery on or before Week 24 and excluding participants who 
discontinue due to lack of efficacy on or before Week 24. All of the imputed complete data will 
be analyzed by descriptive statistics with the 95% CI. The summarized mean changes obtained 
from each imputed dataset will be combined using Rubin’s rule for a single estimate. 
The following steps will be used to create the primary imputed datasets: 
• Impute any missing baseline values with the mean baseline value of all participants with 
non-missing baseline data. 
• For participants who are rescued (undergo surgery for NP or receive SCS for any reason) 
or discontinue treatment early due to lack of efficacy: 
- 
Set all data on or after earliest date of rescue or treatment discontinuation to missing. 
- 
Replace all missing values with the worst observation prior to the missing data through 
Week 24, including baseline values. 
• For participants who are not rescued, discontinue treatment for reasons other than lack of 
efficacy, or complete the study: 


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Create 1 dataset with monotone missing pattern using the Markov Chain Monte Carlo 
(MCMC) method including values at all applicable visits through Week 24 in 
chronological order including baseline. 
• For participants having missing data at Week 24 regardless of reason(s), a multiple 
imputation (MI) approach will be used to impute the missing endpoint value 
• Set both datasets together. 
• The remaining missing data will be imputed 40 times using the regression method for the 
monotone pattern with adjustment for values at all applicable visits through Week 24 in 
chronological order including baseline. 
• Applying Rubin’s rule to combine analysis results (means and standard errors) from 40 
imputations using PROC MIANALYZE for the final estimated mean and 95% CL. 
Missing data related to the key secondary endpoints will be tabulated including by relation to the 
COVID-19 pandemic. If necessary, additional supplementary analyses will be presented. 
4.4.1.3 Supplementary analyses  
The key secondary endpoint, change from baseline to Week 24 for Bilateral NPS, NC symptom 
severity score and LMK score will be analyzed using the mITT population and the following 
methodologies for intercurrent events: 
• Treatment policy strategy: Discontinuing the treatment prematurely (Participants who 
did not take rescue medications or undergo surgery): all data collected after treatment 
discontinuation will be used in the analysis 
• Hypothetical strategy: Taking rescue medications or undergo surgery for CRSwNP prior 
to Week 24: data will be set to missing after the medication usage, and the participant’s 
worst postbaseline value on or before the time of the medication usage or surgery will be 
used to impute the missing Week 24 value (for participants whose postbaseline values are 
all missing, the baseline will be used to impute). 
4.4.2 Supportive secondary endpoints  
• Change from baseline at Week 24: Total symptom score (TSS) 
• Change from baseline at Week 24: Loss of smell severity score 
• Visual analogue scale for rhinosinusitis 
4.4.2.1 Definition of endpoints  
Change from baseline at Week 24 in TSS and Loss of smell severity score 
TSS is a composite score (ranging between 0 and 9) consisting of the sum of the following 
symptoms assessed daily in the morning: nasal congestion/obstruction, decreased/loss of sense of 
smell, and rhinorrhea (average of the non-missing anterior/posterior nasal discharge). At least 2 
symptoms scores must be reported to calculate the TSS, otherwise the score will remain missing. 


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The symptoms scores at baseline and changes from baseline will be calculated using the same 
approach as for NC as described in Section 4.4.1.1. Baseline is defined as the average of the 
non-missing 7 days prior to enrollment and requires ≥4 responses. Timepoints will be evaluated 
using the average symptom severity from the most recent 28 days before each scheduled visit. 
Participants with fewer than 28 days in between visits will use data from one day after the 
previous visit through the day of the current visit. At least 50% of days (with a maximum of 28) 
must be non-missing in order to calculate the average symptom severity. 
Change from baseline to Week 24 in reported Visual analogue scale (VAS) for rhinosinusitis 
The VAS for rhinosinusitis is used to evaluate the total severity (4) based on the distance (cm) 
from 0 to a subject’s response to the following question: 
“How troublesome are your symptoms of your rhinosinusitis?” 
 
The response can be categorized as MILD, MODERATE, and SEVERE based on total severity 
VAS score [0 (Not troublesome) to 10 cm (Worst thinkable troublesome)]: 
• MILD = VAS 0 to 3 cm 
• MODERATE = VAS >3 to 7 cm 
• SEVERE = VAS >7 to 10 cm 
4.4.2.2 Main analytic approach  
The supportive secondary efficacy endpoints (TSS, Loss of smell severity, VAS) will be analyzed 
using similar methodology as the key secondary endpoints using the PP population. Additionally, 
the number and percent of participants with VAS scores ≤7 cm will be presented using similar 
methodology for intercurrent events as the primary endpoint (Estimand 1). 
4.5 
TERTIARY/EXPLORATORY ENDPOINTS ANALYSIS  
4.5.1 Tertiary/Exploratory Endpoints  
• Proportion of participants with NPS improvement from baseline ≥1 at Week 52 
• Change from baseline to Week 52 in bilateral NPS 
• Change from baseline to Week 52 in NC symptom severity score using the CRSwNP nasal 
symptom diary 
• Change from baseline to Week 52 in opacification of sinuses assessed by CT scan using 
the LMK score 
• Change from baseline to Week 52 in TSS 
• Same as primary and secondary endpoints 


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4.5.2 Main Analytical approach  
4.5.2.1 Proportion of participants with NPS improvement from baseline ≥1 at Week 52  
The number of participants and percentage with the 95% continuity corrected Wilson confidence 
interval (CI) will be provided at Week 52 in the PPE analysis population, similar to the primary 
endpoint (Estimand 1). 
Participants who are rescued (undergo surgery for NP or receive SCS for any reason) will be 
considered nonresponders for time points after rescue. Participants who have missing data at 
Week 52 will be considered nonresponders. 
4.5.2.2 Change from baseline to Week 52  
Descriptive statistics for the exploratory efficacy endpoints (NPS, NC symptom severity score, 
LMK score, and TSS at Week 52) will be presented by dose regimen group and overall using the 
PPE analysis population.  
 
4.5.2.3 Same as primary and secondary endpoints  
Primary and secondary endpoints up to Week 24 will be summarized each visit. These endpoints 
after Week 24 up to Week 52 will be summarized each visit by dose regimen group and overall. 
Imputation will not be used. 
4.6 
MULTIPLICITY ISSUES  
No hypothesis testing will be performed within this study. 
4.7 
SAFETY ANALYSES  
4.7.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and compliance and 
summarized within the Safety population until Week 24 and the Safety for extension term 
population after Week24. 
If needed, extent of exposure to investigational medicinal product will be summarized for 
participants experiencing disruption due to COVID-19. 
The participants who received COVID-19 vaccines are summarized. 
Duration of IMP exposure 
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• + 14 days at the time of last IMP for the q2w group and  
• + 28 days at the time of last IMP for the q4w regimen,  
regardless of unplanned intermittent discontinuations. If the date of the last dose of IMP is 
missing, the duration of IMP will be left as missing. 
Duration of IMP exposure will be summarized quantitatively and categorically: 1 to 2 weeks, 3 to 
4 weeks, 5 to 8 weeks, 9 to 12 weeks, 13 to 18 weeks, 19 to 24 weeks, 25 to 30 weeks, 31 to 36 
weeks, 37 to 42 weeks, 43 to 48 weeks, 48 to 52 weeks, and >52 weeks. The duration of treatment 
exposure in weeks will be the duration (in days)/7, rounded to the nearest integer. 
Duration of study will be summarized separately and analyzed descriptively as a quantitative 
variable (number, mean, SD, median, minimum, and maximum). The duration of study is defined 
as date of study completion (or discontinuation) – date of first dose of IMP + 1.  
Treatment compliance 
A given administration will be considered noncompliant if the participant did not take the planned 
number of doses as required by the protocol.  
Percentage of treatment compliance for a participant will be defined as the number of injections (a 
partial injection will be counted as 1 injection) a participant took divided by the total number of 
planned injections from the first to the last injection of IMP *100. Number of planned injections is 
calculated as: 
• For q2w participants, 
1 + (last dose date – first dose date + 1)/14, rounded to the nearest integer 
• For q4w participants, 
1+ [(Week 24 date – 1) – first dose date + 1)/14 + 
 
(last dose date  – Week 24 date + 1)/28, rounded to the nearest integer 
Treatment compliance will be summarized descriptively as quantitative variables (number, mean, 
SD, median, minimum, and maximum). The percentage of participants whose compliance is <60, 
≥60 and <80, ≥80% and ≤100%, or >100% will be summarized. 
4.7.2 Adverse events  
General common rules for adverse events 
All safety analyses up to Week 24 will be analyzed for the SAF. Safety data collected during the 
extension term after Week 24 up to Week 52 will be reported for the SAFE. Safety analyses for 
the extension term will be presented by dose regimen group and overall. 
All adverse events (AEs) will be coded to a lower-level term (LLT), preferred term (PT), high-
level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the latest MedDRA version currently in effect at the time of DBL. 


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AEs will be categorized as: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened or became 
serious during the treatment-emergent period 
• Post-treatment AEs: AEs that developed, worsened or became serious after the treatment-
emergent period. 
Similarly, deaths will be categorized in the pre-treatment and treatment-emergent periods.  
The primary focus of AE reporting will be on TEAEs. Pre-treatment AEs will be described 
separately.  
An AE with incomplete or missing date/time of onset will be classified as a TEAE unless there is 
definitive information to determine it is a pre-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If severity is missing for 1 of the treatment-emergent occurrences of an AE, the 
severity will be imputed as the maximal severity of the other occurrences. If the severity is 
missing for all the occurrences, severity will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase.  
The AE tables will be sorted as indicated in Table 7.  
Table 7 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs.  
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa,  
SMQ/CMQ and PT 
By decreasing frequency of SMQs/CMQs and PTs 
SOC 
By the internationally agreed SOC order 
PT 
By decreasing frequency of PTs 
a The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by SOC and PT, unless otherwise specified. 
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE  
• Any severe TEAE 
• Any TEAE related to IMP 


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• Any treatment emergent SAE 
• Any treatment emergent SAE related to IMP 
• TEAE leading to death 
• Any TEAE leading to permanent treatment discontinuation 
• Any treatment emergent AE of special interest (AESI) 
The AE summaries in Table 8 will be generated with number (%) of participants experiencing at 
least one event.  
Table 8 - Analyses of adverse events  
Type of AE 
MedDRA levels 
Overview 
 
TEAE 
Primary SOC, HGLT, HLT and PT 
 
Primary SOC and PT 
 
Primary SOC 
 
PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC, and PT 
Treatment emergent SAE 
Primary SOC, HGLT, HLT and PT 
TEAE leading to permanent discontinuation 
Primary SOC, HGLT, HLT and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) 
Primary SOC, HGLT, HLT and PT 
TEAE by maximal intensity 
Primary SOC, HGLT, HLT and PT  
Pretreatment AE 
Primary SOC, HGLT, HLT and PT 
Post-treatment AE 
Primary SOC, HGLT, HLT and PT 
TEAE(s) related to COVID-19 
Primary SOC, HGLT, HLT and PT 
TEAE(s) occurred within 2 weeks of a COVID-19 vaccine 
Primary SOC, HGLT, HLT and PT 
a Will include the following AE categories: any AEs, AEs by severity, any related AEs, any serious AEs, any related serious AEs, any AEs 
leading to death, any AEs leading to permanent IMP discontinuation 
Analysis of adverse events of special interest (AESIs) 
Adverse events of special interest (AESIs) will be selected for analyses as indicated inTable 9. 
Number (%) of participants experiencing at least one event will be provided for each event of 
interest, sorted by decreasing incidence of PTs within each SMQ in the 300 q2w . Tables will be 
sorted as indicated in Table 7.  


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Table 9 - Selections for AESIs and other AEs of interest  
AESIs [and other AEs of interest] 
Selection 
AESI 
 
Anaphylactic reactions 
Anaphylactic reaction algorithmic approach (Introductory Guide for 
Standardised MedDRA Queries (SMQs)): includes anaphylactic reaction 
narrow SMQ (20000021) terms and programmatic identification of cases 
based on occurrence of at least two preferred terms meeting the algorithm 
criteria occurring within 24 hours of each other. The latter cases identified 
using the algorithm will undergo blinded medical review taking into account 
the timing of events relative to each other and to IMP administration for final 
determination of an anaphylactic reaction or not. 
Systemic hypersensitivity reactions 
SMQ [20000214] hypersensitivity narrow search and [AE corrective 
treatment/therapy=’Y’ or Action taken with IMP=’Drug withdrawn’ or Action 
taken with IMP=’Drug interrupted’] followed by blinded medical review 
(documented process) for selection of relevant systemic hypersensitivity 
events 
Helminthic infections 
CMQ10544 based on HLGT as “Helminthic disorder” 
Any severe type of conjunctivitis 
CMQ10498 based on PTs (See Section 5.6)a and “Severe” ticked in Adverse 
Events eCRF page 
Any severe type of blepharitis. 
CMQ10497 based on HLT as “Lid, lash and lacrimal infections, irritations and 
inflammations” and “Severe” ticked in Adverse Events eCRF page 
Keratitis 
CMQ10642 based on the following PTs [keratitis, allergic keratitis, ulcerative 
keratitis, atopic keratoconjunctivitis, herpes ophthalmic, ophthalmic herpes 
simplex, corneal infection]a 
Clinically symptomatic eosinophilia (or 
eosinophilia associated with clinical 
symptoms)b 
CMQ10641 based on HLT = Eosinophilic disorders or PT=Eosinophil count 
increased 
Significant ALT elevation 
ALT >5 × the ULN in participants with baseline ALT ≤2 × ULN for age;  
OR ALT >8 × ULN for age if baseline ALT >2 × ULN for age 
Pregnancy of a female subject entered in a 
study as well as pregnancy occurring in a 
female partner of a male subject entered in a 
study with IMP/NIMP 
“Pregnancy” or “Partner Pregnancy” checked on thePregnancy eCRF page as 
reported by the investigator 
Symptomatic overdose (serious or 
nonserious) with IMP/NIMP. 
Symptomatic Overdose is answered Yes, with Overdose of IMP answered Yes 
on AE eCRF. 
 
 
Other selected AE Grouping 
 
Serious injection site reactions or severe 
injection site reactions that last longer than 24 
hours 
HLT = ‘Injection site reaction’ and either with serious status, or with severe 
status and (AE end date/time - AE start date/time) ≥ 24 hours or ongoing 
Severe or serious infection 
Primary SOC = ‘Infections and infestations’ and with severe or serious status 
Parasitic infection 
The Infection Type ‘Parasitic’ was checked on eCRF page "Infection Defined 
as AESI Complementary Form" 
Opportunistic infection 
The Infection Type ‘Opportunistic’ was checked Yes on eCRF page “Infection 
Defined as AESI Complementary Form” 


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AESIs [and other AEs of interest] 
Selection 
Drug-related hepatic disorder 
SMQ [20000006] Drug-related hepatic disorders- narrow 
Injection site reaction 
HLT = ‘Injection site reaction’ 
Suicidal behavior 
CMQ10639 based on the following PTs [Completed suicide, Suicidal ideation, 
Depression suicidal, Suicidal behavior, Suicide attempt]a 
Conjunctivitis (narrow) 
CMQ10644 based on the following PTs [Conjunctivitis, Conjunctivitis allergic, 
Conjunctivitis bacterial, Conjunctivitis viral, Atopic keratoconjunctivitis]a 
Conjunctivitis (broad) 
CMQ10645 based on the following PTs [Conjunctivitis, Conjunctivitis allergic, 
Conjunctivitis bacterial, Conjunctivitis viral, Atopic keratoconjunctivitis, 
Blepharitis, Dry eye, Eye irritation, Eye pruritus, Lacrimation increased, Eye 
discharge, Foreign body sensation in eyes, Photophobia, Xerophthalmia, 
Ocular hyperaemia, Conjunctival hyperaemia]a 
Conjunctivitis (FDA) 
CMQ10643 based on the following PTs [Conjunctivitis, Conjunctivitis allergic, 
Conjunctivitis bacterial, Conjunctivitis viral, Eye irritation, Eye inflammation, 
Giant papillary conjunctivitis]a 
a The list of terms may be adjusted according to MedDRA version changes 
b All cases of Eosinophilia will be included in the analysis, where cases associated with clinical symptoms will be further described in the 
CSR 
4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables and vital signs will be converted into standard international 
units and analyzed.  
• Hematology:  
- 
Red blood cells and platelets and coagulation: [hemoglobin, hematocrit, red blood cell 
count, platelet count  
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• Clinical chemistry: 
- 
Metabolism: glucose, total cholesterol, total protein, albumin, creatine phosphokinase 
- 
Electrolytes: sodium, potassium, chloride  
- 
Renal function: creatinine, blood urea nitrogen, uric acid.  
Creatinine clearance will be derived with the equation of Cockroft and Gault using 
weight assessed at the same visit as creatinine. eGFR will be derived using the 
Modification of the Diet in Renal Disease (MDRD) equation. 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin 
- 
Pregnancy test: Serum and urine β-human chorionic gonadotropin (all childbearing 
potential female participants) 
• Urinalysis: 


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- 
Urinalysis for quantitative analysis: pH, specific gravity, glucose, protein, blood, 
ketones, urobilinogen, nitrite by dipstick  
• Vital signs:  
- 
pulse rate, systolic and diastolic blood pressure, weight, respiratory rate, temperature 
ECG data are used for screening purposes only. 
Data below the lower limit of quantitation/detection limit (LLOQ) will be replaced by half of the 
LLOQ, data above the upper limit of quantification will be replaced by ULOQ value. 
Grading (LLN, ULN) will be derived using local laboratory normal ranges. 
Quantitative analyses 
For all laboratory variables and vital signs above, descriptive statistics for results and changes 
from baseline will be provided for each planned visit during the on-treatment period. These 
analyses will be performed using local measurements, converted into SI units for laboratory 
variables.  
Analyses according to PCSA 
Potentially clinically significant abnormality (PCSA) analyses will be performed based on the 
PCSA list currently in effect at Sanofi at the time of the database lock. Parameters with no PCSA 
criteria defined, similar analyses will be done using the local normal ranges, if applicable.  
Analyses according to PCSA will be performed based on the worst value during the treatment-
emergent period, using all measurements. 
For laboratory variables and vital signs above, the incidence of participants with at least one 
PCSA during the treatment-emergent period will be summarized regardless of the baseline level 
and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
Additional analyses for drug-induced liver injury(if applicable) 
The following additional analyses will be performed for drug-induced liver injury:  
• A graph of the distribution of peak values of ALT versus peak values of total bilirubin 
during the treatment-emergent period will be provided. 
4.8 
OTHER ANALYSES  
No other analyses are planned. 


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4.9 
INTERIM ANALYSES  
No interim analysis is planned. 


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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
CI: 
confidence interval, confidence interval 
CRSwNP: 
chronic rhinosinusitis with nasal polyps 
CT: 
computerized tomography 
HGLT: 
high level group term, high level group term, high level group term, high level 
group term 
HLT: 
high level term 
INCS: 
intranasal corticosteroid 
ITT: 
intent-to-treat 
LLT: 
lower-level term 
LMK: 
Lund Mackay 
MCMC: 
Markov Chain Monte Carlo 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
modified intent-to-treat 
NE: 
nasal endoscopy 
NPS: 
nasal polyp score 
PCSA: 
potentially clinically significant abnormality 
PP: 
per protocol  
PPE: 
per protocol extension 
PT: 
preferred term 
q2w: 
every 2 weeks 
q4w: 
every 4 weeks 
SAF: 
safety population 
SAFE: 
safety population for extension 
SAP: 
statistical analysis plan 
SCS: 
systemic corticosteroid 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
WHO-DD: 
World Health Organization-Drug Dictionary 
WOCF: 
worst observation carried forward 
 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
 
Protocol 
 Version 
Approval 
 Date 
Changes 
Rationale 
1 
11-May-2021 
4.1 GENERAL CONSIDERATIONS 
This is to prevent the case that 
patient discontinues treatment very 


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Protocol 
 Version 
Approval 
 Date 
Changes 
Rationale 
Observation period 
• 
The treatment-emergent period is defined as the 
period from the first IMP administration to the 
last visit in the study or the date of treatment 
discontinuation if discontinued from the 
study, whichever is earlier.   
early, but have a EOS conducted, 
for example, 24 weeks after the 
last IMP. 
 
 
4.1 GENERAL CONSIDERATIONS 
Rescue 
Participants who have undergone surgery or received 
SCS for any reasons, and/or received selected 
prohibited medications are considered rescued. NP 
surgery and SCS use will be determined by the 
corresponding eCRF pages, while selected prohibited 
medications will be determined based on 
corresponding WHODD code in EFC14280.  
The date of rescue will be the earliest date of having 
undergone surgery or received SCS for any reason, 
and/or received selected prohibited medications. 
 
And delete “selected prohibited medications” in the 
sections related to changes to the above definitions. 
For the purpose of consistency with 
EFC14280, it focus the following 
data handling. 
• 
only surgery for NP or 
receive SCS triggers non-
responder imputation 
• 
rescue treatment define as 
undergone surgery or 
received SCS 
 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
5.3.1 Protocol deviations  
Critical and major protocol deviations (automatic or manual), including drug dispensing 
irregularities, will be summarized in the Enrolled analysis population. Protocol deviations due to 
the COVID-19 pandemic will be categorized as such. 
5.3.2 Demographics and baseline characteristics  
Demographic variables are 
• Gender (Male, Female) 
• Race 
• Ethnicity 
• Age in years (quantitative and qualitative variable: 18-64, 65-74, ≥75) 
• Region 
• Weight in kg (quantitative and qualitative variable: <50, 50-<100, ≥100 kg) 


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• BMI in kg/m2 (quantitative and qualitative variable: <30, ≥30 kg/m2)  
Continuous data will be summarized using the number of available data, mean, standard deviation 
(SD), median, minimum, and maximum for all enrolled participants. Categorical and ordinal data 
will be summarized using the number and percentage of participants enrolled. 
Baseline safety and efficacy parameters will be presented along with the safety and efficacy 
summaries.  
5.3.3 Medical or surgical history  
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the participant. 
This information will be coded to a LLT, PT, HLT, HLGT, and associated primary SOC using the 
version of Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at the time 
of database lock. 
Comorbidity will be summarized separately. The following comorbid disease will be summarized 
from eCRF pages completed by investigators based on participant reporting. Asthma will be 
captured under disease characteristics at baseline. 
Medical and surgical history will be summarized for enrolled participants and by SOC and PT, 
sorted by internationally agreed order of SOC and by the decreasing frequency of PT within SOC.  
5.3.4 Disease characteristics at baseline  
The following baseline disease characteristics will be summarized (see Section 5.4.1 for 
calculation details): 
• Time since first diagnosis of nasal polyposis (years) 
• Age of onset at nasal polyposis (years) 
• Number of previous surgeries for nasal polyposis (0, 1, 2, ≥3) 
• Number of previous surgeries for nasal polyposis by type 
- 
Nasal/sinus endoscopy, surgical, with ethmoidectomy, total (anterior and posterior) 
Nasal/sinus endoscopy, surgical, with maxillary and antrostomy with removal of tissue 
from maxillary sinus 
- 
Nasal/sinus endoscopy, surgical, with frontal sinus exploration, with or without 
removal of tissue from frontal sinus 
- 
Nasal/sinus endoscopy, surgical, with maxillary antrostomy 
- 
Nasal/sinus endoscopy, surgical, with sphenoidotomy with removal of tissue from the 
sphenoid sinus 
- 
Nasal/sinus endoscopy, surgical, with sphenoidotomy 


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- 
Nasal/sinus endoscopy, surgical, with ethmoidectomy, partial (anterior) 
- 
Excision, nasal polyp(s), extensive 
- 
Excision, nasal polyp(s), simple 
- 
Excision or destruction (eg,laser), intranasal lesion; internal approach 
• Time since most recent nasal polyposis surgery (years) 
• Smoking history (former, current, never) 
• Cessation prior to screening (months) for former smokers 
• Smoking quantity (cigarettes per day) 
• Frequency of alcohol drinking in the past 12 months (never, occasional, at least monthly, 
as least weekly, at least daily) 
• For daily drinkers, Number of standard alcohol drinks on a typical day (1 or 2, >2) 
• Asthma comorbidity status (Yes, No) 
For asthma participants, the following will be provided: 
- 
Age at onset of asthma (Years) 
- 
Time since first diagnosis of asthma (years)  
- 
Time since last asthma exacerbation (days) 
- 
Number of asthma exacerbations experienced 1 year before visit 1 (comorbid asthma 
patients only, quantitative variable and qualitative variable: 0, 1, 2, 3, ≥4) 
• Number of courses of systemic corticosteroid (SCS) use during the past 2 years (0, 1, 2, 3, 
4, ≥5). A course of SCS is considered continuous if treatment is separated by less than 7 
days. 
• Number of days of SCS use during the past 2 years (0, >0 - ≤7, >7 - ≤14, >14 - ≤21, 21 - 
≤28, >28) 
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 5.4.2. 
Continuous data will be summarized using the number of available data, mean, standard deviation 
(SD), median, minimum, and maximum for enrolled participants. Categorical and ordinal data 
will be summarized using the number and percentage of enrolled participants. 
5.3.5 Prior and concomitant medications  
All medications taken within 30 days prior to screening and until end of the study, including nasal 
polyposis medications, chronic rhinosinusitis medications, asthma medications, and all other 
medications are to be reported in the case report form (CRF) pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD)) 
version currently in effect at the time of database lock. 


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Prior medications are those the participant used prior to first IMP injection. Prior medications can 
be discontinued before first administration or can be ongoing during treatment phase. 
Concomitant medications are any treatments received by the participant concomitantly to the 
IMP, anytime from the first administration of IMP to the end of study. A given medication can be 
classified as a prior medication and a concomitant medication at the same time. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 5.4.4. 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the first 3 
digits of the ATC class (therapeutic category). All ATC codes corresponding to a medication will 
be summarized, and patients will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore, patients may be counted several times for the same 
medication. 
Medication tables will be sorted by decreasing frequency of ATC followed by all other 
therapeutic classes. In case of equal frequency regarding ATCs (anatomic or therapeutic 
categories), alphabetical order will be used. Concomitant medication received during first IMP to 
last IMP +14 days and concomitant medication received during first IMP to end of study will be 
summarized separately.  
Medications will also be summarized by generic name sorted by decreasing frequency. 
COVID-19 vaccines 
The participants who received COVID-19 vaccines are summarized. 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
5.4.1 Demographic formulas  
Age (years) = Year of informed consent - Year of birth 
Age at onset of nasal polyposis (years) =  
 
Year of nasal polyposis diagnosis date - Year of birth 
BMI (kg/m2) = Weight (kg) / height2 (meters) 
They all will be 18 and above per the inclusion, creatinine clearance (CLcr) value will be derived 
using the equation of Cockroft and Gault: 
CLcr (ml/min) =  
 
(140-age) × weight (kg) × (1 - 0.15 × sex(0-M, 1-F)) / (0.814 × creatinine (µmol/l)) 


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CLcr will be calculated using the last weight measurement on or before the visit of the 
 
creatinine measurement and age at the lab sampling date.  
 
Here age is calculated as following: 
 
 
Age = Year of lab sampling date - Year of birth 
5.4.2 Disease characteristics formulas  
• Time since first diagnosis of nasal polyposis (years): 
(Year of enrollment – Year of first diagnosis of nasal polyposis) + (month of enrollment-
month of first diagnosis of nasal polyposis)/12 
• Time since most recent nasal polyposis surgery (years): 
(Year of enrollment – Year of most recent nasal surgery) + (month of enrollment-month of 
most recent nasal surgery)/12 
• Cessation prior to screening (months) for former smokers: 
(Year of enrollment - Year of cessation)×12 + (month of enrollment – month of cessation) 
• For asthma participants, the following will be provided: 
- 
Time since first diagnosis of asthma (years): 
(Year of enrollment - Year of first diagnosis of asthma) + (month of enrollment - 
month first diagnosis asthma)/12Times since last asthma exacerbation (days):  
Date of enrollment - date of last asthma exacerbation 
5.4.3 Reference dates  
The baseline value of efficacy parameters is defined as the last available value up to enrollment 
but prior to the first dose of study medication unless otherwise specified. The baseline value of 
safety parameters is defined as the last available value prior to the first dose of investigational 
medicinal product (IMP). 
5.4.4 Missing Data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
Treatment Duration when IMP end date is missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment case report form page. If this date is 
missing, the exposure duration should be left as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 


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Medication missing/partial dates  
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior and a concomitant medication. 
Adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started prior to 
treatment, the adverse event will be classified as treatment emergent. These data imputations are 
for categorization purpose only and will not be used in listings. No imputation is planned for 
date/time of adverse event resolution. 
Missing date and time of first IMP administration 
When the date and time of the first IMP administration is missing, all adverse events that 
occurred on or after the day of randomization should be considered as treatment-emergent adverse 
events.  
The exposure duration should be kept as missing. 
Missing assessment of relationship of AEs to IMP 
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered. If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
Missing data while evaluating PCSAs 
Participants missing baseline will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 


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5.4.5 Timepoint assessment  
Analysis windows for time points 
For VAS for rhinosinusitis, Vital signs, and Laboratory assessments. The analysis windows post 
baseline of Table 10 will be generated. 
A measurement (scheduled or unscheduled) will be used if it is available and measurement date is 
within the analysis window. 
After applying these time windows, if multiple assessments are associated to the same time point, 
the closest from the targeted study day will be used. If the difference is a tie, the value after the 
targeted study day will be used. If multiple valid values exist within a same day, then the first 
value of the day will be selected. 
If there is no measurement for a given parameter in an analysis window, data will be considered 
missing for the corresponding visit. 
Table 10 - Analysis window definition  
Scheduled 
visit 
post 
baseline 
Target 
day 
Nasal 
endoscopy 
CT 
scan 
VAS for 
rhinosinusitis 
Vital 
signs 
Laboratory 
assessments 
V3 (W2) 
15 
- 
- 
1+ to 21 
- 
- 
V4 (W4) 
29 
1+ to 42 
- 
22 to 42 
- 
- 
V5 (W8) 
57 
43 to 84 
- 
43 to 84 
1+ to 84 
1+ to 112 
V6 (W16) 
113 
85 to 140 
- 
85 to 140 
85 to 140 
- 
V7 (W24) 
169 
141 to 224 
1+ to 265 
141 to 224 
141 to 224 
113 to 265 
V8 (W40) 
281 
225 to 321 
- 
225 to 321 
225 to 321 
- 
V9 (W52) 
364 
322 =< 
266 =< 
322 =< 
322 =< 
266 =< 
1+: after 1st dose date/time 
Unscheduled visits 
Unscheduled visit measurements of laboratory data and vital signs will be used for computation of 
baseline, the last on-treatment value, analysis according to PCSAs, and the shift summaries for 
safety. They will also be included in the by-visit summaries if they are re-allocated to scheduled 
visits. 


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5.5 
APPENDIX 5 POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA  
Table 11 - Criteria for Potentially Significant Abnormalities – for Phase 2/3 studies  
Parameter 
PCSA 
Comments 
Clinical Chemistry 
 
 
ALT 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed 
in ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
AST 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed 
in ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed 
in ULN, not in IU/L. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in 
µmol/L or mg/L. Categories are 
cumulative. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI >1.5 
ULN 
Conjugated bilirubin dosed on a case-
by-case basis. 
ALT and Total Bilirubin 
ALT >3 ULN and TBILI >2 ULN 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment 
phase, whatever the interval between 
measurement. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 


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Parameter 
PCSA 
Comments 
CLcr (mL/min) 
(Estimated creatinine clearance based 
on the Cokcroft-Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study design, 
data analysis, and impact on dosing and 
labeling 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on an MDRD 
equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study design, 
data analysis, and impact on dosing and 
labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L 
(fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not 
provided) 
 FDA Sept 2005. 
Hematology 
 
 


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Parameter 
PCSA 
Comments 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L 
(Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential 
count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L 
(Black) 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN 
≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from 
baseline are more relevant than based 
on absolute value. Other categories for 
decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for 
particular drug development, the 
analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
Urinalysis 
 
 
pH 
≤4.6 
≥8 
 
Vital signs 
 
 
HR 
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from baseline 
≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline 
≥20 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline 
≥10 mmHg 
≥110 mmHg and increase from baseline 
≥10 mmHg 
To be applied for all positions (including 
missing) except STANDING. 


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Parameter 
PCSA 
Comments 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
 
 


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5.6 
APPENDIX 6 SELECTION CRITERIA FOR AE/MEDICATION GROUPINGS  
Table 12 - List of PTs or Medications for CMQs/CDGs  
 
Grouping 
Preferred 
Term/Medication 
Code 
Preferred Term/Medication 
Conjunctivitis 
10001257 
Adenoviral conjunctivitis 
Conjunctivitis 
10010725 
Conjunctival irritation 
Conjunctivitis 
10010726 
Conjunctival oedema 
Conjunctivitis 
10010736 
Conjunctival ulcer 
Conjunctivitis 
10010741 
Conjunctivitis 
Conjunctivitis 
10010744 
Conjunctivitis allergic 
Conjunctivitis 
10010745 
Conjunctivitis chlamydial 
Conjunctivitis 
10010749 
Conjunctivitis gonococcal neonatal 
Conjunctivitis 
10010754 
Conjunctivitis tuberculous 
Conjunctivitis 
10010755 
Conjunctivitis viral 
Conjunctivitis 
10018258 
Giant papillary conjunctivitis 
Conjunctivitis 
10021629 
Inclusion conjunctivitis 
Conjunctivitis 
10030861 
Ophthalmia neonatorum 
Conjunctivitis 
10048908 
Seasonal allergy 
Conjunctivitis 
10049458 
Herpes simplex virus conjunctivitis neonatal 
Conjunctivitis 
10051625 
Conjunctival hyperaemia 
Conjunctivitis 
10053991 
Inclusion conjunctivitis neonatal 
Conjunctivitis 
10061784 
Conjunctivitis bacterial 
Conjunctivitis 
10062889 
Pingueculitis 
Conjunctivitis 
10063669 
Photoelectric conjunctivitis 
Conjunctivitis 
10067317 
Oculorespiratory syndrome 
Conjunctivitis 
10067817 
Acute haemorrhagic conjunctivitis 
Conjunctivitis 
10069166 
Blebitis 
Conjunctivitis 
10071570 
Ligneous conjunctivitis 
Conjunctivitis 
10074701 
Noninfective conjunctivitis 
Conjunctivitis 
10075264 
Oculoglandular syndrome 
Conjunctivitis 
10080825 
Conjunctivitis fungal 
Conjunctivitis 
10084034 
Conjunctival suffusion 
 


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Grouping 
Preferred 
Term/Medication 
Code 
Preferred Term/Medication 
Intravenous immunoglobulin therapy 
CAS 8000012671 
IMMUNOGLOBULIN HUMAN NORMAL 
Intravenous immunoglobulin therapy 
CAS 8000050682 
IMMUNOGLOBULIN, PORCINE 
Intravenous immunoglobulin therapy 
CAS 8000056919 
IMMUNOGLOBULIN G HUMAN 
Intravenous immunoglobulin therapy 
CAS 8600000563 
IMMUNOGLOBULINS NOS 
Intravenous immunoglobulin therapy 
CAS 8600001670 
IMMUNOGLOBULIN HUMAN NORMAL SLRA 
Intravenous immunoglobulin therapy 
CAS 8600001671 
IMMUNOGLOBULIN HUMAN NORMAL IFAS 
Intravenous immunoglobulin therapy 
RECNO 900708 
OTHER IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 900722 
IMMUNE SERA AND IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 900728 
IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 900914 
SPECIFIC IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 901112 
IMMUNOGLOBULINS, NORMAL HUMAN 
 


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6 
REFERENCES  
1. Lund VJ, Mackay IS. Staging in Rhinosinusitis. Rhinology. 1993;31:183-4. 
2. Metson R, Gliklich RE, Stankiewicz JA, Kennedy DW, Duncavage JA, Hoffman SR, et al. 
Comparison of sinus computed tomography staging systems. Otolaryngol Head Neck Surg. 
1997;117:372-9. 
3. Oluwole M, Russell N, Tan L, Gardiner Q, White P. A comparison of computerized 
tomographic staging systems in chronic sinusitis. Clin Otolaryngol Allied Sci. 1996;21:91-5. 
4. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European 
position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. 
Rhinology. 2012;50:1-12.