Conditions: Chronic Rhinosinusitis Without Nasal Polyps Sinusitis Chronic Sinusitis Sinus Disorder Respiratory Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 71
Healthy volunteers: no

Brief summary:
Primary Objective:

To evaluate the efficacy of dupilumab as assessed by the reduction at Week 24 in sinus opacification on computerized tomography (CT) scan in the dupilumab group only

Secondary Objectives:

* To evaluate the efficacy of dupilumab as assessed by the reduction at Week 24 in sinus opacification on CT scan and sinus total symptom score (sTSS) compared to placebo
* To evaluate the safety and tolerability of dupilumab in CRSsNP patients compared to placebo
* To evaluate the pharmacokinetics (PK) of dupilumab in CRSsNP patients compared to placebo
* Assessment of immunogenicity to dupilumab over time compared to placebo

Detailed description:
The duration of study for each participant will include 2-4 weeks of screening period, 24-52 weeks randomized investigational medicinal product (IMP) intervention period and 12 weeks of follow-up period.

Arms:
arm 1: Participants received dupilumab 300 milligrams (mg) via SC injection q2w for up to 53.1 weeks. arm 2: Participants received matching placebo via SC injection q2w for up to 53.2 weeks.

Interventions: intervention 1: Dupilumab SAR231893 intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form:Injection solution Route of administration: Subcutaneous intervention 2: Pharmaceutical form:Injection solution Route of administration: Subcutaneous

Protocol document:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02 
Protocol title: 
A randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of dupilumab in patients 
with uncontrolled, chronic rhinosinusitis without nasal 
polyposis (CRSsNP)  
Protocol number: 
EFC16723 
Amendment number 
02 
Compound number 
(INN/Trademark): 
SAR231893 
Dupilumab/Dupixent® 
Study phase: 
Phase 2 
Short title: 
Dupilumab in CRSsNP 
Acronym: Liberty CRSsNP ORION 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address: 
1 avenue Pierre Brossolette 
91380 Chilly-Mazarin, France 
Monitoring Team’s 
Representative Name 
and Contact 
Information 
Regulatory agency identifier number(s): 
IND: 
105379 
EudraCT: 
2020-003117-35 
NCT: 
NCT04678856 
WHO: 
U1111-1246-7522 
EUDAMED 
Not applicable 
Other: 
Not applicable 
Date: 
23-Feb-2023
Total number of pages: 138 
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Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/ 
countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 02  
All 
23 February 2023, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01  
All 
08 July 2021, version 1 (electronic 1.0) 
Original Protocol 
 
14 September 2020, version 1 (electronic 1.0) 
Amended protocol 02 (23 February 2023) 
This amended protocol 02 (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.  
OVERALL RATIONALE FOR THE AMENDMENT  
Due to difficulties in recruitment, the Sponsor is amending the Phase 2/3 (Part A and B) 
EFC16723 efficacy and safety study to be just a Part A Phase 2 study. The purpose of this 
protocol amendment is to remove Part B and for Part A to modify the number of participants to be 
enrolled, shorten treatment period, modify endpoints, and modify overall study phase. In addition, 
the primary analysis population is being updated to the elevated baseline eosinophils population, 
and consequently the sample size is updated so that we will have approximately 30 participants 
with elevated eosinophils (≥300 cells/mm3), which coupled to the existing low eosinophils 
population will bring the total sample size to 70. Other changes include the modification of 
treatment period and primary and secondary endpoints. The following table outlines the changes 
made to the protocol and the affected sections:   
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
Deleted mentions of and relevant text for Part B of the study, 
including objectives and endpoints for Part B. 
The original study design was Phase 2/3 
with Part A (proof-of-concept Phase 2) 
and Part B (Phase 3) changed to a 
Phase 2 study with removal of Part B.  
Deleted nomenclature for Part A and Part B. 
Clarification for removal of Part B. 
Deleted mentions of and relevant text for adolescents, 
parents, LAR, 200 mg dose, Week 48, and Week 52 at 
applicable instances.  
As consequence of Part B removal, no 
adolescent participant will be enrolled.  
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Section # and 
Name 
Description of Change 
Brief Rationale 
The Part A treatment period has been changed from 52 
weeks to at least 24 and no more than 52 weeks. 
To align with the primary analysis 
timepoint at week 24 and to shorten the 
time to study completion while allowing 
for collection of endpoint data to 
evaluate efficacy in participants with 
CRSsNP. 
Updated sample size from: 
140 participants (approximately 70 per arm) with 
approximately 100 participants with blood eosinophils >= 
300 (approximately 50 per arm) 
To: 
70 participants (approximately 35 per arm) with 30 
participants with blood eosinophils>= 300 (approximately 15 
per arm) 
Due to enrollment difficulties, the 
Sponsor proposes a single part Phase 2 
study with reduced sample size. 
Deleted the phrase “2-part” from the study title. 
Due to protocol change, the Part B 
Phase 3 study will no longer be 
conducted. Part A is modified and 
remains a Phase 2 study. 
Updated study Phase from 2/3 to 2 
Minor editorial and typographical changes wherever 
applicable 
Formatting and typographical 
Updated patient to participant wherever applicable 
Formatting and typographical 
1.1 Synopsis 
Deleted note with below text: 
The primary analysis of Part A at Week 24 (details in Section 
9.6) will be conducted both to provide initial evidence of 
efficacy of dupilumab in adult participants with severe or 
uncontrolled CRSsNP and inform the initiation and design of 
Part B. 
Added new note with below text: 
Modification of the treatment period will result in all patients 
who complete the treatment period being treated for a 
minimum of 24 weeks and a maximum of 52 weeks, or until 
the last patient randomized completes a minimum treatment 
period of 24 weeks. 
Since the purpose of the study has now 
changed from Phase 2/3 to a Phase 2 
and there is no longer need to assess 
efficacy beyond 24 weeks, the 52-week 
treatment period for all participants in 
Part A is now variable between 24 
weeks and 52 weeks. A minimum of   
24-week treatment period for all 
participants allows for reliable 
assessment of the LMK endpoint in 
participants with CRSsNP. 
1.1 Synopsis 
3 Objectives and 
Endpoints 
Updated the primary objective and endpoint from:  
Primary Objective 
To evaluate the efficacy of dupilumab as assessed by the 
reduction at Week 24 in sinus opacification on computerized 
tomography (CT) scan and sinus total symptom score 
(sTSS) compared to placebo 
To: 
To evaluate the efficacy of dupilumab as assessed by the 
reduction at Week 24 in sinus opacification on computerized 
tomography (CT) scan in the dupilumab group only 
Because the reduction in sample size 
does not support reasonable power for 
the symptoms score sTSS and for 
placebo comparison.  
 
 
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Page 4 
Section # and 
Name 
Description of Change 
Brief Rationale 
Moved co-primary endpoint (sTSS) to secondary endpoint 
making LMK score a single primary endpoint with evaluation 
only in the dupilumab group: 
• Change from baseline to Week 24 in opacification of
sinuses assessed by CT scan using the Lund Mackay (LMK)
score
To: 
• Change from baseline to Week 24 in opacification of
sinuses assessed by CT scan using the Lund Mackay (LMK)
score in the dupilumab group
To align with the new primary objective. 
Moved the following co-primary endpoint to a secondary 
endpoint: 
• Change from baseline to Week 24 in the sTSS*
For all the secondary objective and endpoints, deleted the 
Week 52 objective/endpoints and requalified to exploratory, 
except the following endpoints listed below. In addition, in 
the asthma subgroup objective and endpoints removed 
comparison to placebo, and for endpoints evaluating the 
≥300 cells/mm3 population changed to ITT.
• Change from baseline to Week 24 in opacification of
sinuses assessed by CT scan using LMK score
• Change from baseline to Week 24 in sTSS
Given that 15 participants per arm 
(primary analysis population is patients 
with blood eosinophil count ≥300 
cells/mm3) does not support reasonable
power, most endpoints moved to 
exploratory. Removed all 52-week 
endpoints as treatment duration 
shortened to 24 weeks. Certain 
endpoints modified to align with primary 
analysis population modification. Since 
the asthma subgroup will be a small 
subset of the primary analysis 
population, FEV1 and ACQ-6 will be 
evaluated in the dupilumab arm only. 
Deleted the following endpoints: 
Endpoints in the asthma subgroup evaluating LMK and 
sTSS. 
Endpoint in other secondary endpoints in the screening 
blood eosinophil count ≥300 cells/mm3 subgroup
Endpoints evaluating rescue therapy for worsening disease. 
Endpoints removed to reflect changes in 
primary analysis population, reduced 
sample size, and shortened treatment 
duration.  
Added new exploratory objective and corresponding 
endpoint for three-Dimensional CT volumetric assessments 
Additional data analysis relevant for 
evaluation of efficacy. 
1.3 Schedule of 
Activities (SoA) 
Added a note with below text for treatment duration: 
The treatment period will be variable between 24 to 52 
weeks, V6 and V7 are optional for participants. 
This allows flexibility for participants on 
study completion due to variable 
treatment period between 24 weeks and 
52 weeks. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Added following text in footnote ‘h’ applicable to Study 
intervention and Efficacy Assessments:  
Questionnaires in paper form are not permitted; only 
electronic form is allowed.  
The study employs exclusively eCROs 
and ePROs; the statement reflects the 
Sponsor’s prohibition on use of 
questionnaire in paper copy. 
Added following text in footnote ‘h’ applicable to Study 
intervention and Efficacy Assessments:  
Physician assessment UPSIT may not be available at some 
sites for visits; in this case the investigator may omit the test 
for that visit. 
To add flexibility in the UPSIT test 
performance. 
3.1 
Appropriateness of 
Measurements 
Deleted text to reflect that sTSS is not a primary endpoint 
now and added “in the dupilumab group” for LMK primary 
endpoint. 
Added text to reflect that LMK and sTSS when comparing 
dupilumab to placebo are secondary endpoints. 
Text adaptation to endpoint hierarchy 
change. 
4.2 Scientific 
Rationale for Study 
Design 
Updated the following text from: 
… participants regardless of screening blood eosinophil 
counts will be included. While the primary analysis 
population will be the ITT population, the treatment effect of 
dupilumab will also be evaluated on the screening blood 
eosinophil count of ≥300 cells/mm3 population. 
To: 
… a subset of patients with blood eosinophil counts of <300 
cells/mm3 will be randomized while the primary analysis 
population will remain as patients who have peripheral blood 
eosinophil counts ≥300 cells/mm3. 
The primary analysis population will be 
participants with blood eosinophil count 
≥300 cells/mm3 as this is the population 
predicted to have most benefit with 
dupilumab. 
 
4.4 End of Study 
Definition 
Updated study completion definition for participants following 
original protocol, amended protocol 1 and 2 
As consequence of treatment period 
shortening from 52 to 24 weeks. 
5.4 Screen Failures 
Added the below sentence: 
All other screening procedures must be repeated for 
rescreening. 
To clarify to participating clinical sites 
that in case of rescreening all 
procedures need to be repeated, except 
CT scan if within the defined window 
period.  
6.1 Study 
Intervention(s) 
Administered 
Addition of the following sentence: ‘During study visits, the 
IMP is administered on sites after all procedures. 
In order to further clarify that IMP will be 
administered at sites at the time of 
Visits. 
6.5.3 Rescue 
medicine 
Changed from  
Short course OCS (prednisone or equivalent prednisolone 
up to 7 days; avoid use 4 weeks before Week 24 or Week 
52, where applicable). 
To 
Short course OCS (prednisone or equivalent prednisolone 
up to 14 days; avoid use 4 weeks before Week 24 or Week 
52, where applicable). 
To clarify an inconsistency between 
Prohibited medications and Rescue 
medications, the short course of OCS is 
up to 14 days. 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
8.6 
Pharmacodynamics 
Removed measurement of secreted P-glycoprotein. 
Test is unable to be performed 
by the Sponsor due to assay 
limitations. 
9.2 Sample size 
determination 
9.3 Populations for 
analyses 
 
Sample size determination updated.  
Primary population changed from ITT population to ITT 
population with screening blood eosinophil count ≥ 300 
cells/mm3. 
To reflect changes in the study primary 
objective and endpoint.  
9.1 Statistical 
hypotheses 
9.4.1 General 
considerations 
9.4.2 Primary 
endpoint(s) 
Statistical hypotheses removed. 
Multiplicity consideration removed. 
Multiple imputation removed. 
Model-based analyses removed. 
Sensitivity and subgroup analyses removed. 
Use of descriptive statistics for all endpoints. 
To apply more appropriate analysis 
methods based on the reduced sample 
size. 
9.4.2 Primary 
endpoint(s) 
 
The intercurrent events handling strategy for taking SCS for 
any reason prior to Week 24 was changed from ’all data 
collected after SCS use will be used in the analysis’ to ‘data 
after the IE will be set to missing and the worst post-baseline 
value on or before the time of the IE will be used to impute 
missing Week 24 value (WOCF)’. 
To change handling of taking SCS for 
any reason in the primary estimand to 
an approach more appropriate for this 
clinical setting. 
9.4.3 Secondary 
endpoint(s) 
Description of secondary analyses for proportion and time-
to-event endpoints removed. 
To reflect changes in the secondary 
objectives and endpoints. 
9.6 Timing of 
statistical analyses 
Updated the timing of analyses to only one database lock 
after all participants have completed the study. 
To reflect the removal of Part B and 
shortened treatment duration of Part A. 
10.8 Appendix 8: 
Clinician-Reported 
Outcomes and 
Patient-Reported 
Outcomes 
Added new appendices with samples for following 
questionnaires: 
10.8.6 Morning Diary, 
10.8.7 Healthcare Resource Utilization (HCRU) 
questionnaire 
Addition of screenshots of patient 
reported outcome tools to allow 
clarification to sites. 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 02 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 7 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 12 
1 
PROTOCOL SUMMARY ............................................................................................................... 13 
1.1 
SYNOPSIS ..................................................................................................................................... 13 
1.2 
SCHEMA ........................................................................................................................................ 19 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 20 
2 
INTRODUCTION ............................................................................................................................ 25 
2.1 
STUDY RATIONALE...................................................................................................................... 25 
2.2 
BACKGROUND ............................................................................................................................. 26 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 28 
2.3.1 
Risk assessment ............................................................................................................................ 28 
2.3.2 
Benefit assessment ........................................................................................................................ 30 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 31 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 32 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 34 
4 
STUDY DESIGN ............................................................................................................................ 35 
4.1 
OVERALL DESIGN ........................................................................................................................ 35 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 35 
4.2.1 
Participant input into design ........................................................................................................... 36 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 36 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 37 
5 
STUDY POPULATION .................................................................................................................. 38 
5.1 
INCLUSION CRITERIA .................................................................................................................. 38 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 40 
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5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 44 
5.4 
SCREEN FAILURES...................................................................................................................... 44 
6 
STUDY INTERVENTION ............................................................................................................... 45 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 45 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 46 
6.2.1 
Storage and Handling .................................................................................................................... 46 
6.2.2 
Responsibilities .............................................................................................................................. 47 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 47 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 48 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 49 
6.5.1 
Background treatments .................................................................................................................. 49 
6.5.2 
Prohibited medications ................................................................................................................... 50 
6.5.3 
Rescue medicine ............................................................................................................................ 50 
6.6 
DOSE MODIFICATION .................................................................................................................. 51 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 51 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 52 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 52 
7.1.1 
Definitive discontinuation ............................................................................................................... 52 
7.1.2 
Temporary discontinuation ............................................................................................................. 54 
7.1.2.1 
Rechallenge ................................................................................................................................... 54 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 54 
7.3 
LOST TO FOLLOW-UP ................................................................................................................. 55 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 56 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 57 
8.1.1 
Computerized Tomography Scans using Lund-Mackay ................................................................ 57 
8.1.2 
CRSsNP Sinonasal Symptom Diary, including nasal congestion/obstruction, loss of sense 
of smell, anterior and posterior rhinorrhea, facial pain/pressure and headache symptoms .......... 58 
8.1.3 
University of Pennsylvania Smell Identification Test (UPSIT) ....................................................... 58 
8.1.4 
Sino-Nasal Outcome Test-22-Items ............................................................................................... 59 
8.1.5 
Three-dimensional volumetric measurement of the sinuses ......................................................... 59 
8.1.6 
Rhinosinusitis Severity Visual Analog Scale .................................................................................. 59 
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8.1.7 
Asthma Control Questionnaire 6-item version ............................................................................... 60 
8.1.8 
Patient Global Impression of Severity of CRSsNP and Patient Global Impression of 
Change of CRSsNP ....................................................................................................................... 60 
8.1.9 
EuroQol-5 dimensions questionnaire ............................................................................................. 60 
8.1.10 
Health care resource utilization and missed days at work/missed days at school ........................ 61 
8.1.11 
CRSsNP Worsening/Acute Sinusitis .............................................................................................. 61 
8.1.12 
Spirometry ...................................................................................................................................... 61 
8.1.13 
........................................................................................... 61 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 62 
8.2.1 
Physical examinations ................................................................................................................... 62 
8.2.2 
Vital signs ....................................................................................................................................... 62 
8.2.3 
Electrocardiograms ........................................................................................................................ 62 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 62 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 63 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 63 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 64 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 64 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 64 
8.3.5 
Pregnancy ...................................................................................................................................... 65 
8.3.6 
Adverse event of special interest ................................................................................................... 65 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 66 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 66 
8.5 
PHARMACOKINETICS AND IMMUNOGENICITY ASSESSMENTS ............................................ 67 
8.5.1 
Systemic drug concentration and anti-drug antibodies .................................................................. 67 
8.5.1.1 
Sampling time ................................................................................................................................ 67 
8.5.1.2 
Handling procedures ...................................................................................................................... 67 
8.5.1.3 
Bioanalytical method ...................................................................................................................... 67 
8.6 
PHARMACODYNAMICS ............................................................................................................... 68 
8.7 
GENETICS ..................................................................................................................................... 69 
8.8 
 ............................................................................................................................... 69 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................... 70 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 70 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 72 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 72 
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9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 72 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 72 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 73 
9.4.1 
General considerations .................................................................................................................. 73 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 73 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 74 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 74 
9.4.5 
Other safety analyses .................................................................................................................... 74 
9.4.6 
Other analyses ............................................................................................................................... 76 
9.5 
INTERIM ANALYSES .................................................................................................................... 76 
9.6 
TIMING OF STATISTICAL ANALYSES......................................................................................... 76 
9.7 
DATA MONITORING COMMITTEE (DMC) ................................................................................... 76 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 77 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 77 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 77 
10.1.2 
Financial disclosure........................................................................................................................ 78 
10.1.3 
Informed consent process .............................................................................................................. 78 
10.1.4 
Data protection ............................................................................................................................... 79 
10.1.5 
Committees structure ..................................................................................................................... 81 
10.1.6 
Dissemination of clinical study data ............................................................................................... 81 
10.1.7 
Data quality assurance .................................................................................................................. 82 
10.1.8 
Source documents ......................................................................................................................... 82 
10.1.9 
Study and site start and closure ..................................................................................................... 83 
10.1.10 Publication policy ........................................................................................................................... 84 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 85 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 87 
10.3.1 
Definition of AE .............................................................................................................................. 87 
10.3.2 
Definition of SAE ............................................................................................................................ 88 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 89 
10.3.4 
Reporting of SAEs.......................................................................................................................... 91 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 92 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 95 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 96 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 97 
10.7.1 
China .............................................................................................................................................. 97 
10.8 
APPENDIX 8: CLINICIAN-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES .................................................................................................................................. 98 
10.8.1 
Sino-Nasal Outcome Test .............................................................................................................. 98 
10.8.2 
Rhinosinusitis Severity Visual Analog Scale .................................................................................. 99 
10.8.3 
Asthma Control Questionnaire 6-item version ............................................................................. 100 
10.8.4 
Patient Global Impression of Severity (PGIS)/ Patient Global Impression of Change (PGIC) .... 103 
10.8.5 
EuroQol-5 dimensions ................................................................................................................. 104 
10.8.6 
CRSsNP Morning Diary ............................................................................................................... 107 
10.8.7 
Healthcare Resource Utilization (HCRU) questionnaire .............................................................. 109 
10.8.7.1 HCRU questionnaire at Visit 1 ..................................................................................................... 111 
10.8.7.2 HCRU questionnaire at Week 12 ................................................................................................. 114 
10.8.7.3 HCRU questionnaire at Week 24 ................................................................................................. 117 
10.8.7.4 HCRU questionnaire at Week 40 ................................................................................................. 120 
10.8.7.5 HCRU questionnaire at Week 52 ................................................................................................. 123 
10.9 
APPENDIX 9: DEFINITION OF ANAPHYLAXIS ......................................................................... 126 
10.10 
APPENDIX 10: LIST OF OPPORTUNISTIC INFECTIONS......................................................... 127 
10.11 
APPENDIX 11: ABBREVIATIONS ............................................................................................... 128 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 130 
10.12.1 Amended protocol 01 (08 July 2021) ........................................................................................... 130 
10.12.1.1 OVERALL RATIONALE FOR THE AMENDMENT ...................................................................... 130 
11 
REFERENCES ............................................................................................................................. 135 
 
LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 32 
Table 2 - Overview of study interventions administered ............................................................................... 45 
Table 3 - Summary of handling procedures .................................................................................................. 67 
Table 4 - Summary of bioanalytical methods for functional dupilumab and anti-dupilumab antibodies ....... 67 
Table 5 - Populations for analyses ................................................................................................................ 72 
Table 6 - Summary of primary estimand for primary endpoint ...................................................................... 73 
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Table 7 - Protocol-required laboratory assessments .................................................................................... 85 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 19 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A randomized, double-blind, placebo-controlled study to evaluate the efficacy 
and safety of dupilumab in patients with uncontrolled, chronic rhinosinusitis 
without nasal polyposis (CRSsNP) 
Short title: 
Dupilumab in CRSsNP 
Liberty CRSsNP ORION 
Rationale: 
Chronic rhinosinusitis (CRS) is an inflammatory disease of the nasal cavity and paranasal sinuses 
characterized by 2 or more symptoms (lasting for ≥12 weeks), one of which is nasal obstruction or 
nasal discharge (anterior and/or posterior), and may also include facial pressure/pain and/or 
reduced sense of smell. It is estimated to affect approximately 10% of the population in the United 
States (US) and Europe (1, 2). Chronic rhinosinusitis phenotypically is broadly divided into 
2 types based on the presence or absence of nasal polyps: CRS with nasal polyposis (CRSwNP) 
and CRS without nasal polyposis (CRSsNP) (3). Chronic rhinosinusitis without nasal polyposis is 
the most common type of CRS, accounting for approximately two-thirds of the overall CRS 
population (3, 4). 
While the underlying etiopathogenesis of CRSsNP is likely multifactorial, there is a subset of 
CRSsNP patients, representing nearly one-third of the overall CRSsNP population, where the 
disease process appears to be predominantly driven by type-2 inflammation. In this subset of 
type-2 CRSsNP patients, transcriptomic and proteomic analyses of surgical sinonasal tissues 
reveal elevated levels of type-2 inflammatory markers, such as interleukin (IL)-5, 
immunoglobulin E (IgE), eosinophilic cationic protein (ECP), Charcot-Leyden crystal galectin 
(CLC), etc (5, 6, 7). The type-2-associated molecular signature identified in these type-2 CRSsNP 
patients suggests that the underlying pathophysiological disease process is similar to that found in 
CRSwNP patients where it is well known that type-2 inﬂammation with prominent eosinophilia 
and elevated levels of type-2 cytokines, such as IL-4, IL-5, and IL-13, plays a key role in the 
disease process (5, 6, 7, 8, 9, 10). Consistent with the implication of type-2 inflammation 
underlying the disease process in these CRS patients, asthma is a common comorbid condition for 
both CRSsNP and CRSwNP patients, 20% to 40% in the former and 50% to 60% in the latter (4, 
11) and about 52% of CRSsNP patients have comorbid allergic rhinitis (4). Clinical features more 
commonly reported in CRSsNP patients with type-2 endotype include loss of sense of 
smell/reduced taste (5). Comorbid asthma and peripheral blood eosinophilia have been associated 
with higher risk of need for recurrent sinonasal surgery (12, 13).  
Standard medical therapies, including topical and oral corticosteroids (OCS), and antibiotics, do 
not provide adequate or lasting control of the symptoms in many patients with CRSsNP. In a 
study of CRSsNP, 45% of patients “failed” medical therapy, defined as persistent symptoms and 
31% remained symptomatic enough to elect to pursue surgery (14). In the GA2LEN study, 70% to 
80% of patients did not have lasting benefits from the medical therapies (including OCS, 
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antibiotics, and intranasal corticosteroids [INCS]) (11). Also, many CRSsNP patients have 
reported at least one prior surgery or are planning to have surgery in the near future for better 
control of symptoms (11). In patients who have undergone sinonasal surgery, comorbid asthma 
and peripheral blood eosinophilia are risk factors for recurrence of CRS post-operatively (12, 13), 
suggesting that type-2 CRSsNP patients may be more at risk for disease recurrence after surgery. 
Consequently, because of the chronic and unremitting nature of the condition in many patients, 
CRS is associated with a substantial socioeconomic burden that results from the costs of 
diagnostic tests, medical and surgical therapies, lost and reduced school and work productivity, 
and a detrimental impact on physical and emotional health (15).  
Dupilumab blockade of 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) 
(16), asthma (17), eosinophilic esophagitis (EoE) (18), and CRSwNP (19); diseases where type-2 
inflammation is a key driver of the underlying disease process.  
This study will evaluate the clinical efficacy and safety profile of dupilumab administered to 
type-2 CRSsNP patients who are inadequately controlled by or have intolerance/contraindication 
to INCS, systemic corticosteroids (SCS), and antibiotics or sinonasal surgery. 
This study consists of:  
A screening period of up to 4 weeks, followed by a randomized, double-blind, 
placebo-controlled, 2-arm, parallel-group, 24 to 52 -week treatment period. The primary 
endpoint will be assessed at Week 24. Participants who complete treatment will continue 
to a 12-week post-treatment follow-up period. 
Note: Modification of the treatment period will result in all patients who complete the treatment 
period being treated for a minimum of 24 weeks and a maximum of 52 weeks, or until the last 
patient randomized completes a minimum treatment period of 24 weeks.  
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Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of dupilumab as 
assessed by the reduction at Week 24 in sinus 
opacification on computerized tomography (CT) 
scan in the dupilumab group only 
• 
Change from baseline to Week 24 in opacification of 
sinuses assessed by CT scan using the Lund-Mackay 
(LMK) score in the dupilumab group  
Secondary 
• 
To evaluate the efficacy of dupilumab as 
assessed by the reduction at Week 24 in sinus 
opacification on CT scan and sinus total symptom 
score (sTSS) compared to placebo 
• 
Change from baseline to Week 24 in opacification of 
sinuses assessed by CT scan using the LMK score  
• 
Change from baseline to Week 24 in sTSS* 
*Composite severity score consisting of nasal congestion, 
anterior/posterior rhinorrhea, facial pain/pressure items of the 
CRSsNP sinonasal symptom e-diary 
 
• 
To evaluate the safety and tolerability of 
dupilumab in CRSsNP patients compared to 
placebo 
• 
Incidence of treatment-emergent adverse events 
(TEAEs), of treatment-emergent serious AEs 
(TESAEs), and TEAEs leading to treatment 
discontinuation, abnormal laboratory values, and vital 
signs 
• 
To evaluate the pharmacokinetics (PK) of 
dupilumab in CRSsNP patients compared to 
placebo 
• 
Dupilumab concentration in serum 
• 
Assessment of immunogenicity to dupilumab over 
time compared to placebo 
• 
Assessment of immunogenicity to dupilumab as 
determined by the incidence, titer, and neutralizing 
antibody (NAb) status of treatment-emergent anti-drug 
antibody (ADA) response over time compared to 
placebo 
Overall design: 
This is a Phase 2 multicenter study to evaluate the efficacy and safety of dupilumab compared to 
placebo, in participants with uncontrolled CRSsNP. This is a randomized, double-blind, placebo-
controlled study in adult participants regardless of screening eosinophil count to evaluate the 
treatment effect of dupilumab on sinus opacification as assessed by the Lund-Mackay (LMK) 
sinus computed tomography (CT) scan total score, and to provide data on safety.  
All participants in the study (adults only) will enter a screening period (2 to 4 weeks), with 
a 24 to 52 -week treatment period, followed by post-treatment follow-up (12 weeks). 
Approximately 70 adult participants will be randomized 1:1 (approximately 35 participants 
per arm) into 2 treatment groups as follows:  
- 
Arm A: Dupilumab 300 mg every 2 weeks (q2w),  
- 
Arm B: Matching placebo. 
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Randomization will be stratified by screening blood eosinophil count (≥300 cells/mm3 or 
<300 cells/mm3), background INCS use (yes or no) and region.  
To ensure enrollment according to the intended distribution of screening blood eosinophil 
count, alerts will be built into the IRT to control the number of participants in each 
stratification group as follows: 
- 
≥300 cells/mm3: approximately 15 participants per arm, 
- 
<300 cells/mm3: approximately 20 participants per arm. 
In addition, in order to have an adequate number of participants with comorbid asthma, alerts will 
be built into the IRT to limit the number of participants without comorbid asthma to no more than 
70% of the randomized population.  
During the study, participants who report deterioration requiring medical/surgical intervention 
may come to the 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. 
Disclosure Statement:  
This is an interventional study with 2 study treatment arms and the study treatment assignment is 
blinded to the Participant and Investigator.  
Number of participants: 
Approximately 35 participants will be enrolled to each study intervention arm for an estimated 
total of study enrollment of approximately 70 participants. 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process and is 
randomized into the study at Visit 2. Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.  
Intervention groups and duration: 
Study interventions 
Participants who satisfy the inclusion and exclusion criteria will be randomized (1:1) to one of the 
following investigational medicinal product (IMP) treatment groups: 
• Dupilumab 300 mg q2w  
• Matching placebo 
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Duration of study period (per participant): 
• Screening period (2 to 4 weeks) 
• Randomized IMP intervention period (24 up to 52 weeks) 
• Follow-up period (12 weeks) 
Note: The treatment will stop for all participants when the LPI has completed 24 weeks of 
treatment. Therefore, all participants following Amendment 02 will be treated for at least 24 
weeks and the other participants (enrolled before Amendment 02) will have variable treatment 
period and may continue up to 52 weeks. 
Investigational medicinal products: 
• Dupilumab 300 mg and placebo matching dupilumab 300 mg supplied in pre-filled 
syringes that are visually indistinguishable. 
Dupilumab 
Formulation: 
• Dupilumab 300 mg: a 150 mg/mL dupilumab solution in a pre-filled syringe to deliver 
300 mg in a 2 mL injection. 
Route of administration: Subcutaneous (SC) injection. 
Dose regimen: 
• One injection of 300 mg q2w for all adult  
Placebo 
Formulation: 
• Placebo matching dupilumab 300 mg: identical formulation to the active 300 mg 
formulation without dupilumab, in a pre-filled syringe to deliver placebo in a 2 mL 
injection. 
Route of administration: SC injection 
Dose regimen: 
• One injection of placebo matching dupilumab 300 mg q2w  
Post-trial access to study medication: 
Post-trial access to study medication will not be provided. 
Statistical considerations: 
The primary efficacy analysis population will be the ITT population with screening blood 
eosinophil count ≥ 300 cells/mm3 (see Section 9.3). 
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• Primary endpoint: 
In the primary analysis approach for the primary endpoint, for participants who undergo 
sinonasal surgery for CRSsNP or take SCS for any reason, data collected after surgery or 
initiation of SCS will be set to missing and the worst post-baseline value on or before the 
time of surgery or SCS will be used to impute missing Week 24 value (ie, worst 
observation carried forward [WOCF] approach). For participants with no post-baseline 
values, the baseline value will be used. Participants who discontinue the study intervention 
prematurely are encouraged to follow the planned clinical visits and, in these participants, 
who did not undergo surgery or receive SCS, all data collected after study intervention 
discontinuation will be used in the analysis. No missing data will be imputed. Descriptive 
statistics and 95% CI in the dupilumab group will be provided.  
Main secondary endpoints: 
The change from baseline to Week 24 in the secondary efficacy endpoints will be analyzed 
using the same analysis approach as for the primary endpoint. For endpoints comparing 
dupilumab to placebo, 95% CI of the treatment difference will be provided 
The safety variables, including adverse events (AEs), laboratory parameters, and vital 
signs, will be summarized using descriptive statistics. 
Data Monitoring Committee: Due to the extensive safety record of the post-marketed IMP 
(dupilumab), it is not planned to have a Data Monitoring Committee for this study. 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Procedure 
Screening 
(2 to 4 weeks 
before Day 1) 
D-28 
Intervention Period (Weeks) 
Follow-up 
W36 to W64 
(12 weeks)a 
Notes 
 
 
W0 
W2 
W12 
W24 
W40 
W52 
 
 
Visit 
1 
2b 
3 
4 
5 
6a 
 
7 
(EoT)a c 
8 (EOS) 
Visit window: +3 days for Visit 2, ±3 
days for visits 3 to EOT, and ±5 days 
for EOS 
Informed consentd 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Recheck clinical status before 
randomization 
Participant demographics 
X 
 
 
 
 
 
 
 
 
Full physical examination  
X 
X 
 
 
X 
 
X 
 
Including skin (full body skin exam), 
nasal cavities, eyes, ears, 
respiratory, cardiovascular, 
gastrointestinal, neurological, 
lymphatic, and musculoskeletal 
systems 
Medical/surgical historye 
X 
 
 
 
 
 
 
 
 
Record planned endoscopic 
sinus surgeryf 
-----------------------------------------------------------------------------------------------------------------------------→ 
 
Nasal endoscopyg 
X 
 
 
 
 
 
 
 
Central reading for excluding polyps 
and local reading for excluding 
purulent discharge  
Prior/concomitant/rescue 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
Check INCS background medication 
at screening and throughout the 
study period. Record rescue therapy 
if applicable 
Randomization 
 
X 
 
 
 
 
 
 
 
Log-in to IRT 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study interventionh,i  
IMP administrationj 
 
---------------------------------------------------------------------------→ 
 
IMP will be administered every 14 ±3 
days (q2w). Between visits at site 
home administration is allowed after 
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appropriate training of the participant 
(or caregiver). The planned last dose 
is up to Week 50. 
Efficacy assessmentsh 
CT scank 
X 
 
 
 
X 
 
X 
 
Initial CT scan to be done during 
screening period, results should be 
available prior to randomization 
(Visit 2).  
Dispense or download daily 
diary for symptomsl 
X 
X 
X 
X 
X 
X 
X 
X 
Device will be dispensed at screening 
(including instructions for use). At 
EOS, the e-diary will be returned to 
the site. 
CRSsNP Symptom Diary 
(includes nasal 
congestion/obstruction, facial 
pain/pressure, anterior and 
posterior rhinorrhea; sTSS 
derived from these 4 items, as 
well as loss of smell and 
headache)l,m  
------------------------------------------------------------- Daily Diary----------------------------------------------------------→ 
Every day (morning assessment) as 
of screening. Participant will continue 
to assess daily symptoms during 
follow-up (important to assess 
disease relapse after treatment) 
Sino-Nasal Outcome Test-22 
item (SNOT-22)m 
 
X 
 
 
X 
X 
X 
X 
 
University of Pennsylvania 
Smell Identification Test 
(UPSIT) 
 
X 
X 
 
X 
X 
X 
X 
Baseline value to be collected ahead 
of first dose IMP 
Rhinosinusitis Severity Visual 
Analog Scalem 
 
X 
X 
 
X 
X 
X 
X 
 
EQ-5D-5Lm 
 
X 
 
 
X 
X 
X 
 
 
Spirometryn 
X 
X 
 
X 
X 
 
X 
X 
At Visit 1, all participants will have 
spirometry to confirm exclusion 
criteria. Afterwards spirometry will be 
locally collected and read in 
participants with asthma only. 
Asthma Control Questionnaire 
([ACQ-6] participants with 
comorbid asthma)m 
 
X 
 
X 
X 
X 
X 
X 
 
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Health Care Resource 
Utilization/Productivity 
(HCRU/P) 
 
X 
 
X 
X 
X 
X 
 
Health Care Resource 
Utilization/Productivity will be 
captured in the eCRF 
Patient global impression of 
severity (PGIS)m 
 
X 
 
X 
X 
X 
X 
 
 
Patient global impression of 
change (PGIC)m 
 
 
 
X 
X 
X 
X 
 
 
Safety assessmentsh 
Vital signso 
X 
X 
X 
X 
X 
X 
X 
 
Height at V1 only 
12-Lead ECG 
X 
 
 
 
 
 
 
 
Locally collected and read 
AE review 
------------------------------------------------------------------------------------------------------------------------------------------→ 
 
SAE reviewp 
------------------------------------------------------------------------------------------------------------------------------------------→ 
 
Laboratory testing 
Laboratory assessmentsq 
X 
X 
 
X 
X 
X 
X 
 
Includes hematology, serum 
chemistry, liver function tests 
Urinalysis (urine dipstick) q 
X 
X 
 
X 
X 
X 
X 
 
For participants enrolled in China, the 
urine analysis will be performed at 
laboratory (not dipstick) 
HBV, HCV, HIV, TB testingr 
X 
 
 
 
 
 
 
 
TB test (performed locally if required 
and results noted in the eCRF) 
Pregnancy test (WOCBP only)s  
X 
X 
 
X 
X 
X 
X 
 
Serum pregnancy test at screening 
and then urine pregnancy test at Visit 
2 and every 4 weeks thereafter. It 
can be done by participant at home 
between on-site visits and after 
training 
Sampling for serum drug 
concentration (PK)p  
 
X 
 
X 
X 
 
X 
 
 
Antidrug antibody (ADA) 
samplingp 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
Spot urine test, if applicable 
 
 
X 
 
X 
X 
 
X 
 
 
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Nasal brushing for RNA and 
cytologyu 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
Optional 
 
 
X 
 
 
 
 
 
 
Optional 
 
X 
 
 
X 
 
X 
 
Optional for adults only  
ACQ-6:Asthma Control Questionnaire 6-question version, ADA: anti-drug antibody, AE: adverse event, AESI: adverse event of special interest, CRSsNP: chronic rhinosinusitis without nasal polyposis, 
CT: computerized tomography, COVID-19: Coronavirus Disease 2019, D: day, DBP: diastolic blood pressure, ECG: electrocardiogram, eCRF: electronic case report form, EOS: end of study, EOT: end of treatment, 
EQ-5D-5L: 5-level version of the EuroQol 5 dimensions European quality of life-5D scale, FEF: forced expiratory flow, FEV1: forced expiratory volume, FVC: forced vital capacity, HBcAb: hepatitis B core antibody, 
HBsAb: hepatitis B surface antibody, HBsAg: hepatitis B surface antigen, HBV: hepatitis B virus, HCRU/P: Healthcare Resource Utilization/Productivity, HCV: hepatitis C virus, HCVAb: hepatitis C virus antibodies, 
HIV: Human Immunodeficiency Virus, IEC: independent ethics committee, Ig: immunoglobulin, IRB: institutional review board, IMP: investigational medicinal product, IRT: interactive response technology, INCS: 
intranasal corticosteroids, LABA: long-acting beta-agonists; LAMA: long-acting muscarinic acetylcholine, LTE4: leukotriene 4, PGDM: prostaglandin D2 metabolite, PGIS: patient global impression of severity, PGIC: 
patient global impression of change, PK: pharmacokinetic, PRO: patient-reported outcome, q2w: every 2 weeks, SAE: serious adverse event, SBP: systolic blood pressure, SC: Subcutaneous, SCS: systemic 
corticosteroids, sTSS: sinus Total Symptom Score, SNOT-22: Sino-Nasal Outcome Test – 22 item, TB: tuberculosis, TARC: thymus-and activation-regulated chemokine, UPSIT: University of Pennsylvania smell 
identification test, VAS: visual analog scale, V: Visit, W: week, WOCBP: women of childbearing potential.  
a The treatment period will be variable between 24 to 52 weeks; therefore, follow up may be between 36 to 64 weeks. V6 and V7 are optional for participants given variable treatment period. 
b All assessments at Randomization Visit (V2) are to be conducted pre-IMP dose with the exception of the assessment of local tolerability of subcutaneous (SC) injections. 
c Participants who discontinue the study treatment prematurely (prior to completing Week 24 of treatment period) will perform the end of treatment (EOT) assessments at the time of discontinuation to assure a 
complete clinical assessment in close temporal proximity to the premature termination of study treatment. In addition, to allow assessment of participant outcomes over the stipulated study period, participants will 
be asked and encouraged to complete all remaining study visits and participate in all assessments according to the visit schedule.  
d Consent to be obtained for optional procedures (whole blood DNA, whole blood RNA sampling, and serum/plasma sampling for archival; human immunodeficiency virus (HIV) test if specific consent locally 
required). 
e Past medical history including allergic comorbidities (asthma, aspirin sensitivity, allergic rhinitis etc). Surgeries will be assessed including type and dates of sinonasal surgeries in the past. Systemic corticosteroids 
(SCS) use (number of courses, doses, way of administration and duration) in the past 2 years before V1 and/or contraindication/intolerance to SCS, as well as long-term antibiotics use (>2 weeks) in the previous 
year will be entered in the electronic case report form (eCRF).  
f 
Details on actual or planned date for surgery type and outcome (whenever possible) of surgery will be recorded in a specific eCRF page. If surgery is performed during the study treatment period or follow-up an 
adverse event (AE) or serious adverse event (SAE) page will be completed. Participants will be discontinued from study treatment and assessed as soon as possible using the procedures normally planned for the 
EOT Visit. If surgery is scheduled after the planned end of study, a follow-up contact(s) may be required to document the surgery date and outcome. 
g Nasal endoscopy: Endoscopy (including use of decongestants before the procedure) will be performed at Screening Visit only for eligibility confirmation. At V2, Investigator will review V1 results from central reader 
to confirm entry criteria and reconfirm eligibility based on review of inclusion/exclusion criteria.  
h Assessments/procedures should be conducted in the following order: Patient-Reported outcome (PRO) assessments, Investigator assessments, safety and laboratory assessments (including sample collection for 
ADA, PK, biomarker, and optional DNA and RNA), and administration of IMP. Questionnaires in paper form are not permitted; only electronic form is allowed. Physician assessment UPSIT may not be available at 
some sites for visits; in this case the investigator may omit the test for that visit. 
i 
In case of emergency (eg, natural disaster, pandemic) remote visit could be considered (eg, homenursing, telehealth, except for baseline and Week 24) and will be documented in the participant’s study file. 
Arrangements could also be made for qualified site personnel and/or health care professionals (eg, visiting nurse service) to collect study samples, administer IMP at participant’s home or perform study 
examinations as needed. “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on the conduct of clinical trials, some laboratory tests and clinical assessment procedures can be considered to 
conduct locally per local regulatory requirement. 
j 
Refer to Section 4 for details on treatment arms. The IMP will be administered after completion of all scheduled clinical assessments and sample collections at the visit or at home. 
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k A CT scan should be performed during screening period (before first administration of IMP), at V5 (Week 24), , and central reading will be used for comparison of baseline to Week 24 for the primary analysis. In 
countries for which a specific approval procedure for the CT scan is required by a different committee than the IEC/IRB, these countries will be exempted from all the planned study CT scans until approval from 
these committees is received. A 4-month window must be required between 2 CT scans. It is recommended to avoid use of OCS as rescue therapy during the Week 20 to Week 24 or the Week 48 to Week 52. If a 
participant must use OCS during this period to control CRSsNP worsening/acute sinusitis based on Investigator judgment the site should make every effort to schedule the Week 24th CT scan prior to OCS rescue 
therapy. 
l 
An electronic diary (ie, CRSsNP sinonasal symptom diary) is used for daily recording of nasal symptoms (from V1 to EOS): 1) nasal congestion/obstruction 2) anterior rhinorrhea (runny nose), 3) posterior 
rhinorrhea (post-nasal drip), 4) loss of sense of smell, 5) facial pain/pressure, and 6) headache. This device is dispensed at V1, and information is downloaded from this device on the other indicated days. For 
sTSS (nasal congestion, anterior/posterior rhinorrhea, facial pain/pressure), a score of ≥5 at Visit 1 (day score) and at Visit 2 (weekly average score) is required. 
m During the study the PROs should be completed by the participants in the e-diary before seeing the physician, in the following order: The CRSsNP sinonasal symptom diary (Nasal congestion, loss of sense of 
smell, rhinorrhea, facial pain/pressure) and a headache symptom; SNOT-22; rhinosinusitis severity VAS; PGIS, PGIC, EQ-5D-5L, and ACQ-6 (in participants with asthma)  
n Spirometry (FEV1, FVC, and FEF 25 to 75): should be performed before randomization for all participants, locally after withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for 6 hours 
and long-acting muscarinic acetylcholine (LAMA) receptor antagonists and Long-Acting Beta-Agonists for 24 hours. All participants should have the result of FEV1 (% of predicted normal) recorded in eCRF before 
V2. Participants with FEV1 of 50% or less (of predicted normal) will not be randomized. For the other scheduled visits during the randomized treatment period, spirometry will be performed only in participants with 
asthma; and the result of FEV1, FVC, and FEF 25 to 75 will be recorded in the eCRF at the study scheduled visits. 
o Vital signs, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per minute), body temperature (degrees Celsius), and body weight (kg), will be measured at the screening (V1), 
randomization visits (V2) and subsequent visits prespecified in the flow-chart. Height (cm) will be measured at V1 only. Vital signs will be measured in a semi-supine or sitting position using preferably the same 
arm at each visit prior to receiving IMP at the clinic visits.. 
p At indicated visit serum dupilumab concentration and ADA assessment samples will be collected and archived prior to administration of IMP during the randomized treatment period. In the event of a suspected 
SAEs or AESIs like anaphylaxis or hypersensitivity, AE of severe injection site reaction lasting longer than 24 hours, or systemic allergic reaction that is related to IMP and that requires treatment, additional PK and 
ADA samples may be collected closer to the event, based on the judgment of the medical Investigator and/or Sponsor or Sponsor representative(s). Pharmacokinetic and ADA samples will be collected unless 
restricted due to local regulation. However, the PK and ADA sample will be collected for safety assessment in the event of a SAE.  
q Refer to Section 10.2 and central laboratory manual for collection details.  
r 
Clinical laboratory testing at V1 includes hepatitis screen covering hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb) including total HBcAb, hepatitis C 
virus antibodies (HCVAb), HIV screen (anti-HIV-1 and HIV-2 antibodies). In case of results showing HBsAg (negative) and HBcAb (positive), an HBV DNA testing will be performed and should be confirmed 
negative prior to randomization. In case of results showing HCVAb (positive), HCV RNA testing will be performed and should be confirmed negative prior to randomization. 
s Serum pregnancy test at V1 and urine pregnancy tests at Visit 2 and every 4 weeks thereafter. A negative result must be obtained between V1 and V2 prior to randomization. Urine pregnancy test could be 
performed at home with or without the assistance of a home care provider. In case of positive urine test, the study treatment will be withheld and a serum pregnancy test should be performed as soon as possible, 
to confirm the pregnancy. 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 interleukin 4 receptor alpha 
subunit (IL-4Rα), which is a component of IL-4 receptors type-1 and Type-2, as well as the IL-13 
Type-2 receptor. The binding of dupilumab to IL-4Rα results in blockade of IL-4 and IL-13 
intracellular signaling.  
As a targeted/specific immunomodulatory agent, dupilumab is expected to 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 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 (eosinophilic phenotype) in adults. 
2.1 
STUDY RATIONALE  
Dupilumab blockade of IL-4 and IL-13 signaling has demonstrated a favorable efficacy and an 
acceptable safety profile for the treatment of a variety of atopic disease states, including AD (16), 
asthma (17), EoE (18), and CRSwNP (19), 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 adult participants with severe CRSwNP have demonstrated that dupilumab 
300 mg q2w is significantly better than placebo for the reduction of polyp size, sinus 
opacification, and severity of symptoms, and is generally well tolerated (19). Similarly, in the 
dupilumab asthma Phase 3 study that included both adult and adolescent participants, dupilumab 
significantly reduced the adjusted annualized rate of severe asthma exacerbations compared to 
placebo in pre-specified subgroups of participants with elevated blood eosinophil counts and high 
Fractional exhaled nitric oxide (FeNO) levels, both markers of Type-2 inflammation (17). Of 
note, in the asthma Phase 3 study EFC13579 (QUEST), a subset of asthma patients with CRSsNP, 
treated, with dupilumab appeared to have greater improvement in Sino-Nasal Outcome 
Test-22-item (SNOT-22) from baseline to Week 24 compared with placebo-treated participants. 
Compared with placebo, dupilumab also led to greater suppression of markers of Type-2 
inflammation, including FeNO, IgE, and thymus-and activation-regulated chemokine (TARC) 
levels, in the subset of asthma patients with CRSsNP in EFC13579 (20). The totality of the data 
from the completed AD, asthma, and CRSwNP clinical development programs indicates that 
dupilumab has broad therapeutic benefit in various conditions with strong Type-2 immunologic 
signatures. 
The key objective of this study will be to evaluate the clinical efficacy and safety profile of 
dupilumab administered to type-2 CRSsNP patients with difficult-to-treat disease.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of dupilumab is 
provided in the Investigator’s Brochure (IB). 
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2.2 
BACKGROUND  
Chronic rhinosinusitis is an inflammatory disease of the nasal cavity and paranasal sinuses 
characterized by 2 or more symptoms (lasting for ≥12 weeks), one of which is nasal obstruction or 
nasal discharge (anterior and/or posterior) and may also include facial pressure/pain and/or 
reduced sense of smell. It is estimated to affect approximately 10% of the population in the US 
and Europe (1, 2); based on real-world data a large majority of CRSsNP patients are adults 
(≥18 years old). However, lower estimates for symptomatic patients are reported; in the US, the 
percentage of the population that met the initial symptom criteria compatible with a diagnosis of 
CRS was reported at 2.1% (21). Chronic rhinosinusitis phenotypically is broadly divided into 2 
types based on the presence or absence of nasal polyps: CRSwNP and CRSsNP (3). Chronic 
rhinosinusitis without nasal polyposis is the most common type of CRS, accounting for 
approximately two-thirds of the overall CRS population (3, 4). 
While the underlying etiopathogenesis of CRSsNP is likely multifactorial, there is a subset of 
CRSsNP patients, representing nearly one-third of the overall CRSsNP population, where the 
disease process appears to be predominantly driven by type-2 inflammation. In this subset of 
type-2 CRSsNP patients, transcriptomic and proteomic analyses of surgical sinonasal tissues 
reveal elevated levels of Type-2 inflammatory markers, such as IL-5, IgE, ECP, CLC, etc (5, 6, 
7). The Type-2-associated molecular signature identified in these Type-2 CRSsNP patients 
suggest that the underlying pathophysiological disease process is similar to that found in 
CRSwNP patients, where it is well known that Type-2 inﬂammation with prominent eosinophilia 
and elevated levels of Type-2 cytokines, such as IL-4, IL-5, and IL-13, plays a key role in the 
disease process (5, 6, 7, 8, 9, 10).  
Several reports suggest peripheral blood eosinophilia is well correlated with tissue Type-2 
inflammation (sinus tissue eosinophilia) in CRS patients with or without nasal polyps (22, 23, 24, 
25, 26). In one cohort, receiver operating characteristic (ROC) curve analysis predicted high tissue 
eosinophilia from ethmoid sinus biopsies (>10/high power field [HPF]) using a peripheral blood 
eosinophil cutoff level of 240 cells/mm3 (sensitivity 70.9%, speciﬁcity 78.4%, AUC: 0.792, 
p<0.01). This cutoff level produced a positive predictive value (PPV) of 83.0%, negative 
predictive value (NPV) of 64.5%, positive likelihood ratio (LR+) of 3.28 (24). Similarly, in 
another cohort, a cutoff value of 215 cells/mm3 for the absolute blood eosinophil count yielded a 
sensitivity of 74.2% and a specificity of 86.5%, PPV of 80.3% and NPV of 81.9%, LR+ of 5.51 
(25). Generally, a higher cutoff for peripheral blood eosinophil count is associated with greater 
specificity, but correspondingly lesser sensitivity, for identifying Type-2 inflammation 
(eosinophilia) in sinus tissue.  
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Consistent with the implication of type-2 inflammation underlying the disease process in these 
CRS patients, asthma is a common comorbid condition for both CRSsNP and CRSwNP patients: 
20% to 40% in the former and 50% to 60% in the latter (4, 11), and about 52% of CRSsNP 
patients are reported to have comorbid allergic rhinitis (4). Fractional exhaled nitric oxide has 
been reported to be significantly correlated with other markers of type-2 inflammation, including 
elevated peripheral blood eosinophil counts and tissue eosinophilia, which also correlates with 
LMK scores in patients with CRS (27). Fractional exhaled nitric oxide has been noted to be 
elevated in CRSwNP patients with tissue eosinophilia independent of a diagnosis of asthma (27). 
Further peripheral blood eosinophilia, ≥300 cells/mm3 (sensitivity 70%, speciﬁcity 70%), has 
been reported as a predictor of bronchial hyperresponsiveness in CRSsNP patients without a 
diagnosis of asthma (22). Comorbid asthma and peripheral blood eosinophilia have been 
associated with a higher risk of need for recurrent sinonasal surgery and need for systemic therapy 
after sinus surgery (12, 13, 28). Other clinical features more commonly reported in CRSsNP 
patients with type-2 endotype include loss of sense of smell/reduced taste; the type-2 CRSsNP 
patients also have more complaints of headache/migraine as compared with the non-type-2 
CRSsNP patients (5). 
The pathological hallmark of CRSsNP-associated upper airway disease is mucus secretion and 
goblet cell and glandular hyperplasia. Goblet cells are responsible for the production of mucin 
5AC, one of the main secreted mucins in the human airway (29). The increase in mucous gland 
density that occurs in patients with severe CRSsNP is in contrast to those with CRSwNP who 
show a signiﬁcant decrease in mucous gland density (30, 31, 32, 33). Glandular hypertrophy and 
mucous secretion in the airway mucosa are likely to be mediated by various cytokines, including 
IL-13 (34, 35, 36). 
Standard medical therapies, including topical and oral corticosteroids, and antibiotics, do not 
provide adequate or lasting control of the symptoms in many patients with CRSsNP. In a study, 
45% of patients “failed” medical therapy, defined as persistent symptoms; and 31% remained 
symptomatic enough to elect to pursue surgery (14). In the GA²LEN study, 70% to 80% of 
patients do not sustain adequate benefits from the medical therapies (including OCS, antibiotics 
and INCS) (11). Also, many CRSsNP patients have reported at least 1 prior surgery or are 
planning to have surgery in the near future for better control of symptoms (11). In patients who 
have undergone sinonasal surgery, comorbid asthma and peripheral blood eosinophilia are risk 
factors for the recurrence of CRS post-operatively (12, 13), suggesting that CRSsNP patients with 
type-2 inflammation (as indicated by increased peripheral blood eosinophilia and comorbid 
asthma) may be more at risk for disease recurrence after surgery. Consequently, because of the 
chronic and unremitting nature of the condition in many patients, CRS is associated with 
substantial socioeconomic burden that results from the costs of diagnostic tests, medical and 
surgical therapies, lost and reduced school and work productivity, and detrimental impact on 
physical and emotional health (15). Therefore, a high unmet medical need for efficacious therapy 
remains for CRSsNP patients who are inadequately treated by currently available treatment 
options, and dupilumab may become a novel effective treatment option for CRSsNP patients with 
peripheral blood eosinophilia (a marker of type-2 inflammation) who are inadequately controlled 
with available therapies. 
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2.3 
BENEFIT/RISK ASSESSMENT  
COVID-19 Benefit-risk assessment 
Dupilumab has shown clinical benefit in several type-2 driven immunological disorders, such as 
AD, asthma, and CRSwNP. 
To date, more than 8000 participants have been treated with dupilumab during the clinical 
development program in several indications, of which AD, asthma, and CRSwNP are licensed in 
some countries.  
Currently, there are insufficient data in participants with Coronavirus Disease-2019 (COVID-19) 
who are being treated with dupilumab. Thus, the safety and efficacy of dupilumab in COVID-19 
patients are unknown. During the course of the clinical trial program, respiratory infections 
including viral infections were monitored and these events are not listed as adverse drug reactions 
(ADRs) with dupilumab 
The target population of EFC16723 is patients with uncontrolled, CRSsNP who have evidence of 
type-2 inflammation. 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 
EFC16723 will provide an opportunity for these patients to be treated with a novel therapy that 
has proven efficacy in certain other disease states (ie, AD, asthma, and CRSwNP) where type-2 
inflammation is the underlying driver of the disease process. 
Based on the aforementioned potential benefits to patients participating in EFC16723, the 
Sponsor’s assessment is that the benefit-risk remains favorable for patients to participate in this 
trial.  
The Sponsor also recognizes that the COVID-19 pandemic may have an impact on the conduct of 
clinical trials. The Sponsor will monitor the situation closely and ensure the integrity of the trial 
conduct and data (see Section 8).  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of dupilumab is available in the IB. 
2.3.1 Risk assessment  
No tissue targets or specific hazards to humans were identified in nonclinical general and 
reproductive toxicology studies. 
Dupilumab has an extensive safety database. As of 28 March 2020, 10 191 participants were 
enrolled into the development program for dupilumab and included in the safety population: 382 
as healthy volunteers, 4405 from AD studies, 3614 from asthma studies, 782 from CRSwNP 
studies, 232 from EoE studies, 103 from the grass allergy study, 145 from peanut allergy studies, 
511 from the chronic obstructive pulmonary disease (COPD) study, 5 from prurigo nodularis (PN) 
studies, and 12 from the chronic spontaneous urticaria (CSU) study. The number of participants 
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exposed to dupilumab in clinical studies was 8720 (356 in healthy volunteer studies, 4052 in AD 
studies, 3263 in asthma studies, 470 in CRSwNP studies, 166 in EoE studies, 52 in the grass 
allergy study, 96 in peanut allergy studies, 256 in the COPD study, 3 in PN studies, and 6 in the 
CSU study. For the latest information, please refer to the current IB. 
Based on the information retrieved from Intercontinental Marketing Services Health and using the 
World Health Organization’s defined daily dose for dupilumab of 21.4 mg/day, the cumulative 
post marketing exposure to dupilumab is estimated to be 161 582 patient-years (01 January 2017 
through 31 March 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 (ADR) identified to 
date for dupilumab include injection site reactions, conjunctivitis (including allergic and 
bacterial), oral herpes, herpes simplex, blepharitis, keratitis, dry eye, eye pruritus, eosinophilia, 
serum sickness, anaphylactic reaction, angioedema, and arthralgia. These ADRs were generally 
mild or moderate, transient, and manageable. These ADRs were not observed consistently in all 
indications (see IB for greater details). More significant serious allergic reactions were very rare. 
Importantly, no increased overall infection risk was observed in patients treated with dupilumab.  
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/serum sickness-like reaction in the adult AD program and anaphylaxis related to 
dupilumab in the adult asthma clinical trials. 
The important potential risk for dupilumab is “eosinophilia associated with clinical symptoms in 
asthma patients.” The observed increase in eosinophil count is transient, which is consistent with 
the current understanding of the mechanism of action of dupilumab. In dupilumab asthma studies, 
a small number of patients with asthma experienced serious systemic eosinophilia presenting with 
clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic 
granulomatosis with polyangiitis, conditions which are often treated with systemic corticosteroid 
therapy. These events have been seen in other drug development programs for severe asthma and 
usually, but not always, have been associated with the reduction of oral corticosteroid therapy 
suggesting possible unmasking of these conditions with tapering of corticosteroids during 
dupilumab therapy. The association of dupilumab treatment and these events has not been 
established. Health care providers should be alert to eosinophilia associated with vasculitic rash, 
worsening of pulmonary symptoms, pulmonary infiltrate, cardiac complications, and/or 
neuropathy presenting in their patients, especially upon reduction of SCS. 
Patients with known helminth infections were excluded from participation in clinical studies; 
therefore, it is not known if dupilumab will influence the immune response against helminth 
infections. Consequently, patients with pre-existing helminth infections should be treated for their 
helminth infection before initiating therapy with dupilumab.  
The common ADR across all indications is injection site reactions. Other potential risks based on 
the safety profile in particular indications are discussed in the IB.  
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While long-term data are still accumulating, data from randomized, placebo-controlled trials and 
open-label extension studies to date have not identified any new safety concern in these 
populations. It is anticipated that dupilumab in patients with type-2 CRSsNP will have a favorable 
safety profile as observed across other type-2 driven immunological disorders. 
2.3.2 Benefit assessment  
Dupixent® (dupilumab) is authorized for marketing in over 60 countries worldwide including the 
US, European Union (EU) (Centralized Procedure), Japan, Canada, and Australia for the adult AD 
indication. Dupilumab is also authorized in the US, EU, and other jurisdictions for the adolescent 
AD indication, in the US for children 6 to 12 years old with AD, and in the US, EU, Japan, and 
other jurisdictions for the adult and adolescent asthma indication. Dupilumab also has approval 
for its CRSwNP indication in the US, EU, and Japan. For the latest information, please refer to the 
current IB. 
There are no treatments specifically approved for CRSsNP in the US. Standard medical therapies, 
such as those based on EPOS 2020 guidelines, which include topical and oral corticosteroids, and 
antibiotics, do not provide adequate or lasting control of the symptoms in many patients with 
CRSsNP. A high unmet medical need exists for therapies that target underlying inflammatory 
processes in type-2 CRSsNP patients who are inadequately treated by the current standard of care.  
Considering this unmet medical need and the known mechanism of action of dupilumab, the 
Sponsor is proposing to develop dupilumab for the treatment of type-2 CRSsNP for the following 
reasons: 
1. There is a subset of CRSsNP patients with an underlying pathophysiology that is driven 
primarily by Type-2 inflammatory processes and is characterized by increased type-2 
biomarkers such as blood eosinophils, type-2 comorbidities or recurrence after surgery. 
Dupilumab has demonstrated favorable safety and efficacy profiles across a broad range of 
diseases including AD, asthma, and CRSwNP where type-2 inflammation is a key driver 
of the underlying disease process. 
2. Dupilumab has demonstrated significant efficacy in reducing sinus opacification, severity 
of CRS symptoms and nasal polyp burden in CRSwNP, a disease that shares several 
clinical and molecular features with CRSsNP with evidence of Type-2 inflammation. 
3. A post-hoc analysis of the LIBERTY ASTHMA QUEST study demonstrated that 
dupilumab treatment improved sinonasal symptoms and health-related quality of life 
(HRQoL), as assessed by SNOT-22, in patients with CRS (20) and suppressed airway 
(FeNO) and systemic (total IgE, TARC) type-2 inflammatory biomarkers versus placebo 
(20). Furthermore, clinically meaningful improvement from baseline in SNOT-22 was 
observed primarily in patients who had peripheral blood eosinophil counts 
≥300 cells/mm3.  
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2.3.3 Overall benefit: risk conclusion  
Therefore, based on the totality of evidence to support the potential therapeutic benefit in 
CRSsNP, a patient population with an unmet medical need, the favorable benefit/risk profile 
across multiple indications, and the extensive safety database for dupilumab, the Sponsor is 
proposing to conduct a Phase 2 program with dupilumab for the treatment of CRSsNP with 
evidence of type-2 inflammation. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of dupilumab as 
assessed by the reduction at Week 24 in sinus 
opacification on computerized tomography (CT) 
scan in the dupilumab group only 
• 
Change from baseline to Week 24 in opacification of 
sinuses assessed by CT scan using the Lund-Mackay 
(LMK) score in the dupilumab group  
Secondary 
• 
To evaluate the efficacy of dupilumab as 
assessed by the reduction at Week 24 in sinus 
opacification on CT scan and sinus total symptom 
score (sTSS) compared to placebo 
• 
Change from baseline to Week 24 in opacification of 
sinuses assessed by CT scan using the LMK score  
• 
Change from baseline to Week 24 in sTSS* 
*Composite severity score consisting of nasal congestion, 
anterior/posterior rhinorrhea, facial pain/pressure items of the 
CRSsNP sinonasal symptom e-diary 
 
• 
To evaluate the safety and tolerability of 
dupilumab in CRSsNP patients compared to 
placebo 
• 
Incidence of treatment-emergent adverse events 
(TEAEs), of treatment-emergent serious AEs 
(TESAEs), and TEAEs leading to treatment 
discontinuation, abnormal laboratory values, and vital 
signs 
• 
To evaluate the pharmacokinetics (PK) of 
dupilumab in CRSsNP patients compared to 
placebo 
• 
Dupilumab concentration in serum 
• 
Assessment of immunogenicity to dupilumab over 
time compared to placebo 
• 
Assessment of immunogenicity to dupilumab as 
determined by the incidence, titer, and neutralizing 
antibody (NAb) status of treatment-emergent anti-drug 
antibody (ADA) response over time compared to 
placebo 
Exploratory 
• 
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Objectives 
Endpoints 
• 
i
i
 
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3.1 
APPROPRIATENESS OF MEASUREMENTS  
The primary efficacy assessment of change from baseline in the LMK CT scan score at Week 24 
in the dupilumab group, will provide objective imaging-based measurement of benefit of CRSsNP 
patients. The LMK and a related total symptom score (TSS), as secondary endpoint with 
dupilumab group comparison to placebo, are 2 of the key assessments that have been successfully 
implemented and have provided clinically meaningful evidence of therapeutic benefit of 
dupilumab treatment after 24 weeks in the completed clinical development program of dupilumab 
in CRSwNP (19). The sTSS in this trial is a total score composed of three common, cardinal 
symptoms of CRSsNP, including nasal congestion, rhinorrhea (anterior/posterior), and facial 
pain/pressure that are daily assessed by the participant. This score will provide a comprehensive 
clinical assessment of the impact of dupilumab on the key symptoms of CRSsNP, and will 
complement the objective assessment provided by the well-validated LMK score. Other 
supportive assessments, including individual scores for the main symptoms in CRSsNP 
(NC/obstruction, loss of sense of smell, facial pain/pressure, and rhinorrhea) and visual analog 
scale (VAS) for rhinosinusitis severity will also be assessed. The SNOT-22 will also be collected 
to provide additional evidence of therapeutic benefit. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 2 multicenter study to evaluate the efficacy and safety of dupilumab, in 
participants with uncontrolled CRSsNP. This is a randomized, double-blind, placebo-controlled 
study in adult participants regardless of screening eosinophil count to evaluate the treatment effect 
of dupilumab on sinus opacification as assessed by the LMK sinus CT scan total score and to 
provide data on safety.  
All participants (adults only) will enter a screening period (2 to 4 weeks), with a 24 to 
52-week treatment period, followed by post-treatment follow-up (12 weeks). 
Approximately 70 adult participants will be randomized 1:1 (approximately 35 participants 
per arm) into 2 treatment groups as follows:  
- 
Arm A: Dupilumab 300 mg q2w, 
- 
Arm B: Matching placebo. 
Randomization will be stratified by screening blood eosinophil count (≥300 cells/mm3 or 
<300 cells/mm3), background INCS use (yes or no) and region. 
To ensure enrollment according to the intended distribution of screening blood eosinophil 
count, alerts will be built into the IRT to control the number of participants in each 
stratification group as follows: 
- 
≥300 cells/mm3: approximately 15 participants per arm, 
- 
<300 cells/mm3: approximately 20 participants per arm. 
Note: The treatment will stop for all participants when the LPI has completed 24 weeks of 
treatment. Therefore, all participants following Amendment 02 will be treated for at least 
24  weeks and the other participants (enrolled before Amendment 02) will have variable treatment 
period and may continue up to 52 weeks. 
In addition, in order to have an adequate number of participants with comorbid asthma, alerts will 
be built into the IRT to limit the number of participants without comorbid asthma to no more than 
70% of the randomized population. 
During the study, participants who report deterioration requiring medical/surgical intervention 
may come to the 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. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
EFC16723 is designed as a double-blind, randomized, placebo-controlled, study to minimize bias 
in data collection and interpretation. The presence of a placebo arm is appropriate for the 
objectives of this study since it will provide the most robust assessment of the efficacy and safety 
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of dupilumab. The study has a 24 to 52 -week study treatment period to provide initial evidence 
related to the treatment effect of dupilumab in patients with Type-2 inflammation (as indicated by 
peripheral blood eosinophil counts ≥300 cells/mm3) CRSsNP and to provide safety information.  
In addition, a post-hoc analysis to assess the efficacy of dupilumab on upper airway symptoms as 
measured by SNOT-22 in the subset of asthma patients with CRS from the dupilumab Phase 3 
asthma study EFC13579 (QUEST) was performed. Clinically meaningful improvement from 
baseline in SNOT-22 was observed only in patients who had peripheral blood eosinophil counts 
≥300 cells/mm3 and not in those with <300 cells/mm3. In the study, to further evaluate the 
predictive value of baseline peripheral blood eosinophil counts as a potential marker of treatment 
response to dupilumab, a subset of participants with blood eosinophil counts of <300 cells/mm3 
will be randomized while the primary analysis population will remain as participants who have 
peripheral blood eosinophil counts ≥300 cells/mm3. 
The 24-week treatment duration should be sufficient for the demonstration of the efficacy with 
dupilumab based on the efficacy results seen in CRSwNP. This duration is also sufficient for 
safety assessment given the extensive safety experience with dupilumab including in the related 
condition of CRSwNP.  
Rescue medications and/or surgery for CRSsNP deemed necessary by Investigators will be 
allowed, which mirror the expected future therapeutic paradigm of dupilumab in this population in 
clinical practice. 
The primary efficacy assessment will be change from baseline in the LMK at Week 24 in the 
dupilumab group. Other supportive assessments, including sTSS scores for the main symptoms in 
CRSsNP (nasal congestion [NC]/obstruction, loss of sense of smell, rhinorrhea, facial 
pain/pressure), VAS for rhinosinusitis severity, and SNOT-22 will also be collected, to provide 
additional evidence of therapeutic benefit. 
Changes in the LMK and sTSS, as secondary endpoint, will provide both objective imaging 
measure of benefit and evidence of symptomatic improvement in the cardinal clinical 
manifestations of CRSsNP patients, respectively other secondary and exploratory measures, 
including individual scores for the main symptoms in CRSsNP, VAS for rhinosinusitis severity, 
and SNOT-22, that assess other disease manifestations of CRSsNP and the associated impact on 
the quality of life in participants.  
4.2.1 Participant input into design  
Participants were not involved in the design of the clinical trial. 
4.3 
JUSTIFICATION FOR DOSE  
Based on the known pharmacokinetics (PK), safety, and efficacy of dupilumab, the selected 
dosing regimen for EFC16723 study is dupilumab 300 mg q2w.  
This dose regimen is expected to achieve concentrations in serum that saturate the target-mediated 
clearance pathway and has demonstrated similar efficacy in adult patients with asthma and AD, 
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and in adults with CRSwNP. The PK of dupilumab have been found to be consistent across 
populations of patients with AD, asthma, and CRSwNP, as well as healthy volunteers. 
Furthermore, the sources of variability of dupilumab PK identified in each population and the 
magnitude of the covariate effects indicate that body weight is the most influential factor, whereas 
other covariates identified as being statistically significant have no meaningful impact on 
dupilumab PK. Overall, it is expected that the PK of dupilumab is similar in healthy adults and 
participants with a range of type-2 diseases, with body weight being the most influential covariate 
affecting exposure. The immunogenicity of dupilumab is also comparable in these populations 
(see approved Dupixent prescribing information).  
The 300 mg q2w dose regimen has been proven to be effective with an acceptable safety profile in 
patients with moderate-to-severe AD, moderate-to-severe asthma, and CRSwNP. The 300 mg 
q2w without a loading dose has been demonstrated to be efficacious for adult participants with 
severe CRSwNP, where differential treatment responses between dupilumab- and placebo-treated 
patents were observed as early as after 4 weeks of study treatment. Consistent with the observed 
PK and pharmacodynamic (PD) profile of nasal polyp score (NPS) response (gradual 
development of response during the treatment period as well as slow offset of response during 
off-treatment period) in patients with CRSwNP, PK/PD simulation of the co-primary endpoints of 
NPS and NC showed minimal difference in the development of treatment effect and steady-state 
response of NPS and NC in the presence and absence of the loading dose of 600 mg on Day 1 in 
patients with CRSwNP. Therefore, no loading dose is included in the present study for CRSsNP 
adult participants. 
The collective PK/PD, clinical efficacy, and safety data of dupilumab across diverse disease 
populations suggest that the selected dose regimens for EFC16723 will be efficacious and safe for 
the treatment of adult CRSsNP patients. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the Follow-up visit (EOS Visit).  
• For participants actively followed under original protocol or Amendment 1, if a participant 
discontinues study intervention prematurely before Week 40 but completes follow-up to 
Week 52, he/she will be considered to have completed the study.  
• For participants actively followed under Amendment 2, if a participant discontinues study 
intervention prematurely before Week 12 but completes follow-up to Week 24, he/she will 
be considered to have completed the study.  
The end of the study is defined as the date of the last visit of the last participant in the study. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be at least 18 years of age at the time of signing the informed consent 
form (ICF).  
Type of participant and disease characteristics 
I 02. Participants must have bilateral inflammation of paranasal sinuses in CT scan with LMK 
≥8 and bilateral ethmoid opacification before randomization. 
I 03. Participants must have ongoing symptoms of loss of smell and rhinorrhea 
(anterior/posterior) of any severity, with or without facial pain/pressure for at least 
12 consecutive weeks by Visit 1. 
I 04.  Participants must have ongoing symptoms of NC/obstruction at least 12 consecutive 
weeks before Visit 1 and a NC score of ≥2 at Visit 1 (day score) and Visit 2 (weekly 
average score). 
I 05. Participants must have sTSS (NC, rhinorrhea, facial pain/pressure) ≥5 at Visit 1 (day 
score) and Visit 2 (weekly average score). 
I 06. Participants must have at least one of the 2 following features: 
a) Prior sinonasal surgery (see note at end of section 5.2 for definitions of sinonasal 
surgery) for CRS,  
b) Treatment with SCS therapy for CRS as defined by any dose and duration within the 
prior 2 years before screening (Visit 1) or intolerance/contraindication to SCS. 
I 07. No restrictions on eosinophil count. 
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Weight  
I 08. Body weight ≥30 kg. 
Sex 
I 09. Male or female 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
- 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies: 
- 
Is not a woman of childbearing potential (WOCBP).  
OR 
- 
Is a WOCBP and agrees to use a contraceptive method that is highly effective, with 
a failure rate of <1%, as described in Appendix of the protocol during the study (up 
to 12 weeks after the last administration of the study treatment). 
- 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) on Day 1 before the first dose of study intervention, 
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive, 
- 
Additional details can be found in Appendix 4 (Section 10.4) of the protocol, 
- 
The Investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed Consent 
I 10. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3) of 
the protocol which includes compliance with the requirements and restrictions listed in the 
ICF and in this protocol. In countries where the legal age of majority is above 18 years, a 
specific ICF must also be signed by the participant’s legally authorized representative. 
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Participants with conditions/concomitant diseases making them non-evaluable at Visit 1 or 
for the primary efficacy endpoint such as:  
a) Participants with nasal polyposis observed during nasal endoscopy at Visit 1,  
b) Participants with past history of nasal polyposis, 
c) Nasal septal deviation that would cause complete occlusion of at least one nostril, 
d) Acute sinusitis or purulent drainage or nasal infection, or upper respiratory infection 
at Visit 1 or Visit 2, 
e) Ongoing rhinitis medicamentosa, 
f) 
Eosinophilic granulomatous polyangitis (Churg-Strauss syndrome), granulomatosis 
with polyangiitis (Wegener’s granulomatosis), microscopic polyangiitis, Young’s 
syndrome, Kartagener’s syndrome or other dyskinetic ciliary syndromes, cystic 
fibrosis. 
E 02. Participants with nasal cavity malignant tumor and benign tumors (eg, papilloma, 
hemangioma). 
E 03. Participants with Forced expiratory volume (FEV1) ≤50% of predicted normal at Visit 1. 
E 04. Radiologic suspicion or confirmed invasive or expansive fungal rhinosinusitis. 
E 05. Diagnosed with, suspected of, or at high risk of endoparasitic infection, and/or use of 
antiparasitic drug within 2 weeks before the Screening Visit (Visit 1) or during the 
screening period.  
E 06. History of human immunodeficiency virus (HIV) infection or positive HIV screen 
(anti-HIV-1 and HIV-2 antibodies) serology at the Screening Visit (Visit 1). 
E 07. Severe concomitant illness(es) that, in the Investigator’s judgment, would adversely affect 
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 [eCRFs], etc). 
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E 08. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections eg, tuberculosis (TB), histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, and aspergillosis), despite infection resolution, or otherwise recurrent 
infections of abnormal frequency or prolonged duration suggesting an 
immune-compromised status, as judged by the Investigator. 
E 09. Participants with active TB, non-tuberculous mycobacterial infection, or a history of 
incompletely treated TB will be excluded from the study unless it is well documented by a 
specialist that the participant has been adequately treated and can now start treatment with 
a biologic agent, in the medical judgment of the Investigator and/or infectious disease 
specialist. Tuberculosis testing would be performed on a country-by-country basis 
according to local guidelines if required by regulatory authorities or ethics boards. 
E 10. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
or antifungals within 2 weeks before the Screening Visit (Visit 1) or during the screening 
period. 
E 11. History of malignancy within 5 years before Visit 1, except completely treated in situ 
carcinoma of the cervix, and completely treated and resolved nonmetastatic squamous or 
basal cell carcinoma of the skin. 
E 12. Known or suspected alcohol and/or drug abuse. 
E 13. History of systemic hypersensitivity or anaphylaxis to dupilumab or any of its excipients. 
E 14. Planned major surgical procedure during the patient’s participation in this study. 
E 15. Participant with any other medical or psychological condition including relevant laboratory 
or electrocardiogram abnormalities at screening that, in the opinion of the Investigator, 
suggest a new and/or insufficiently understood disease, may present an unreasonable risk 
to the study participant as a result of his/her participation in this clinical trial, may make 
patient's participation unreliable, or may interfere with study assessments. The specific 
justification for participants excluded under this criterion will be noted in study documents 
(chart notes, eCRF, etc). 
Prior/concomitant therapy 
E 16. Participation in prior dupilumab clinical study or have been treated with commercially 
available dupilumab within 12 months or who discontinued dupilumab use due to adverse 
event.  
E 17. Participants who have taken: 
- 
Biologic therapy/systemic immunosuppressant such as methotrexate, cyclosporine, 
mycophenolate, tacrolimus, etc to treat inflammatory disease (including CRSsNP) 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, 
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- 
Any investigational monoclonal antibody (mAb) within 5 half-lives or within 6 months 
before Visit 1 if the half-life is unknown, 
- 
Anti-immunoglobulin E therapy (omalizumab) within 4 months prior to Visit 1. 
E 18. Treatment with a live (attenuated) vaccine within 4 weeks before the Screening Visit 
(Visit 1). 
NOTE: For participants who have vaccination with live, attenuated vaccines planned 
during the course of the study (based on national vaccination schedule/local guidelines), it 
will be determined, after consultation with a physician, whether the administration of 
vaccine can be postponed until after the end of study (EOS), or preponed to before the start 
of the study without compromising the health of the participant: 
Participants for whom administration of live (attenuated) vaccine can be safely postponed 
would be eligible to enroll into the study. 
Participants who have their vaccination preponed can enroll in the study only after a gap of 
4 weeks following administration of the vaccine. 
E 19. Leukotriene antagonists/modifiers unless participant is on a continuous treatment for at 
least 30 days prior to Visit 1.  
E 20. Initiation of allergen immunotherapy within 3 months prior to Visit 1 or a plan to begin 
therapy or change its dose during the screening period or the randomized treatment period. 
E 21. Sinus surgery within 6 months before screening (Visit 1) or sinonasal surgery (see note at 
end of Section 5.2 for definitions of sinonasal surgery) changing the lateral wall structure 
of the nose making the evaluation of LMK impossible. 
E 22. Participants on unstable dose of INCS spray 4 weeks prior to Screening Visit (Visit1) and 
during screening period. 
E 23. Participants treated with intranasal corticosteroid drops, intranasal steroid emitting 
devices/stents, nasal spray using exhalation delivery system, such as Xhance™ during 
screening period. 
E 24. Participants who received SCS during screening period (between Visit 1 and Visit 2).  
E 25. Either intravenous immunoglobulin (IVIG) therapy and/or plasmapheresis within 30 days 
prior to Screening Visit (Visit 1). 
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Diagnostic assessments 
E 26. Participants with any of the following results at the Screening Visit (Visit 1): 
a) Positive (or indeterminate) hepatitis B surface antigen (HBsAg) or,  
b) Positive total HBcAb and a negative HBsAg confirmed by positive hepatitis B virus 
(HBV) DNA or, 
c) Positive hepatitis C virus antibody (HCVAb) confirmed by positive HCV RNA. 
Noncompliance to completion of the e-diary 
E 27. Participants must demonstrate at least the following for acceptable compliance: 
Completing the e-diary for any 4 in the 7 days immediately preceding the Baseline Visit 
(Visit 2). 
Other exclusions 
E 28. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 29. Any country-related specific regulation that would prevent the participant from entering 
the study. 
E 30. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions or participants potentially at risk of 
noncompliance to study procedures. 
E 31. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals (in 
conjunction with Section 1.61 of ICH-GCP Ordinance E6). 
E 32. Not applicable as per Amended protocol 02. 
E 33. 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.  
Note: Definitions of sinonasal surgery 
• Endoscopic sinus surgery (ESS), include all the current procedural terminology (CPT) 
codes used for sinus surgery, which implies restitution of physiology and is used to create 
a sinus cavity opening that incorporates the natural ostium; allows adequate sinus 
ventilation; facilitates mucociliary clearance; facilitates instillation of topical therapies: 
- 
ESS may include also balloon sinuplasty: endoscopic nasal surgery that uses small 
balloon catheters that inflate to drain the large nasal sinuses. 
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• Or “Full ESS’ defined as complete sinus opening including anterior and posterior 
ethmoidectomy, maxillary antrostomy (could be large), sphenoidotomy and frontal 
sinusotomy in the same context as ‘full’ (eg, Draf III) but could also include extension 
beyond the confines of sinuses ie, skull base, orbit, pterygopalatine and infratemporal 
fossa. 
• Or radical Functional endoscopic sinus surgery which includes significant removal of 
inflamed/dysfunctional mucosa. 
5.3 
LIFESTYLE CONSIDERATIONS  
No restrictions. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure reasons, eligibility criteria, and any serious adverse event (SAE). 
In the case of technical malfunction of equipment, the participants may be rescreened. 
Individuals who do not meet the inclusion criteria or fail the exclusion criteria may be rescreened 
once as per Investigator decision. Rescreened participants will be assigned a new participant 
number versus the one received for the initial Screening Visit (Visit 1). 
There is no requirement for a waiting period between the screen failure date and the rescreening 
date. The interactive response technology (IRT) report will flag rescreened participants. 
Participants that are rescreened must sign a new consent form. 
If certain dynamic laboratory tests do not meet the eligibility criteria at the screening period, these 
laboratory assessments may be repeated at the discretion of the Investigator, if it is judged to be 
likely to return to the acceptable range for study inclusion within the screening window prior to 
Day 1. A baseline CT scan must be repeated for these rescreened participants if the previous 
CT scan done between Visit 1 and Visit 2 is more than 31 days in the past (28 days+3 days). If, 
the rescreening cannot be done within 31 days (28 days + 3 days), then these rescreened 
participants must wait for 4 months to repeat CT scan to prevent over exposure to CT radiation. 
All other screening procedures must be repeated for rescreening. 
 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
ARM name 
Dupilumab 
Placebo 
Intervention name 
Dupilumab 300 mg 
Placebo 
Type  
Biological 
Other 
Dose formulation 
Dupilumab 300 mg:  
A 150 mg/mL dupilumab solution in a 
pre-filled syringe to deliver 300 mg in 
2 mL 
Placebo matching dupilumab 300 mg will be 
supplied as an identical formulation to the 
active 300 mg formulation without dupilumab, in 
a pre-filled syringe to deliver placebo in 2 mL 
Unit dose strength(s) 
300 mg 
0 mg 
Dosage level(s) 
One injection of 300 mg q2w for all 
adults  
One injection of placebo matching 300 mg q2w 
for all adults  
Route of administration 
Subcutaneous injection 
Subcutaneous injection 
Use 
Experimental 
Experimental 
IMP 
IMP 
IMP 
Packaging and labeling 
 
Each dose of dupilumab will be 
supplied as 1 glass pre-filled syringe 
packed in a participant kit box. Both 
glass pre-filled syringe and box will be 
labeled as required per country 
requirement 
Each dose of placebo will be supplied as 1 
glass pre-filled syringe packed in a participant 
kit box. Both glass pre-filled syringe and box 
will be labeled as required per country 
requirement 
Abbreviations: q2w: every 2 weeks, IMP: investigational medicinal product.  
Investigational medicinal product(s) 
The IMP is administered every 14 ± 3 days (q2w) during the treatment period (with the last IMP 
administration at Week 22-50). 
During study visits, the IMP is administered on sites after all procedures. For the doses that are 
not scheduled to be given at the study site, home administration of IMP is allowed after 
appropriate training of the participant or caregiver). Investigator or delegate will prepare and 
inject the first dose of IMP at Visit 2, in front of the participant (or caregiver). The participant (or 
caregiver) will prepare and inject the IMP under the supervision of the Investigator or delegate at 
Visit 3. The training must be documented in the participant’s study file. In case of emergency (eg, 
natural disaster, pandemic, etc) different training ways (eg, training remotely with instruction 
provided by phone, etc) can be performed (and will be documented in the participant’s study file).  
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If the participant (or caregiver) is unable or unwilling to prepare and inject IMP, injections can be 
performed at the study site by way of unscheduled visits; or arrangements can be made for 
qualified site personnel and/or health care professionals (eg, visiting nurse service) to administer 
IMP at participant’s home. 
In case of emergency (eg, natural disaster, pandemic, etc), IMP may be supplied from the site to 
the participant via a Sponsor-approved courier company where allowed by local regulations and 
approved by the participant. When the participant has a study visit, the IMP will be administered 
after clinical procedures and blood collection are performed. Participants should be monitored for 
at least 30 minutes following injection. The monitoring period may be extended as per 
country-specific or local site-specific requirements. 
The participant/parent/legally authorized representative/caregiver should be trained by the site 
staff to recognize potential signs and symptoms of hypersensitivity reaction in order to 
self-monitor/monitor at home for at least 30 minutes (or longer per country-specific or local 
site-specific requirements) following injection. In case of hypersensitivity symptoms, the 
participant should contact healthcare provider/emergency. 
Subcutaneous injection sites should be alternated among the 4 quadrants of the abdomen 
(avoiding navel and waist areas), the upper thighs or the upper arms, so that the same site is not 
injected between two q2w injections. Injections in the upper arms could be done only by a trained 
person (caregiver trained by Investigator or delegate) or health care professional but not the 
participants themselves.  
For doses not given at the study site, paper diaries will be provided to the participant to record 
information related to the home injections. The paper diary will be kept as source data in the 
participant’s study file. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 Storage and Handling  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. At site, all study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
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6.2.2 Responsibilities  
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.7). 
A potential defect in the quality of IMP may be subject to the 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 mail to 
participant shipment, for which a courier company has been approved by the Sponsor), allow the 
IMP to be used other than as directed by this clinical trial protocol, or dispose of the IMP in any 
other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
The randomized intervention kit number list is generated centrally by Sanofi, and IMPs are 
packaged in accordance with this list. The randomization and intervention allocation are 
performed centrally by IRT. The IRT generates the participant randomization list and allocates the 
intervention number and the corresponding intervention kits to the participants according to it. 
Before the study is initiated, the log-in information and directions for the IRT will be provided to 
each site. 
Participants will be randomized in a 1:1 ratio treatment arm described in Table 2.  
Randomization will be stratified by screening blood eosinophil count (≥300 cells/mm3 or 
<300 cells/mm3), background INCS use (yes or no) and region.  
At Screening (Visit 1), the Investigator or designee will contact the IRT to receive the participant 
number. If a participant who had previously failed screening is approached for re-screening, a new 
ICF must be signed. In such case, a new participant number will be assigned by IRT.  
A randomized participant is defined as a participant who has been allocated to a randomized 
intervention regardless of whether the treatment was administered or not (ie, participant registered 
by the IRT). A participant cannot be randomized more than once in the study. 
Study intervention will be dispensed at the study visits summarized in the SoA (Section 1.3). 
Returned study intervention should not be re-dispensed to the participants. 
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Methods of blinding 
Dupilumab 300 mg and placebo 300 mg will be provided in identically matched 2 mL pre-filled 
syringes that are visually indistinguishable for each dose. Syringes and box will be labeled with a 
treatment kit number.  
Code breaking 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s intervention 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If the Investigator decides that unblinding is warranted, he/she may, at his/her 
discretion, contact the Sponsor to discuss the situation prior to unblinding a participant’s 
intervention assignment unless this could delay emergency treatment of the participant. If a 
participant’s intervention assignment is unblinded, the Sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and eCRF, as applicable. 
If the code is broken at the site level, the participant must withdraw permanently from IMP 
administration. 
6.4 
STUDY INTERVENTION COMPLIANCE  
• The Investigator or his/her delegate must ensure that IMP is administered to each 
participant according to the labeling instructions. 
• IMPs accountability: 
- 
Intervention units are returned by the participant at each visit. In case of direct mail to 
participant process, the intervention units can be returned by the carrier (if defined in 
the contract), 
- 
The Investigator or his/her delegate counts the number of remaining kits/pre-filled 
syringes and fills in the Intervention Log Form, 
- 
The Investigator or his/her delegate records the dosing information on the appropriate 
pages of the eCRF, 
- 
The monitor in charge of the study then checks the eCRF data by comparing them with 
the IMP that he/she has retrieved, and the intervention log forms. 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study 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 checking participant 
home-dosing diary and used/unused kits/pre-filled syringes during the site visits and documented 
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in the source documents and eCRF. Changes(s) from the prescribed dosage regimen should be 
recorded in the eCRF. 
Detailed instructions for transport, storage, preparation, and administration of IMP are provided to 
the participant. For doses not given at the study site, participants will complete a dosing diary to 
document compliance with self-injection (or caregiver) of IMP, location of injection, and any 
symptoms. The diary will be kept as source data in the participant’s study file. 
A record of the number of kits/pre-filled syringes dispensed to and taken by each participant must 
be maintained and reconciled with study intervention and compliance records. Relevant data from 
the dosing diary will be recorded in the eCRF. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over the counter or prescription medicines, vitamins, and/or 
herbal supplements or other specific categories of interest) that the participant is receiving at the 
time of enrollment or receives during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The Sponsor or Sponsor representative(s) should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.5.1 Background treatments  
Participants should continue their permitted background INCS spray during the study, if they were 
on stable dose of INCS (except for Xhance™) for at least 4 weeks prior to screening. From the 
time of screening, they should not change their background medications. 
Permitted concomitant medication 
The following treatments are allowed:  
• Intranasal corticosteroid spray (except for Xhance™) is permitted as background 
medication that it should be on the stable dose for at least 4 weeks prior to study screening, 
and participants must maintain the same INCS throughout the study treatment period if 
initiated before enrollment. 
• Single dose of topical decongestants administration, for example, oxymetazoline 
hydrochloride (to reduce the swelling and widen the path for the endoscope) as well as a 
topical anesthetic (eg, lidocaine) are allowed before nasal brushing or before endoscopy. 
• Administration of short courses antibiotics for a concurrent infection or CRSsNP 
worsening /acute sinusitis, is allowed during the study (reason for and duration of 
treatment should be documented in the eCRF) (see Section 6.5.3).  
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• Short-acting β2-adrenergic receptor agonists (SABA), long-acting β2-adrenergic receptor 
agonists (LABA), and long-acting muscarinic acetylcholine receptor antagonists (LAMA). 
• Methylxanthines (eg, theophylline, aminophylline).  
• Inhaled corticosteroids. 
• Systemic antihistamines. 
• Leukotriene antagonists/modifiers are only permitted during the study, for participants 
who have been on a continuous treatment for ≥30 days prior to Visit 1. 
• Allergen immunotherapy in place for ≥3 months and dose stable for 1 month prior to 
Visit 1 is permitted. 
• Short courses of SCS to treat other serious co-existing diseases (such as asthma 
exacerbation) or for AEs are allowed (see Section 6.5.3). 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Sponsor or Sponsor representative(s) if required. 
6.5.2 Prohibited medications  
The following concomitant treatments are not permitted during the screening period and the 
randomized treatment period:  
• Any systemic immunosuppressive treatment, such as methotrexate, cyclosporine, 
mycophenolate, tacrolimus, etc. 
• Initiation of allergen immunotherapy. 
• Intranasal corticosteroid drops; intranasal steroid emitting devices/stents; nasal spray using 
Exhalation Delivery System such as Xhance™.  
• All forms of SCS are prohibited during screening and study treatment period except for 
short-term courses (≤2 weeks) of OCS can be used as rescue during treatment period (see 
Section 6.5.3).  
• Live attenuated vaccines. 
• Intravenous immunoglobulin (IVIG) therapy. 
• Other monoclonal antibodies (biological immunomodulators), including but not limited to 
anti-IgE, anti-IL-5, and anti-tumor necrosis factor (TNF), etc. 
• Systemic antibiotics are prohibited during screening and study treatment period except for 
rescue use (see Section 6.5.3). 
6.5.3 Rescue medicine  
During the study treatment and follow-up periods, based on clinical evaluation, in case of 
worsening of signs and/or symptoms/acute sinusitis requiring medical intervention, the 
Investigator may consider rescue treatment with: 
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• Systemic antibiotics (up to 2 weeks) in case of acute infection. 
• Short course OCS (prednisone or equivalent prednisolone up to 14 days; avoid use 
4 weeks before Week 24 or Week 52, where applicable). 
• Sinonasal surgery for CRSsNP (8 weeks of IMP treatment is recommended prior to 
surgery to allow onset of treatment effect). 
• Intranasal corticosteroids spray (initiation of INCS spray or change in dosing of a 
background INCS during the study period). 
Participants receiving rescue treatment other than surgery during the study should continue on 
study drug unless the Investigator decides to withdraw the study treatment. Before starting 
treatment with OCS participants should come to the study site for the clinical assessments. It is 
recommended to avoid use of OCS as rescue therapy during the Week 20 to Week 24 or the Week 
48 to Week 52. If a participant must use OCS during this period to control worsening of 
symptoms based on Investigator judgment the site should make every efforts to schedule the 
Week 24 CT scan or the Week 52 CT scan prior to OCS rescue therapy.  
For participants who undergo or are planned for surgery for CRSsNP the Investigator may decide 
to continue IMP up to the time of surgery or end of treatment (EOT) whichever date comes first. 
At the time of surgery participants will be permanently discontinued from study treatment and 
assessed as soon as possible using the procedures normally planned for the EOT Visit. In any case 
participants who prematurely discontinued the treatment will be encouraged to return to the study 
site for the efficacy and safety assessments planned at EOT Visit and for additional visits. 
Additional appropriate medical/therapy per local guideline or per Investigators decision may be 
considered to use as rescue medicine. The date and time of rescue medication administration as 
well as the name and dosage regimen of the rescue medication must be recorded in the eCRF. 
6.6 
DOSE MODIFICATION  
No IMP dose modification is allowed. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
Sponsor will not be responsible for intervention after the EOS Visit. Study intervention after the 
EOS Visit will be at the discretion of Investigator or treating physician. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for safety and efficacy. 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.  
The participants may withdraw from treatment with the IMP if he or she decides to do so at any 
time for any reason, or based on the Investigator’s decision. All efforts should be made to 
document the reason(s) for study intervention discontinuation and recorded in the eCRF. 
Participants must be permanently withdrawn from the study intervention for the following 
reasons:  
• At their own request or at the request of their legally authorized representative (legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective participant to participate in the 
procedure(s) involved in the research). 
• If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
participant’s well-being.  
• At the specific request of the Sponsor.  
• If the participant is treated with the specific prohibited medications mentioned in 
Section 6.5. 
• If the participant misses 2 consecutive IMP doses. 
• In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor.  
• Any code broken at the requested of the Investigator.  
• Pregnancy. 
• Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (see Section 10.9).  
• Diagnosis of a malignancy during the study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin.  
• Any opportunistic infection or other infections whose nature or course may suggest an 
immunocompromised status (see Section 10.10).  
• Serum alanine aminotransferase (ALT) >3 ×upper limit of normal (ULN) and total 
bilirubin >2 × ULN (see Section 10.6).  
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• Serum ALT >5 ×ULN if baseline ALT ≤2 ×ULN, or ALT >8 × ULN if baseline 
ALT >2 × ULN (see Section 10.6). 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula [QTcF] after enrollment), the Investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the electrocardiogram (ECG) printed at the time 
of collection must be documented. Any new clinically relevant finding should be reported as an 
AE. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation within a reasonable timeframe as assessed by the Investigator before making a 
decision of definitive discontinuation of the IMP for the concerned participant. 
Handling of participants after definitive intervention discontinuation 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented.  
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
Participants who discontinue the study intervention prematurely (prior to completing the treatment 
period) will perform, as soon as possible, the Early Termination Visit with all the assessments 
normally planned for the EOT Visit (refer to Section 8.1.1), to assure a complete clinical 
assessment in close temporal proximity to the premature termination of study intervention is 
available. A CT scan can be done at time of Early Termination Visit if the previous CT scan is 
performed at least 4 months ago. Otherwise, the CT scan should be performed at the next 
scheduled timepoint (ie, Week 24).  
In addition, and to allow assessment of participant outcomes over the stipulated study period, 
participants will be asked and encouraged to complete all remaining study treatment visits and 
participate in all assessments according to the visit schedule with a ±3 days window. Under 
exceptional circumstances when a participant cannot come to the site for a scheduled visit, a 
phone contact can be made. During the phone contact, at least information about AEs, 
concomitant medication, and the status of CRSsNP should be collected. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
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7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs. For all temporary intervention discontinuations, duration should be recorded by 
the Investigator in the appropriate pages of the eCRF. 
Temporary intervention discontinuation decided by the Investigator corresponds to at least 1 dose 
not administered to the participant. Following a temporary interruption or missed dose, the study 
intervention should be reinitiated at the next scheduled administration, maintaining the planned 
dose. 
If 2 consecutive IMP doses have been missed, the study intervention will be definitively 
discontinued (see Section 7.1.1). Investigator must contact the participant to instruct not to take 
any subsequent injection. 
7.1.2.1 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator considers this to be appropriate according to his/her 
best medical judgment that the responsibility of the IMP(s) in the occurrence of the concerned 
event was unlikely and if the selection criteria for the study are still met (refer to Section 5). 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request or if his/her 
caregiver(s) or may be withdrawn at any time at the discretion of the Investigator for 
safety, behavioral, compliance, or administrative reasons. This is expected to be 
uncommon. 
• At the time of discontinuing from the study, if possible, an early follow-up/EOS Visit 
should be conducted, as shown in the SoA (Section 1.3).  
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for the 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. 
• All study withdrawals should be recorded by the Investigator in the appropriate screens of 
the eCRF and in the participant’s medical records. In the medical record, at least the date 
of the withdrawal and the reason should be documented. 
• In addition, a participant may withdraw his/her consent to stop participating in the study. 
A participant’s decision to discontinue intervention should be distinguished from 
withdrawal of consent for follow-up visits and from withdrawal of consent for 
non-participant contact follow-up, eg, medical record checks. The site should document 
any case of withdrawal of consent. 
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Participants who have withdrawn from the study cannot be rerandomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW-UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• If the participant continues to be unreachable, he/she will be considered to have withdrawn 
from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Section 1.3). 
• Assessments/procedures should be conducted in the following order:  
- 
CRSsNP sinonasal symptom diary (nasal congestion, loss of sense of smell, 
rhinorrhea, facial pain/pressure, and headache symptoms);  
- 
SNOT-22;  
- 
Rhinosinusitis severity VAS;  
- 
PGIS; PGIC; EQ-5D-5L;  
- 
ACQ-6 (in participants with asthma); 
- 
Investigator assessments (smell test [UPSIT], HCRU/P, spirometry [baseline and 
subsequently in participants with asthma], physical examination, AE/SAEs, 
concomitant medications, nasal endoscopy (V1 only), nasal secretion, nasal brushing, 
sinus CT scan); 
- 
Laboratory assessments (including sample collection for ADA, PK, biomarker, and 
optional DNA and RNA);  
- 
And, administration of IMP. 
• Patient-Reported Outcome (PRO) questionnaires should be completed by the participants 
before the consultation and/or clinical tests in a quiet place (at home in e-diary and at 
clinic). The questionnaires should be completed by the participants themselves, 
independently from their physician, the study nurse, or any other medical personnel, and 
without any help from friends or relatives. 
• The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 
approximately 179 mL. Repeat or unscheduled samples may be taken for safety reasons or 
for technical issues with the samples. 
• In light of the public health emergency related to COVID-19 (or in case of any other 
public health emergency), the continuity of clinical study conduct and oversight may 
require implementation of temporary or alternative mechanisms, such as phone contact, 
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virtual visits, online meetings, use of local clinic or laboratory locations, and home visits 
by skilled staff. Implementation of such mechanisms may differ country by country, 
depending on country regulations and local business continuity plans. Additionally, no 
waivers to deviate from protocol enrollment criteria due to COVID-19 (or any other 
pandemic) will be granted. All temporary mechanisms utilized, and deviations from 
planned study procedures are to be documented as being related to COVID-19 (or any 
other public health emergency) and will remain in effect only for the duration of the public 
health emergency.  
8.1 
EFFICACY ASSESSMENTS  
8.1.1 Computerized Tomography Scans using Lund-Mackay  
Computerized tomography scans using the LMK allows the assessment of sinus opacification 
(37).  
The CT scan LMK staging system represents the most widely established method of sinus CT 
scoring in clinical trials. The LMK total score is based on assessment of the CT scan findings for 
each sinus area (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinus on 
each side). The extent of mucosal opacification is rated on a 3-point scale ranging from 
0 = normal to 2 = total opacification. In addition, the ostiomeatal complex is graded as 
0 = not occluded or 2 = occluded. The maximum score is therefore 12 per side for a maximum 
total score of 24, corresponding to the sum of all sinuses and the ostiomeatal unit. 
This scoring system has been validated in several studies (37, 38, 39). 
The CT scans should be performed anytime during the screening period before first administration 
of IMP at Visit 2 (baseline CT data), Visit 5 (Week 24). The Visit 7 (Week 52) CT scan is 
optional due to variable treatment period. Whenever possible a cone beam CT scan should be 
utilized. In countries for which a specific approval procedure for the CT scan is required by a 
different committee than the local IEC/IRB, a 4-month window is required between 2 CT scans. If 
a participant needs to be rescreened or is terminated early from the study intervention, the 
repeated CT scan or following CT scan must be done over a 4-month restriction window. If 
Participant who discontinue the study intervention prematurely, the CT scan will be performed as 
soon as possible, with all other assessments normally planned in EOT Visit as long as between 2 
CT scans can meet a 4-month restriction window. Otherwise, the CT scan can be done in next 
scheduled visit. 
It is recommended to avoid use of OCS as rescue therapy during the Week 20 to Week 24 or the 
Week 48 to Week 52. If a participant must use OCS during this period to control CRSsNP 
worsening/acute sinusitis based on Investigator judgment the site should make every efforts to 
schedule the Week 24 CT scan or the Week 52 CT scan prior to OCS rescue therapy. 
The CT scan will be performed locally and reviewed centrally in a pre-specified manner as 
described in the Image Acquisition Standards (IAS) and Image Interpretation Standards (IIS) 
(refer Section 1.3).  
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8.1.2 CRSsNP Sinonasal Symptom Diary, including nasal congestion/obstruction, loss of 
sense of smell, anterior and posterior rhinorrhea, facial pain/pressure and 
headache symptoms  
The CRSsNP sinonasal symptom diary is designed to assess the severity of CRS sinonasal 
symptoms on a daily basis. These symptoms include NC/obstruction, anterior rhinorrhea and 
posterior rhinorrhea, and facial pain/pressure, and loss of smell (39). Each of the individual items 
of the diary are scored from 0 (“No symptoms”) to 3 (“Severe symptoms – symptoms that are 
hard to tolerate, cause interference with activities or daily living”). Higher scores on the items of 
the individual symptoms denote greater symptom severity.  
The CRSsNP sinus Total Symptom Score (sTSS) is a composite score derived from the 
following individual items: NC, anterior/posterior rhinorrhea, and facial pain/pressure. The total 
score ranges from 0 to 9 and consists of the sum of NC, the averaged rhinorrhea item scores, and 
facial pain/pressure scores. Higher scores on sTSS indicate greater overall symptom severity. 
The CRSsNP sinonasal symptom diary also includes an individual item about headache. 
Headache severity is scored on a scale ranging from 0 (“No symptoms”) to 3 (“Severe symptoms 
– symptoms that are hard to tolerate, cause interference with activities or daily living”). The score 
is not a part of sTSS. 
The CRSsNP sinonasal symptom diary will be administered electronically. The e-diary is used for 
daily recording of participant’s answers to the questionnaires. This device will be dispensed at the 
Screening Visit (Visit 1), including instructions for use. Participants will be instructed on the use 
of the device. Recorded information will be downloaded from this device daily. At EOS Visit, the 
e-diary will be downloaded and returned to the site. On regular basis, the site staff should review 
on the vendor’s website the information downloaded from participants’ e-diary. They should 
particularly check status of the disease as well as compliance to background/rescue therapy and 
overall e-diary compliance. The site should follow-up with the participant as appropriate. 
Participants will complete the CRSsNP sinonasal symptom diary as described in the SoA 
(Section 1.3). 
8.1.3 University of Pennsylvania Smell Identification Test (UPSIT)  
The UPSIT is a rapid and easy-to-administer method to quantitatively assess human olfactory 
function. The test consists of 4 booklets, each containing 10 odorants with one odorant per page. 
Above each odorant strip is a multiple-choice question with 4 alternative words to describe the 
odor that the participant is asked to indicate which word best describes the odor. The score ranges 
from 0 to 40, with 40 being the best possible score. Participant’s olfactory function can be 
classified based on their scores (40). The UPSIT will be procured and used to match to each 
culture easing participants identifications of the odorant depending on degree of loss of sense of 
smell. 
The clinician will administer and score the UPSIT as described in the SoA (Section 1.3). 
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8.1.4 Sino-Nasal Outcome Test-22-Items  
The SNOT-22 is a PRO questionnaire designed to assess the impact of CRS on participants’ 
HRQoL (41). SNOT-22 has 22 items covering symptoms, social/emotional impact, productivity, 
and sleep consequences of CRS. The recall period is past 2 weeks. Each item is rated on a 6-point 
Likert scale response option, ranging from 0 (‘No problem’) to 5 (‘Problem as bad as it can be’). 
A global score ranging from 0 to 110 is calculated by summing the responses to all items; higher 
score indicates greater rhinosinusitis-related health burden. The questionnaire is an easy, valid, 
and reliable tool (41). The minimally important difference that is the smallest change in SNOT-22 
score that can be detected by a participant was found to be 8.9 points (41). 
The SNOT-22 is provided in Appendix 8 (Section 10.8).  
Participants will complete the SNOT-22 as described in the SoA (Section 1.3). 
8.1.5 Three-dimensional volumetric measurement of the sinuses  
This method is used to calculate: (42) 
• The volume of the air (mL) 
• The volume of mucosa (mL) 
• % occupied by disease 
• Thickness of lateral wall 
For the analysis, central reading at baseline will be used for comparison with EOT reading. The 
sites will remove participant-identifying information from the imaging data header prior to 
sending the imaging data to the central reader. The % change in opacification from baseline to 
EOT will be calculated. 
8.1.6 Rhinosinusitis Severity Visual Analog Scale  
The rhinosinusitis severity VAS is used to evaluate the overall severity of the rhinosinusitis (41). 
It is a recommended scale to determine the participant’s disease severity and to guide the 
treatment for CRS. The participant is asked to answer the following question: “How troublesome 
are your symptoms of your rhinosinusitis” on a 10-cm VAS from 0 (‘not troublesome’) to 10 
(‘worst thinkable troublesome’). Based on their score on the VAS, the severity of rhinosinusitis 
can be divided into 3 categories as follows: 
• Mild = VAS 0 to 3  
• Moderate = VAS >3 to 7 
• Severe = VAS >7 to 10 
The rhinosinusitis severity VAS is provided in in Appendix 8 (Section 10.8).  
Participants will complete the rhinosinusitis severity VAS as described in the SoA (Section 1.3). 
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8.1.7 Asthma Control Questionnaire 6-item version  
The asthma control questionnaire 6-items (ACQ-6) was designed to measure both the adequacy of 
asthma control and the change in asthma control that occurs either spontaneously or as a result of 
treatment (43). The ACQ-6 has 6 questions that assess the most common asthma symptoms: 1) 
Frequency in past week awoken by asthma during the night, 2) Severity of asthma symptoms in 
the morning, 3) Limitation of daily activities due to asthma, 4) Shortness of breath due to asthma, 
5) Frequency of wheezing, and 6) Short-acting bronchodilator use.  
Participants are asked to recall how their asthma has been during the previous week and to 
respond to the symptom questions on a 7-point scale (0 = no impairment, 6 = maximum 
impairment). The questions are equally weighted; and the ACQ-6 global score is the mean of the 
6 questions ranging from 0 (totally controlled) to 6 (severely uncontrolled). A higher score 
indicates lower asthma control. On the 7-point scale of the ACQ-6, a change or difference in score 
of 0.5 is the smallest change that can be considered clinically important, corresponding to the 
minimal clinically important difference (MCID) defined by the developer (44). Measurement 
properties such as reliability and the ability to detect change have been documented in the 
literature (44).  
The ACQ-6 is provided in Appendix 8 (Section 10.8).  
Participants with comorbid asthma will complete the ACQ-6 as described in the SoA 
(Section 1.3). 
8.1.8 Patient Global Impression of Severity of CRSsNP and Patient Global Impression of 
Change of CRSsNP  
The Patient Global Impression of Change (PGIC) is a 1-item questionnaire that asks the 
participant to provide the overall self-assessment of change in their CRSsNP on a 7-point scale 
compared to just before the participant started taking the study treatment. The response choices 
are: 0 = “Very much better”, 1 = “Moderately better”, 2 = “A little better”, 3 = “No change”, 
4 = “A little worse”, 5 = “Moderately worse”, and 6 = “Very much worse”.  
The Patient Global Impression of Severity (PGIS) is a 1-item questionnaire that asks participants 
to provide the overall self-assessment of their CRSsNP severity on a 4-point scale for the past 
week. Response choices are: 1 = “None”, 2 = “Mild”, 3 = “Moderate”, and 4 = “Severe”. 
The PGIS and PGIC are provided in Appendix 8 (Section 10.8).  
Participants will complete the 2 items as described in the SoA (Section 1.3). 
8.1.9 EuroQol-5 dimensions questionnaire  
The EuroQol-5 dimensions (EQ-5D) is a standardized PRO measure of health status developed by 
the EuroQol Group in order to provide a simple, generic measure of health for clinical and 
economic appraisal. The adult version of the questionnaire is adapted to participants age 16 and 
older and can be used for participants aged 12-15 as stated in the EQ-5D user guide. The EQ-5D 
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consists of 2 parts: the descriptive system and the EuroQol-VAS. The EQ-5D-5L descriptive 
system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels of perceived problems: “no 
problem”, “slight problems”, “moderate problems”, “severe problems”, and “extreme problems” 
(45). The respondent is asked to indicate his/her health state by ticking (or placing a cross) in the 
box against the most appropriate statement in each of the 5 dimensions; this results in a 1-digit 
number expressing the level for that dimension. The digits for 5 dimensions can be combined in a 
5-digit number describing the respondent’s health state. The EQ-VAS records the respondent’s 
self-rated health on a vertical, VAS where the endpoints are labeled “best imaginable health state 
(100)” and “worst imaginable health state (0)”. This information can be used as a quantitative 
measure of health outcome as judged by the individual respondents. The recall period of the 
questionnaire is “today”. 
The EQ-5D-5L is provided in Appendix 8 (Section 10.8). 
Participants will complete the questionnaire as described in the SoA (Section 1.3). 
8.1.10 Health care resource utilization and missed days at work/missed days at school  
A questionnaire about health care resource utilization and productivity (missed days of 
school/workdays) will be collected by the Investigator for all participants throughout the study 
through eCRF. 
8.1.11 CRSsNP Worsening/Acute Sinusitis  
The CRSsNP worsening/acute sinusitis is defined as worsening of any of CRS symptoms that 
requires initiation of rescue therapy as assessed by Investigator. 
8.1.12 Spirometry  
Spirometry will be performed at the local level (study site or another facility) in the morning after 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 
6 hours and LAMA and LABA for 24 hours. The FEV1, forced vital capacity (FVC), and forced 
expiratory flow at 25% to 75% of forced vital capacity (FEF 25 to 75) will be determined at the 
designated treatment visits. The results of FEV1 (% of predicted normal), FVC and FEF 25 to 75 
should be recorded in the eCRF during the screening period (before V2) for all participants and in 
participants with asthma for the other scheduled visits during the randomized treatment period. 
Whenever possible, the same spirometer and standard spirometric techniques, including 
calibration, will be used to perform spirometry at all visits and, the same person should perform 
the measurements. 
8.1.13 
 
 
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 (Section 1.3). 
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the skin (full 
body skin examination), nasal cavities, eyes, ears, respiratory, cardiovascular, 
gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
• Participants should be disrobed and provided with a hospital gown before the skin 
examination. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new adverse 
event. 
8.2.2 Vital signs  
Vital signs will be measured in a semi-supine or sitting position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse, and respiratory rate.  
Blood pressure and pulse measurements should be assessed using the same arm with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
Body weight (kg) will be measured at Screening (Visit 1), Baseline (Visit 2) and following visits. 
Height (cm) will be measured only at Screening (Visit 1). 
8.2.3 Electrocardiograms  
As defined in SoA (Section 1.3), single 12-lead ECG will be obtained for screening purpose only. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency.  
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying disease, 
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unless judged by the Investigator to be more severe than expected for the participant’s 
condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 12 weeks after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or Sponsor or Sponsor representative(s). 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified, 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA 
(Section 1.3), 
- 
If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE, AE or dose 
modification), then the results must be recorded in the eCRF.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7).  
8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the informed consent form (ICF) until the EOS 
Visit at the time points specified in the SoA (Section 1.3). 
All AEs will be collected from the signing of the ICF 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 it being 
available. 
Investigators are not obligated to actively seek 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 
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related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the prespecified study end-date, all SAEs, and AEs of 
special interest (as defined in Section 8.3.6), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators. 
• Adverse events that are considered expected will be specified in the reference safety 
information.  
• Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows: 
• For SUSARs that are life-threatening or result in death, reporting is no later than 7 days 
after first knowledge by the Sponsor, with all relevant follow-up information subsequently 
reported within an additional 8 days, 
• For SUSARs, other than those that are life-threatening or result in death, reporting is no 
later than 15 days after first knowledge by the Sponsor. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR and, therefore, is expedited to regulatory authorities. 
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8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until the outcome has been 
determined. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs 
8.3.6 Adverse event of special interest  
Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified, or removed during a study by protocol amendment. 
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described in Section 10.3, even if not fulfilling a seriousness criterion, using the 
corresponding pages in the eCRF (to be sent) or screens in the eCRF. Adverse event of special 
interests for this study include:  
• Anaphylactic reactions. 
• Systemic hypersensitivity reactions. 
• Helminthic infections. 
• Any severe type of conjunctivitis or blepharitis.  
• Keratitis. 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms). 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in the study with IMP: 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial will be qualified as an SAE 
only if it fulfills one of the seriousness criteria, 
- 
In the event of pregnancy in a female participant, IMP should be discontinued, 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined, 
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
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• Significant ALT elevation: 
- 
ALT >5 × ULN in participants with baseline ALT ≤2 × ULN, 
- 
OR 
- 
ALT >8 × ULN if baseline ALT >2 × ULN. 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the intended dose during an interval of less than 11 days. The circumstances 
(ie, accidental or intentional) should be clearly specified in the verbatim and 
symptoms, if any, entered on separate AE forms, 
- 
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the maximum prescribed daily dose, within the intended therapeutic interval. The 
circumstances (ie, accidental or intentional) should be clearly specified in the overdose 
form. 
8.3.7 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
Overdose is an AESI (defined in Section 8.3.6). No antidote is available for dupilumab. The 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Provide symptomatic care. 
2. Contact the Sponsor or Sponsor representative(s) immediately. 
3. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
dupilumab can no longer be detected systemically. 
4. Obtain a plasma sample for PK analysis as soon as possible if requested by the Sponsor or 
Sponsor representative(s) (determined on a case-by-case basis). 
5. Document appropriately in the eCRF. 
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Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor or Sponsor representative(s) based on the clinical evaluation of the 
participant. 
8.5 
PHARMACOKINETICS AND IMMUNOGENICITY ASSESSMENTS  
8.5.1 Systemic drug concentration and anti-drug antibodies  
8.5.1.1 Sampling time  
Blood samples will be collected for determination of functional dupilumab and anti-dupilumab 
antibodies in serum as specified in the SoA (Section 1.3). Special procedures for collection, 
storage, and shipping of serum are described in separate operational manuals. The date of 
collection should be recorded in the eCRF. 
8.5.1.2 Handling procedures  
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of handling procedure for samples used in the determination of 
systemic drug concentration and anti-drug antibody (ADA) is provided in Table 3. 
Table 3 - Summary of handling procedures  
Sample type 
Functional dupilumab 
Anti-dupilumab antibody 
 
 
8.5.1.3 Bioanalytical method  
Serum PK and ADA samples will be analyzed using validated methods as described in Table 4. 
Table 4 - 
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Note: In the event of any suspected SAE, any AE of severe injection site reaction lasting longer 
than 24 hours, or any AESI like anaphylactic reaction hypersensitivity, PK and ADA samples will 
be collected at or near the onset of the event. The exact date and time of sample collection must be 
recorded and entered into the database by the central laboratory. An unscheduled systemic drug 
concentration page in the eCRF must be completed as well. 
Specifically for PK, any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member and then 
archived in the Sponsor and site study files but will not constitute a protocol amendment. The 
IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the ICF. 
8.6 
PHARMACODYNAMICS  
(Section 1.3)  
 (Section 1.3).  
•
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•
Section 8.7. 
8.7 
GENETICS  
Pharmacogenetic/pharmacogenomic testing from whole blood samples is optional and voluntary. 
Written informed consent must be obtained before sampling.  
For those participants who consent to the optional pharmacogenetic/pharmacogenomic sample 
collection section of the ICF, blood samples for exploratory genetic analysis of DNA or RNA will 
be collected at the study visit as specified in the SoA (Section 1.3), and these samples will be 
stored for future analysis. Specific procedures for collection, storage and shipping of 
pharmacogenetic/pharmacogenomic samples will be provided in a lab manual. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
For participant(s) who have consented to it, the samples that are archived, unused or left over after 
planned testing may be used for additional research purposes refer to Appendix 5 (Section 10.5).  
8.8 
  
 Section 8.6 and Section 8.7. 
• 
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8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS  
Health care resource utilization and productivity (missed days of school/workdays) are described 
in Section 8.1.10. 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
and used for future research when consented to by participants (see Section 10.1.3) unless 
prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will not be 
included in the local ICF).  
For participants who consent to the storage and use of their data and remaining and/or extra 
clinical samples, data and samples may be used after the study ends for future research related 
either to the drug, the mechanism of action, and the disease or its associated conditions. Such 
research may include, but is not limited to, performing assessments on DNA, RNA, proteins, or 
metabolites. If future research on genetic material is performed, this will also be limited to the 
purpose of addressing research questions related to the drug, the mechanism of action, the disease 
or its associated conditions. 
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. 
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research). 
All study participant data and samples will be coded such that no participant direct identifiers will 
be linked to them. Coded data and samples may be transferred to a Sponsor site (or a 
subcontractor site), which may be located outside of the country where the study is conducted. 
The Sponsor adopts safeguards for protecting participant confidentiality and personal data (see 
Section 10.1.4). 
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The samples will be stored for a maximum of 15 years after the end of the study. Any samples 
remaining at the end of retention period will be destroyed. If a participant requests destruction of 
his/her samples before the end of the retention period, the Investigator must notify the Sponsor (or 
its contract organization) in writing. In such case, samples will be destroyed and related coded 
data will be anonymized unless otherwise required by applicable laws. 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
No statistical hypotheses will be tested in this study. 
9.2 
SAMPLE SIZE DETERMINATION  
Sample size calculation was performed to ensure reasonable accuracy for the estimation of the 
primary endpoint in participants treated with dupilumab with screening blood eosinophil count 
≥300 cells/mm3. With a 1:1 randomization ratio, a standard deviation (SD) of 5 and a dropout rate 
of 10%, a sample size of approximately 30 participants with screening blood eosinophil count 
≥300 cells/mm3 will provide a half-width of approximately less than 3 for the 2-sided 95% CI in 
the dupilumab group which is deemed reasonable. 
In addition, it is planned to include approximately 40 participants with screening blood eosinophil 
count <300 cells/mm3. Thus, the planned total sample size is approximately 35 participants per 
arm.  
9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined in Table 5 for this study. The primary population of the 
efficacy endpoints will be the ITT population with screening blood eosinophil count ≥ 300 
cells/mm3. 
Table 5 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF. 
Randomized 
The randomized population includes all participants with a treatment kit number allocated and recorded in the 
IRT database, and regardless of whether the treatment kit was used or not. Participants treated without being 
randomized will not be considered randomized and will not be included in any efficacy population. 
Intent-to-treat (ITT) 
All randomized participants analyzed according to the treatment group allocated by randomization 
regardless if treatment kit is used or not. 
ITT with screening 
blood eosinophil 
count 
≥300 cells/mm3 
All randomized participants with screening blood eosinophil count ≥300 cells/mm3 analyzed according to 
the treatment group allocated by randomization regardless if treatment kit is used or not. 
Safety 
All participants randomly assigned to study intervention and who take at least 1 dose of study intervention. 
Participants will be analyzed according to the intervention they actually received. Randomized participants for 
whom it is unclear whether they took the study medication will be included in the safety population as 
randomized. For participants who accidentally receive different study intervention from the planned, the actual 
intervention allocation for as-treated analysis will be the dupilumab group. 
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Population 
Description 
Pharmacokinetic 
(PK) 
The PK population includes all participants in the safety population with at least 1 non-missing result for 
functional dupilumab concentration in serum after the first dose of the study intervention. Participants will 
be analyzed according to the intervention actually received. 
Anti-drug antibody 
(ADA) 
ADA population includes all participants in the safety population who have at least 1 non-missing result 
in the ADA assay after the first dose of the study intervention. Participants will be analyzed according to 
the intervention actually received. 
ADA: anti-drug antibody; ICF: informed consent form; IRT: interactive response technology; ITT: intent-to-treat; PK: pharmacokinetic 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will include more technical and detailed descriptions of the 
statistical analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary and secondary endpoints. 
9.4.1 General considerations  
The baseline value is defined generally as the last available value before randomization. For 
endpoints collected on the daily CRSsNP sinonasal symptom diary, baseline is defined as the 
average of the scores in the 7 days prior to randomization. 
9.4.2 Primary endpoint(s)  
The primary estimand for the primary endpoint is the hypothetical/treatment policy strategy as 
described in Table 6.  
Table 6 - Summary of primary estimand for primary endpoint  
Endpoint 
Category 
Estimands 
Endpoints 
Population 
Intercurrent event(s) handling 
strategy and missing data 
handling 
Population-level 
summary  
 
Primary objective: To evaluate the efficacy of dupilumab as assessed by the reduction at Week 24 in sinus opacification on 
computerized tomography (CT) scan in the dupilumab group only 
Primary endpoint 
Change from 
baseline in LMK 
score at Week 24 
 
 
ITT with 
screening blood 
eosinophil 
count ≥ 300 
cells/mm3 
The intercurrent events (IEs) will be 
handled as follows: 
• 
Undergoing sinonasal surgery for 
CRSsNP or taking SCS for any 
reason prior to Week 24: data 
after the IE will be set to missing 
and the worst post-baseline value 
on or before the time of the IE will 
be used to impute missing Week 
24 value (WOCF). For participants 
with no post-baseline values, the 
baseline value will be used 
(hypothetical strategy). 
Descriptive statistics 
and 95% CI in the 
dupilumab group will be 
provided.  
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Endpoint 
Category 
Estimands 
Endpoints 
Population 
Intercurrent event(s) handling 
strategy and missing data 
handling 
Population-level 
summary  
 
• 
Taking other prohibited/rescue 
medications: all data collected 
after use will be used in the 
analysis (treatment policy 
strategy). 
• 
Discontinuing the study 
intervention: all data collected 
after discontinuation will be used 
in the analysis (treatment policy 
strategy). 
Missing data will not be imputed.  
 
In the primary analysis approach for the primary endpoint, for participants who undergo sinonasal 
surgery for CRSsNP or take SCS for any reason, data collected after surgery or initiation of SCS 
will be set to missing and the worst post-baseline value on or before the time of surgery or SCS 
will be used to impute missing Week 24 value (ie, WOCF approach). For participants with no 
post-baseline values, the baseline value will be used. Participants who discontinue the study 
intervention prematurely are encouraged to follow the planned clinical visits and, in these 
participants, who did not undergo surgery or receive SCS, all data collected after study 
intervention discontinuation will be used in the analysis. No missing data will be imputed. 
Descriptive statistics (number of participants, mean, SD, median, minimum and maximum) and 
95% CI in the dupilumab group, will be provided. 
Supplementary analyses 
Supplementary analyses to assess the robustness of intercurrent event handling may be performed. 
Details will be provided in the SAP. 
9.4.3 Secondary endpoint(s)  
- 
The change from baseline to Week 24 in the secondary endpoints will be analyzed 
using the same analysis approach as for the primary endpoint. For endpoints 
comparing dupilumab to placebo, 95% CI of the treatment difference will be provided.    
9.4.4 Tertiary/exploratory endpoint(s)  
Analysis of exploratory endpoints will be detailed in the SAP.  
9.4.5 Other safety analyses  
All safety analyses will be performed on the safety population. The summary of safety results will 
be presented by treatment group.  
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Analyses of Adverse Events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order) and preferred term (PT), the number (n) and percentage (%) of 
participants experiencing an AE. Multiple occurrences of the same event in the same participant 
will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group.  
The proportion of participants with at least 1 treatment-emergent adverse event (TEAE), 
treatment-emergent serious adverse event (TESAE), TEAE leading to death, and TEAE leading to 
permanent study intervention discontinuation will be tabulated by treatment group. In addition, 
TEAEs will be described according to maximum intensity and relation to the study intervention. 
Serious AEs and AEs leading to study discontinuation that occur outside the treatment-emergent 
period will be summarized separately.  
The incidence of each type of AESI and other AE groupings will be tabulated by treatment group. 
For each type of AESI, the following analysis will be generated: 
• A summary of the number (%) of participants with: 
- 
Any TEAE,  
- 
Any SAE (regardless of treatment-emergent status),  
- 
Any TESAE, 
- 
Any AE leading to death,  
- 
Any TEAE leading permanent study intervention discontinuation,  
- 
Any TEAE related to study intervention reported by the Investigator,  
- 
Any TEAE by maximum intensity, corrective treatment, and final outcome.  
The method to identify AESIs and other AE groupings will be specified in the SAP.  
The following death summaries will be generated:  
• Number (%) of participants who died by study period (TEAE, on study) summarized on 
the safety population by treatment received.  
• Death in nonrandomized participants or randomized and not treated participants.  
• TEAE leading to death (death as an outcome on the AE eCRF page as reported by the 
Investigator) by primary SOC and PT showing number (%) of participants.  
Analyses of laboratory and vital signs parameters 
Results and change from baseline for the laboratory and vital signs parameters will be 
summarized by treatment group for baseline and each post baseline time point, endpoint, 
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minimum and maximum value. Summary statistics will include number of participants, mean, 
standard deviation, median, Q1, Q3, minimum, and maximum.  
The following definitions will be applied to laboratory and vital signs parameters.  
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor.  
• PCSA criteria will determine which participants had at least 1 PCSA during the 
treatment-emergent period, taking into account all evaluations performed during the 
treatment-emergent period, including unscheduled or repeated evaluations. The number of 
all such participants will be the numerator for the treatment-emergent PCSA percentage.  
The proportion of participants who had at least one incidence of PCSA at any time during the 
treatment-emergent period will be summarized by treatment group. Shift tables showing changes 
with respect to the baseline status will be provided.  
9.4.6 Other analyses  
Pharmacokinetic, immunogenicity, PD, and biomarker exploratory analyses will be described in 
the SAP finalized before the database lock. The population PK and PD analyses might be 
presented separately from the main clinical study report (CSR). 
Data collected regarding the impact of the COVID-19 or other pandemics on the participants will 
be summarized (eg, discontinuation due to COVID-19). Any additional analyses and methods 
required to investigate the impact of COVID-19 or other events requiring public health emergency 
on the efficacy (eg, missing data due to COVID-19) and safety will be detailed in the SAP. 
9.5 
INTERIM ANALYSES  
No interim analysis is planned. 
9.6 
TIMING OF STATISTICAL ANALYSES  
The database lock will be performed after all participants have completed the end of study visit. 
Final analyses in the CSR will be based on all data collected up to this database lock. 
9.7 
DATA MONITORING COMMITTEE (DMC)  
Due to the extensive safety record of the post-marketed IMP (dupilumab), it is not planned to 
have a Data Monitoring Committee for this study. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines, 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR). 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC Determining whether an incidental finding should be 
returned to a participant and, if it meets the appropriate criteria, to ensure the finding is 
returned (an incidental finding is a previously undiagnosed medical condition that is 
discovered unintentionally and is unrelated to the aims of the study for which the tests 
are being performed). The following should be considered when determining the return 
of an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
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, 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity, 
- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
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- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory samples or new samples collected for optional research). 
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Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. A separate signature will be required to 
document a participant's agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide this 
separate signature. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (General Data Protection Regulation). The 
study Sponsor is the Sanofi company responsible for ensuring compliance with this matter, when 
processing data from any individual who may be included in the Sanofi databases, including 
Investigators, nurses, experts, service providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on Afro American population for the FDA or on Japanese population for 
the Pharmaceuticals and Medical Devices Agency in Japan). They will not be collected in the 
countries where this is prohibited by local regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
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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 trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study,  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency. 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
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• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
There will be no study committees.  
10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in participants are required to be submitted to peer-
reviewed journals following internal company review for accuracy, fair balance and intellectual 
property. For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to vivli.org. 
Individual participant data and supporting clinical documents are available for request at vivli.org. 
While making information available we continue to protect the privacy of participants in our 
clinical trials. Details on data sharing criteria and process for requesting access can be found at 
this web address: vivli.org.  
Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/ hospital’s name and location on the China Trial Disclosure website as required 
by the National Medical Products Administration (NMPA) in its guidance “Implementation of 
Drug Clinical Trial Information Registration and Disclosure” (“Notification No. 28”), requesting 
name disclosure of Chinese and foreign investigational sites and Investigators in any eligible 
clinical trial.  
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Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
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• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents. 
Source documents are original documents, data and records such as hospital records, clinic 
and office charts, laboratory notes, memoranda, pharmacy dispensing records, recorded 
data from automated instruments, etc. 
10.1.9 Study and site start and closure  
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. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio, 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines, 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator, 
- 
Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
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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 7 will be performed by the central laboratory.  
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central analysis 
is obtained at the same time. Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be entered into 
the eCRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the Investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant's participation in the study. 
Table 7 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya, b 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose 
 
Lactate dehydrogenase 
 
Uric acid 
 
Total cholesterol 
 
Potassium 
 
Sodium 
 
Chloride 
 
Bicarbonate 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total bilirubin 
 
Albumin 
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Laboratory assessments 
Parameters 
 
Total protein 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstickc 
• 
Creatinine and leukotriene (central laboratory) 
• 
Microscopic examination (if blood or protein is abnormal) f 
Other screening tests 
• 
Highly sensitive serum (at screening) or urine (at other time points) hCG 
pregnancy test (as needed for WOCBP)d 
• 
Serologye: HBsAg, HBsAb, HBcAb, HCVAb, HIV screen (Anti-HIV-1 and HIV-2 
antibodies). 
• 
Tuberculosis test 
• 
All study-required laboratory assessments will be performed by a central 
laboratory, with the exception of TB test, urine pregnancy test, and routine urine 
dipstickc.  
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 antibodies, HIV: Human Immunodeficiency Virus, WOCBP: 
women of childbearing potential, ULN: upper limit of normal. 
NOTES : 
a Details of liver chemistry stopping criteria with suggested actions and follow-up assessments related to liver monitoring are given in 
Section 7.1 and Section 10.6. All events which may indicate severe liver injury (possible Hy’s Law, ALT or AST >3 × ULN and total 
bilirubin >2 × ULN) must be reported as an SAE. 
b All drug-induced liver injury (DILI) testing should be performed locally, unless there is no local support available in which case the analysis 
can be done at the central laboratory. 
c For participants enrolled in China, the urine analysis will be performed at laboratory (not dipstick). 
d After screening local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
e In case of results showing HBsAg (negative) and HBcAb (positive), an HBV DNA testing will be performed and should be confirmed 
negative prior to randomization. In case of results showing HCVAb (positive), HCV RNA testing will be performed and should be 
confirmed negative prior to randomization. 
f 
In case the urine dipstick test result is abnormal, a urine sample should be sent into the central laboratory for microscopic examination. 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of efficacy" or "failure of 
expected pharmacological action" also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
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• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
• The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
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f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent 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:  
- 
Allergic bronchospasm, 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc), 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse,  
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT 
increase >10 × ULN,  
- 
Suicide attempt or any event suggestive of suicidality,  
- 
Syncope, loss of consciousness (except if documented as a consequence of 
blood sampling),  
- 
Bullous cutaneous eruptions, 
- 
Cancers diagnosed during the study or aggravated during the study, 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated 
during the study. 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE/SAE eCRF page. 
• 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. 
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• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.  
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor’s representative with a copy of any post-
mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the protocol. 
SAE reporting to the Sponsor via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the protocol. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea athletes) and a menstrual cycle cannot be confirmed before 
first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal. 
2. Premenopausal female with one of the following: 
- 
Documented hysterectomy, 
- 
Documented bilateral salpingectomy, 
- 
Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
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CONTRACEPTION GUIDANCE: 
Female participants of childbearing potential are eligible to participate if they agree to use 
a highly effective method of contraception consistently and correctly as described below. 
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation  
• 
Oral  
• 
Intravaginal  
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly effective methods that are user independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used. 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. 
• 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 
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female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the delivery date. Any termination of pregnancy will 
be reported, regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in  
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
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10.5 
APPENDIX 5: GENETICS  
 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS  
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.3 for guidance on safety reporting. 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
ALT > 3 ULN
Monitor LFTs every 72 hours
ALT ≤ 5 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
ALT > 5 ULN 
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
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
COMPLETE the specific CRF forms 
for „ALT Increase” and inform the 
Monitoring Team within 24 hours
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
INCREASE IN ALT
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10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
10.7.1 China  
For participants enrolled in China, the urine analysis will be performed at laboratory (not 
dipstick). 
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10.8 
APPENDIX 8: CLINICIAN-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES  
10.8.1 Sino-Nasal Outcome Test  
 
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10.8.2 Rhinosinusitis Severity Visual Analog Scale  
 
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10.8.3 Asthma Control Questionnaire 6-item version  
 
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10.8.4 Patient Global Impression of Severity (PGIS)/ Patient Global Impression of Change 
(PGIC)  
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10.8.5 EuroQol-5 dimensions  
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10.8.6 CRSsNP Morning Diary  
 
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10.8.7 Healthcare Resource Utilization (HCRU) questionnaire  
The HCRU questionnaire presented below is the general one without specific visits. HCRU 
questionnaire versions with Baseline (Visit 1), Week 12 (Visit 4), Week 24 (Visit 5), Week 40 
(Visit 6), and Week 52 (Visit 7) questions are displayed in the sub-headings below. 
 
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10.8.7.1 HCRU questionnaire at Visit 1  
HCRU questionnaire version with Baseline (Visit 1) question is displayed below. 
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10.8.7.2 HCRU questionnaire at Week 12  
HCRU questionnaire version with Week 12 (Visit 4) question is displayed below. 
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10.8.7.3 HCRU questionnaire at Week 24  
HCRU questionnaire version with Week 24 (Visit 5) question is displayed below. 
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10.8.7.4 HCRU questionnaire at Week 40  
HCRU questionnaire version with Week 40 (Visit 6) question is displayed below. 
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10.8.7.5 HCRU questionnaire at Week 52  
HCRU questionnaire version with Week 52 (Visit 7) question is displayed below. 
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10.9 
APPENDIX 9: DEFINITION OF ANAPHYLAXIS  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death (48)”. 
Clinical criteria for diagnosing anaphylaxis 
 
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10.10 APPENDIX 10: LIST OF OPPORTUNISTIC INFECTIONS  
• Aspergillosis 
• Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers) 
• Candidiasis - only systemic or extensive mucosal or cutaneous candidiasis  
• Coccidioides immitis (endemic south-western US and Central and South America) 
• Cryptococcus 
• Cytomegalovirus 
• Herpes simplex (disseminated) 
• Herpes zoster (disseminated; ophthalmic; involvement of 2 or more dermatomes) 
• Histoplasmosis (pulmonary or disseminated; most common tropical areas 
Tennessee-Ohio-Mississippi river basins) 
• Listeriosis 
• Mycobacterium TB 
• Mycobacterium avium 
• NonTB mycobacteria 
• Pneumocystis pneumonia 
This list is indicative and not exhaustive.
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10.11 APPENDIX 11: ABBREVIATIONS  
 
ACQ-6: 
asthma control questionnaire 6-items 
AD: 
atopic dermatitis 
ADA: 
anti-drug antibody 
ADR: 
adverse drug reaction 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
CLC: 
Charcot-Leyden crystal 
COPD: 
chronic obstructive pulmonary disease 
COVID-19: 
Coronavirus Disease-2019 
CRS: 
chronic rhinosinusitis 
CRSsNP: 
chronic rhinosinusitis without nasal polyposis 
CRSwNP: 
chronic rhinosinusitis with nasal polyposis 
CSR: 
clinical study report 
CSU: 
chronic spontaneous urticaria 
CT: 
computed tomography 
ECG: 
electrocardiogram 
ECP: 
eosinophilic cationic protein 
eCRF: 
electronic case report form 
ELISA: 
enzyme-linked immunosorbent assay 
EoE: 
eosinophilic esophagitis 
EOS: 
end of study 
EOT: 
end of treatment 
EQ-5D: 
EuroQol-5 dimensions  
ESS: 
endoscopic sinus surgery 
EU: 
European Union 
FEF: 
forced expiratory flow 
FeNO: 
Fractional exhaled nitric oxide 
FEV1: 
Forced expiratory volume 
FVC: 
forced vital capacity  
GA2LEN: 
Global Allergy and Asthma European Network 
GCP: 
Good Clinical Practice 
GDPR: 
General Data Protection Regulation 
HBcAb: 
hepatitis B core antibody 
HBsAb: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HCRU/P: 
Health Care Resource Utilization/Productivity 
HCV: 
hepatitis C virus 
HCVAb: 
hepatitis C virus antibody 
HIV: 
human immunodeficiency virus 
HRQoL: 
health-related quality of life 
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IB: 
Investigator’s Brochure  
ICF: 
informed consent form 
IEC: 
Independent Ethics Committee 
IgE: 
immunoglobulin E 
IL: 
interleukin 
IL-4Rα: 
interleukin 4 receptor alpha subunit 
IMP: 
investigational medicinal product 
INCS: 
intranasal corticosteroids 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
IVIG: 
intravenous immunoglobulin  
LABA: 
long-acting β2-adrenergic receptor agonists 
LAMA: 
long-acting muscarinic acetylcholine receptor antagonists  
LMK: 
Lund-Mackay 
LTE4: 
leukotriene E4 
NAb: 
neutralizing antibody, neutralizing antibody 
NC: 
nasal congestion 
NES: 
Normalized Enrichment Score 
NMPA: 
National Medical Products Administration 
NPS: 
nasal polyp score 
OCS: 
oral corticosteroids 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
PGDM: 
prostaglandin D2 metabolite 
PGIC: 
Patient Global Impression of Change  
PGIS: 
Patient Global Impression of Severity  
PK: 
pharmacokinetics 
PN: 
prurigo nodularis 
PRO: 
Patient-Reported Outcome  
PT: 
preferred term 
q2w: 
every 2 weeks 
QTcF: 
QT interval corrected using Fridericia's formula 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SCS: 
systemic corticosteroids 
SD: 
standard deviation 
SNOT-22: 
Sino-Nasal Outcome Test 22-item 
SoA: 
Schedule of Activities 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
TARC: 
thymus-and activation-regulated chemokine 
TB: 
tuberculosis 
TEAE: 
treatment-emergent adverse event 
TESAE: 
treatment-emergent serious adverse event 
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TNF: 
tumor necrosis factor 
TSS: 
total symptom score 
ULN: 
upper limit of normal 
UPSIT: 
University of Pennsylvania smell identification test 
US: 
United States 
VAS: 
Visual Analog Scale 
WOCBP: 
women of childbearing potential 
WOCF: 
worst observation carried forward 
 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.12.1 
Amended protocol 01 (08 July 2021)  
This amended protocol 01 (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.  
10.12.1.1 
OVERALL RATIONALE FOR THE AMENDMENT  
The primary purpose of this amendment is to change the primary analysis population to the 
intent-to-treat (ITT) population in Part A and to remove comorbid asthma as inclusion criterion as 
per a Health Authority request. The Sponsor changed the handling of sinonasal surgery from 
composite strategy to hypothetical strategy in the primary estimand to better reflect the clinical 
scenario. Additional changes are described in the table below. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
To add the Sponsor’s name and address that 
were missing 
To add the NCT number 
To provide missing information. 
Section 1.1 Synopsis  
Acronym ‘Liberty CRSsNP ORION’ added 
To provide missing information. 
Sections 1.2 Schema and 1.3 
Schedule of Activities (SoA) 
Following text added: Note that Part B will not 
start until after primary analysis of Part A. 
Clarification 
Section 1.3 SoA 
Nasal endoscopy: Addition of local reading for 
excluding purulent discharge 
To allow for improved visual 
assessment of discharge by local 
investigator as difficult to evaluate 
in video by central readers 
 
Urinalysis (urine dipstick): Note added that China 
will use the urine sample analysis 
To clarify that for participants 
enrolled in China, the urine 
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Section # and Name 
Description of Change 
Brief Rationale 
analysis will be performed at 
laboratory (not dipstick) as per 
local medical practice 
 
Footnote k: V6 was corrected to V5 as follows: 
A CT scan was performed at V5 (Week 24 for 
Parts A and B). 
Correction 
 
Footnote r was changed to: Clinical laboratory 
testing at V1 includes hepatitis screen covering 
hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (HBsAb), hepatitis B core 
antibody (HBcAb) including total HBcAb, 
hepatitis C virus antibodies (HCVAb), HIV screen 
(anti-HIV-1 and HIV-2 antibodies). In case of 
results showing HBsAg (negative) and HBcAb 
(positive), an HBV DNA testing will be performed 
and should be confirmed negative prior to 
randomization. In case of results showing HCVAb 
(positive), HCV RNA testing will be performed and 
should be confirmed negative prior to 
randomization  
HBcAb IgM and IgG were 
removed as only HBcAb total test 
is performed at Central 
Laboratory. 
Adjusted language to allow for 
clarity on when to do reflex testing 
for HBV or HCV. 
 
Footnote t was added: Urine biomarkers (LTE4, 
PGDM, creatinine) collection time and date to be 
collected. 
Clarification 
 
Footnotes v and w: Not applicable in China was 
added. 
Correction 
Section 2.3.1 Risk assessment 
Addition of a reference to the current 
Investigator’s Brochure (IB) for the number of 
participants exposed to dupilumab in clinical 
studies. 
Clarification 
Section 3 Objectives and endpoints 
and 1.1 Synopsis 
Addition of a secondary objective and related 
endpoints in Part A (at Weeks 24 and 52) as 
follows: 
Objective: To evaluate the effect of dupilumab in 
the subgroup of participants with screening blood 
eosinophil count ≥300 cells/mm3 compared to 
placebo 
Endpoints: 
-Change from baseline to Weeks 24 and 52 
(Part A) in opacification of sinuses assessed by 
CT scan using LMK score in the screening blood 
eosinophil count ≥300 cells/mm3 population.  
-Change from baseline to Weeks 24 and 52 
(Part A) in sinus total symptom score (sTSS) 
using the screening blood eosinophil count 
≥300 cells/mm3 population.  
-Evaluation of other secondary endpoints listed 
above in the screening blood eosinophil count 
≥300 cells/mm3 population.  
To evaluate the effect of 
dupilumab in a subgroup of 
interest as the primary analysis 
population was changed to the 
ITT population regardless of 
eosinophil levels in Part A, per 
Health Authority request. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 3.1 Appropriateness of 
measurements 
 
The text was simplified. 
Edited for clarity. 
Section 4.1 Overall design and 
1.1 Synopsis 
Correction of the alert for IRT modified from 50% 
to no more than 70% as follows: Alert built to limit 
the number of participants without comorbid 
asthma to no more than 70% of the randomized 
population. 
To allow flexibility in recruitment 
of comorbid asthma population  
Section 5.1 Inclusion criteria 
I 06. was modified to remove b) comorbid asthma 
as follows: 
Participants must have at least one of the 
2 following features: 
a) Prior sinonasal surgery (see note at end of 
section 5.2 for definitions of sinonasal surgery) for 
CRS 
b) Treatment with SCS therapy for CRS as 
defined by any dose and duration within the prior 
2 years before screening (Visit 1) or 
intolerance/contraindication to SCS. 
Per Health Authority request 
 
Inclusion criterion I 09. was corrected to remove 
‘men’ as follows: 
Contraception use by women should be 
consistent with local regulations regarding the 
methods of contraception for those participating in 
clinical studies. 
Correction 
Section 5.2 Exclusion criteria 
Exclusion criterion E 01. was corrected to add 
‘observed during nasal’ as follows: 
a) Participants with nasal polyposis observed 
during nasal endoscopy at Visit 1. 
Correction 
 
Exclusion criterion E 02. was corrected to replace 
blood boil example by hemangioma example. 
Correction 
 
Exclusion criterion E 16. was corrected to add 
‘within 12 months or who discontinued dupilumab 
use due to adverse event’ as follows:  
Participation in prior dupilumab clinical study or 
have been treated with commercially available 
dupilumab within 12 months or who discontinued 
dupilumab use due to an adverse event 
Correction 
Section 5.4 Screen failures 
Removal of the last sentence of the paragraph: 
There is no need to screen fail such participants if 
the test finally meets the eligibility criteria. 
Correction 
Section 6.3 Measures to minimize 
bias: randomization and blinding 
Reference to specific regions (Asia, East Europe 
or Western Countries) was removed from the 
sentence: randomization will be stratified by 
region. 
Removed due to being too 
specific and will be described in 
further detail in the statistical 
analysis plans (SAPs). 
 
Code breaking: Investigator could decide at 
his/her discretion to contact the Sponsor to 
To clarify that the responsibility to 
unblind treatment assignment in 
emergency situations resides 
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Section # and Name 
Description of Change 
Brief Rationale 
discuss the situation in case of unblinding 
participant’s intervention assignment. 
solely with the investigator as per 
the EMA GCP Inspectors Working 
Group (GCP IWG) and the 
Clinical Trial Facilitation Group 
(CTFG). Consequently, the 
Sponsor cannot require or insist 
on being involved in the decision 
to unblind, stall or delay in any 
way the unblinding of trial 
participant treatment in 
emergency situations. 
Section 6.5.2 Prohibited 
medications  
Removal of antifungals as prohibited medication 
and addition of “systemic” to antibiotics. 
Correction  
Section 8 Study assessments and 
procedures 
Addition of the order of assessments/procedures 
to be conducted during study visits. 
For clarity 
 
Correction of amount of blood collected for adults 
in Part A and B and addition of amount of blood 
collected in adolescents in Part B. 
Correction 
Section 8.1.8 EuroQol-5 dimensions 
questionnaire 
Clarification that the adult version of the 
questionnaire that is adapted to participants age 
16 and older “can be used for participants aged 
12-15 as stated in the EQ-5D user guide”. 
For clarity 
Section 8.6 Pharmacodynamics 
Addition of analysis of periostin and total protein in 
nasal secretions. 
Addition of analysis of urine creatinine.  
Nasal brushing biomarkers: addition of nasal 
brushing RNA analysis. 
Addition of whole blood deoxyribonucleic acid for 
pharmacogenetic analysis. 
To add analyses that are intended 
to be performed on samples being 
collected in the protocol that were 
inadvertently omitted 
Section 8.7 Genetics 
Clarification that pharmacogenomic testing from 
whole blood samples was optional while 
transcriptomics on nasal brushings was 
mandatory. 
For clarity 
Section 9.3 Populations for analyses  
Section 9.4.2 Primary endpoint(s) 
and 1.1 Synopsis 
The primary efficacy analysis population was 
changed from ITT population with screening blood 
eosinophil count ≥300 cells/mm3 to ITT population 
for Part A. 
Intercurrent event handling strategy for prohibited 
medications added in Table 7. 
Per Health Authority request for 
Part A 
Section 9.2 Sample size 
determination 
Section 9.4.2 Primary endpoint(s) 
Section 9.4.3 Secondary endpoint(s) 
Power calculations updated for Part A.  
Screening blood eosinophil count added as 
covariate in model-based analyses for Part A. 
To reflect change in the primary 
efficacy analysis population 
Section 9.4.1 General 
considerations 
Multiplicity considerations updated 
 
Section 9.4.2 Primary endpoint(s) 
and 1.1 Synopsis 
Intercurrent event handling strategy for 
undergoing sinonasal surgery for CRSsNP prior to 
To change handling of sinonasal 
surgery in the primary estimand to 
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Section # and Name 
Description of Change 
Brief Rationale 
Week 24 was changed from “data after surgery 
will be assigned to the worst possible score 
(composite strategy)” to “Data collected after 
surgery will be set to missing and the worst post-
baseline value on or before the time of surgery will 
be used to impute missing Week 24 value 
(WOCF). For participants with no post-baseline 
values, the baseline value will be used 
(hypothetical strategy).” 
 
Sensitivity/supplementary analyses updated 
an approach more appropriate for 
this clinical setting and to update 
supplementary analyses 
accordingly 
Section 10.1.7 Data quality 
assurance 
“printed or electronic CRF" was replaced by 
“eCRF” 
Clarification 
Section 10.2 Appendix 2: Clinical 
Laboratory tests 
Table 8: routine urinalysis was replaced by urine 
dipstick. Addition of footnote b: For participants 
enrolled in China, the urine analysis will be 
performed at laboratory (not dipstick). 
Correction  
 
HIV viral load test was removed 
Correction 
 
Only total HBcAb will be performed. 
Revision of HBV DNA testing in case of HBsAg 
(negative) and HBcAb (positive). Revision of HCV 
RNA testing in case of HCVAb (positive). 
Adjusted language to allow for 
clarity on when to do reflex testing 
for HBV or HCV 
Section 10.4 Appendix 4: 
Contraceptive guidance and 
collection of pregnancy information 
For male participants with partners who become 
pregnant, the following sentence was removed: 
‘This applies only to male participants who receive 
dupilumab’. 
Correction 
Section 10.11 Appendix 11: 
Abbreviations 
List of abbreviations updated 
Correction 
Section 10.12 Appendix 12: Protocol 
amendment history 
Section updated to state that the Protocol 
Amendment Summary of Changes Table for the 
current amendment is located directly before the 
Table of Contents 
Aligned with Sanofi procedures. 
Global 
Minor editorial updates and formatting changes 
were made. 
To correct minor errors 
 
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11 
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recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized 
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company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication 
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According to template: Sanofi eSAP Version 2.1, dated 3-JAN-2023 
Page 1 
 
STATISTICAL ANALYSIS PLAN  
Protocol title: 
A randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of dupilumab in patients with 
uncontrolled, chronic rhinosinusitis without nasal polyposis 
(CRSsNP) 
Protocol number: 
EFC16723 
Compound number 
(INN/Trademark): 
SAR231893 
dupilumab/Dupixent® 
Study phase: 
Phase 2 
Short Title: 
Dupilumab in CRSsNP 
Acronym: Liberty CRSsNP ORION 
Statistician: 
Statistical project leader: 
Date of issue: 
26-Jan-2024  
Regulatory agency identifier number(s): 
IND: 
105379 
EudraCT/EU-trial number: 
2020-003117-35 
NCT: 
NCT04678856 
WHO: 
U1111-1246-7522 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
 
 
 
 
 
Date: 
26-Jan-2024 
Total number of pages: 40 
 
 
 
VV-CLIN-0662822 1.0


Statistical Analysis Plan 
26-Jan-2024 
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Page 2 
 TABLE OF CONTENTS  
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION.............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVES AND ENDPOINTS .................................................................................................... 6 
1.2.1 
Estimands ........................................................................................................................................ 8 
2 
ANALYSIS POPULATIONS .......................................................................................................... 10 
3 
STATISTICAL ANALYSES ........................................................................................................... 12 
3.1 
GENERAL CONSIDERATIONS .................................................................................................... 12 
3.2 
PRIMARY ENDPOINT ANALYSIS ................................................................................................ 13 
3.2.1 
Definition of endpoint ..................................................................................................................... 13 
3.2.2 
Main analytical approach ............................................................................................................... 13 
3.3 
SECONDARY ENDPOINTS ANALYSIS ....................................................................................... 13 
3.3.1 
Definition of endpoints ................................................................................................................... 14 
3.3.2 
Main analytical approach ............................................................................................................... 14 
3.4 
EXPLORATORY ENDPOINTS ANALYSIS ................................................................................... 14 
3.4.1 
Definition of endpoints ................................................................................................................... 14 
3.4.2 
Main analytical approach ............................................................................................................... 15 
.................................................................................................................................... 15 
3.5 
MULTIPLICITY ISSUES ................................................................................................................ 15 
3.6 
SAFETY ANALYSES ..................................................................................................................... 15 
3.6.1 
Extent of exposure ......................................................................................................................... 15 
3.6.2 
Adverse events .............................................................................................................................. 16 
3.6.3 
Additional safety assessments ....................................................................................................... 21 
3.6.3.1 
Laboratory variables and vital signs .............................................................................................. 21 
3.7 
OTHER ANALYSES ...................................................................................................................... 23 
3.7.1 
Other variables and/or parameters ................................................................................................ 23 
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3.7.1.1 
PK analyses ................................................................................................................................... 23 
3.7.1.2 
Immunogenicity analyses ............................................................................................................... 23 
3.7.1.3 
Biomarker analyses ....................................................................................................................... 25 
3.7.1.4 
Health care resource utilization and productivity ........................................................................... 26 
3.8 
INTERIM ANALYSES .................................................................................................................... 26 
3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES.................................................................... 26 
4 
SAMPLE SIZE DETERMINATION ................................................................................................ 28 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 29 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 29 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS .............................................................................. 30 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 31 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 35 
5.5 
APPENDIX 5 SELECTION CRITERIA FOR AE GROUPINGS ..................................................... 40 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ................................................................................................................. 6 
Table 2 - Summary of primary estimand for the primary endpoint .................................................................. 8 
Table 3 - Populations for analyses ................................................................................................................ 10 
Table 4 - Sorting of AE tables ....................................................................................................................... 17 
Table 5 - Analyses of adverse events ........................................................................................................... 18 
Table 6 - Selections for AESIs and other AEs of interest.............................................................................. 19 
Table 7 - Major statistical changes in protocol amendment(s) ...................................................................... 26 
Table 8 - Periodical average of daily efficacy assessment from e-diary ....................................................... 36 
Table 9 - Time window for safety endpoints .................................................................................................. 37 
Table 10 - Time window for efficacy variables .............................................................................................. 38 
Table 11 - Time window for pharmacokinetics/pharmacodynamics variables .............................................. 39 
Table 12 - List of PTs for CMQs .................................................................................................................... 40 
 
 
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VERSION HISTORY  
This Statistical Analysis Plan (SAP) for study EFC16723 is based on the protocol dated 
23-Feb-2023 (amended protocol 02).  
The first participant was randomized on 24-Feb-2021. 
 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a Phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of dupilumab in adult participants with uncontrolled chronic rhinosinusitis without nasal 
polyposis (CRSsNP).  
After a screening period of 2 to 4 weeks, approximately 70 participants will be centrally 
randomized (using permuted block randomization schedule) via Interactive Response Technology 
(IRT) in a 1:1 ratio to dupilumab 300 mg q2w or placebo. Randomization will be stratified by 
screening blood eosinophil count (≥300 cells/mm3 or <300 cells/mm3), background intranasal 
corticosteroids (INCS) use (yes or no) and region. To ensure enrollment according to the intended 
distribution of screening blood eosinophil count, the number of participants in each stratification 
group will be controlled as follows: 
• ≥300 cells/mm3: approximately 15 participants per arm, 
• <300 cells/mm3: approximately 20 participants per arm. 
In addition, in order to have an adequate number of participants with comorbid asthma, the 
number of participants without comorbid asthma will be limited to no more than 70% of the 
randomized population.  
The study has a 24 to 52-week treatment period. Study treatment will stop for all participants 
when the last participant has completed 24 weeks of treatment. Therefore, all participants 
following protocol amendment 02 will be treated for at least 24 weeks and the other participants 
(enrolled before amendment 02) will have a variable treatment period which may be up to 
52 weeks. 
1.2 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of dupilumab as assessed by the 
reduction at Week 24 in sinus opacification on 
computerized tomography (CT) scan in the dupilumab 
group only 
• 
Change from baseline to Week 24 in opacification of 
sinuses assessed by CT scan using the Lund-Mackay 
(LMK) score in the dupilumab group  
Secondary 
To evaluate the efficacy of dupilumab as assessed by the 
reduction at Week 24 in sinus opacification on CT scan and 
sinus total symptom score (sTSS) compared to placebo 
• 
Change from baseline to Week 24 in opacification of 
sinuses assessed by CT scan using the LMK score  
• 
Change from baseline to Week 24 in sTSS* 
*Composite severity score consisting of nasal 
congestion, anterior/posterior rhinorrhea, facial 
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Objectives 
Endpoints 
pain/pressure items of the CRSsNP sinonasal 
symptom e-diary 
 
• 
To evaluate the safety and tolerability of 
dupilumab in CRSsNP patients compared to 
placebo 
• 
Incidence of treatment-emergent adverse events 
(TEAEs), of treatment-emergent serious AEs 
(TESAEs), and TEAEs leading to treatment 
discontinuation, abnormal laboratory values, and vital 
signs 
• 
To evaluate the pharmacokinetics (PK) of 
dupilumab in CRSsNP patients  
• 
Dupilumab concentration in serum 
• 
Assessment of immunogenicity to dupilumab over 
time  
• 
Assessment of immunogenicity to dupilumab as 
determined by the incidence, titer, and neutralizing 
antibody (NAb) status of treatment-emergent anti-drug 
antibody (ADA) response over time  
Exploratory 
• 
i
 
 
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Objectives 
Endpoints 
• 
i
 
1.2.1 Estimands  
Primary estimand defined for the primary endpoint is summarized in Table 2. More details are 
provided in Section 3.2.2. 
Table 2 - Summary of primary estimand for the primary endpoint 
Endpoint 
Category 
Estimand 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy and missing data 
handling 
Population-level 
summary  
 
Primary objective: To evaluate the efficacy of dupilumab as assessed by the reduction at Week 24 in sinus opacification on 
computerized tomography (CT) scan in the dupilumab group only 
Primary endpoint 
Change from 
baseline in LMK 
score at Week 24 
 
 
ITT with 
screening blood 
eosinophil 
count ≥ 300 
cells/mm3 
The intercurrent events (IEs) will be 
handled as follows: 
• 
Undergoing sinonasal surgery for 
CRSsNP or taking systemic 
corticosteroids (SCS) for any 
reason prior to Week 24: data 
after the IE will be excluded from 
the analysis and the worst post-
Descriptive statistics 
and 95% confidence 
interval (CI) in the 
dupilumab group will be 
provided.  
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Endpoint 
Category 
Estimand 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy and missing data 
handling 
Population-level 
summary  
 
baseline value on or before the 
time of the IE will be used to 
assign the Week 24 value 
(WOCF). For participants with no 
post-baseline values, the baseline 
value will be used (composite 
strategy). 
• 
Taking other prohibited/rescue 
medications: all data collected 
after use will be used in the 
analysis (treatment policy 
strategy). 
• 
Discontinuing the study 
intervention: all data collected 
after discontinuation will be used 
in the analysis (treatment policy 
strategy). 
Missing data will not be imputed.  
 
 
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2 
ANALYSIS POPULATIONS  
The following populations for analyses are defined. The primary population of the efficacy 
endpoints is the ITT population with screening blood eosinophil count ≥ 300 cells/mm3. 
Table 3 - Populations for analyses 
Population 
Description 
Screened 
All participants who sign the informed consent form. 
Randomized 
The randomized population includes all participants with a treatment kit number allocated and recorded in the 
IRT database, and regardless of whether the treatment kit was used or not. Participants treated without being 
randomized will not be considered randomized and will not be included in any efficacy population. 
Intent-to-treat (ITT) 
All randomized participants analyzed according to the treatment group allocated by randomization 
regardless if treatment kit is used or not. 
ITT with screening 
blood eosinophil 
count 
≥300 cells/mm3 
All randomized participants with screening blood eosinophil count ≥300 cells/mm3 analyzed according to 
the treatment group allocated by randomization regardless if treatment kit is used or not. 
ITT with screening 
blood eosinophil 
count 
<300 cells/mm3 
All randomized participants with screening blood eosinophil count <300 cells/mm3 analyzed according to 
the treatment group allocated by randomization regardless if treatment kit is used or not. 
Safety 
All participants randomly assigned to study intervention and who take at least 1 dose of study intervention. 
Participants will be analyzed according to the intervention they actually received. Randomized participants for 
whom it is unclear whether they took the study medication will be included in the safety population as 
randomized. For participants who accidentally receive different study intervention from the planned, the actual 
intervention allocation for as-treated analysis will be the dupilumab group. 
Pharmacokinetic 
(PK) 
The PK population includes all participants in the safety population with at least 1 non-missing result for 
functional dupilumab concentration in serum after the first dose of the study intervention. Participants will 
be analyzed according to the intervention actually received. 
Anti-drug antibody 
(ADA) 
ADA population includes all participants in the safety population who have at least 1 non-missing result 
in the ADA assay after the first dose of the study intervention. Participants will be analyzed according to 
the intervention actually received. 
Population without 
trial impact 
(disruption) due to 
COVID-19 
All randomized participants: 
• 
without any critical or major deviation related to COVID-19  
• 
and who did not permanently discontinue treatment due to COVID-19  
• 
and who did not permanently discontinue study due to COVID-19. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization (except if the first randomization is done by error) will be used in any analysis 
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population. The safety experience associated with any later randomization will be reported 
separately. 
For participants receiving more than one study intervention during the study, the intervention 
group for as-treated analyses will be the dupilumab group.  
If >10% participants are impacted by the COVID-19 pandemic, additional summaries by 
COVID-19 subgroups will be provided. Participants impacted by the COVID-19 pandemic are 
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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3 
STATISTICAL ANALYSES  
3.1 
GENERAL CONSIDERATIONS  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, minimum, and maximum. Categorical and ordinal data will be 
summarized using the count and percentage of participants. The summary statistics will be 
provided at each visit, including data collected beyond Week 24. 
The baseline value of efficacy parameters is defined as the last available value up to 
randomization date and prior to the first dose of study medication unless otherwise specified. The 
baseline value of the other parameters is defined as the last available value prior to the first dose 
of investigational medicinal product (IMP) if the participant is treated, or the last available value 
up to randomization date if the participant is not exposed to IMP.  
For endpoints collected on the daily CRSsNP sinonasal symptom diary, baseline is defined as the 
average of the scores in the 7 days prior to randomization. If there are less than 7 but at least 4 
non-missing scores available, the baseline score is the average of the available scores in the 
7 days. If there are less than 4 non-missing scores, then baseline will be the average of the most 
recent 4 days with non-missing scores prior to randomization.  
Stratification factors used in analyses will be derived based on eCRF data (for background INCS 
and region) or central laboratory data (for screening blood eosinophil count).  
Unless otherwise specified, analyses will be performed by intervention group and overall for 
baseline and demographics characteristics. 
Observation period  
The observation period will be divided into 4 segments:  
• The pre-treatment period is defined as the period up to the first IMP administration. 
• The treatment-emergent (TE) period is defined as the period from the first IMP 
administration to the last IMP administration + 98 days. The treatment-emergent period 
includes the following 2 periods:  
- 
The on-treatment period is defined as the period from the first IMP administration to 
the last administration of the IMP + 14 days  
- 
The residual treatment period is defined as the period from the end of the 
on-treatment period to the end of the treatment-emergent period.  
• The post-treatment period is defined as the period after the end of the treatment-
emergent period. 
The on-study observation period is defined as the time from the first IMP until the end of the study 
defined as the last scheduled visit for those who completed the study and the end-of-study date 
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collected on electronic case report form (e-CRF) page “Completion of End of Study/Follow-up” for 
those who did not complete the study. If death is the end-of-study reason, date of death will be used. 
3.2 
PRIMARY ENDPOINT ANALYSIS  
3.2.1 Definition of endpoint  
The primary endpoint is the change from baseline to Week 24 in LMK score in the dupilumab 
group. The LMK score is based on assessment of the CT scan findings for each sinus area 
(maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinus on each side). The 
extent of mucosal opacification is rated on a 3-point scale ranging from 0 = normal to 2 = total 
opacification. In addition, the ostiomeatal complex is graded as 0 = not occluded or 2 = occluded. 
The maximum score is therefore 12 per side for a maximum total score of 24, corresponding to 
the sum of all sinuses and the ostiomeatal unit. 
3.2.2 Main analytical approach  
The primary endpoint will be analyzed on the ITT with screening blood eosinophil count ≥ 300 
cells/mm3 population in the dupilumab group. Intercurrent events (IE) handling strategies are 
described below: 
• The following IE will be handled with the composite strategy:  
- 
Undergoing sinonasal surgery for CRSsNP or taking SCS for any reason prior to 
Week 24: data after surgery (actual date) or SCS use will be excluded from the 
analysis and the worst post-baseline value on or before the time of surgery or SCS use 
will be used to assign the Week 24 value (ie, WOCF approach). For participants with 
no post-baseline values, the baseline value will be used.  
• The following IEs will be handled with the treatment policy strategy (without IE that need 
to be handled with composite strategy). Data collected after starting such IEs will be 
included. 
- 
Taking other prohibited/rescue medications. 
- 
Discontinuing the study intervention. 
No missing data will be imputed. Descriptive statistics (number of participants, mean, SD, 
median, minimum and maximum) and 95% CI of the mean (based on the t distribution) in the 
dupilumab group will be provided. 
3.3 
SECONDARY ENDPOINTS ANALYSIS  
Efficacy secondary endpoints are described in this section. Non-efficacy secondary endpoints 
analyses are defined in Section 3.6.2 (AE, SAE), Section 3.6.3.1 (laboratory abnormalities and 
vital signs), Section 3.7.1.1 (PK) and Section 3.7.1.2 (immunogenicity).  
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3.3.1 Definition of endpoints  
The sTSS is the sum of nasal congestion/obstruction, anterior/posterior rhinorrhea, and facial 
pain/pressure. The total score ranges from 0 to 9 with higher scores indicating greater overall 
symptom severity. The sTSS will be analyzed as 28-day averages (Table 8).  
3.3.2 Main analytical approach  
Change from baseline to Week 24 in LMK score and in sTSS comparing dupilumab to placebo 
will be analyzed on the ITT with screening blood eosinophil count ≥ 300 cells/mm3 population. 
Handling of IEs will follow that of the primary endpoint. Otherwise, no missing data will be 
imputed. Descriptive statistics will be provided by intervention group. Mean treatment difference 
(dupilumab vs placebo) and the corresponding 95% CI (based on the t distribution) will be 
provided.  
3.4 
EXPLORATORY ENDPOINTS ANALYSIS  
The exploratory endpoints described in this section are the change from baseline to Week 24 
efficacy endpoints and PGIC at Week 24. Other exploratory endpoints analyses are defined in 
Section 3.7.1.3 (biomarkers) and Section 3.7.1.4 (health care resource utilization and 
productivity). Analyses of
in the type-2 inflammation 
transcriptome signature, as well as endpoints related to 
 will be addressed in separate documents. 
3.4.1 Definition of endpoints  
EQ-5D-5L health status will be converted into a single index value by using value sets based on 
UK population. The anterior/posterior rhinorrhea score is the average of the anterior and posterior 
scores. The ACQ-6 global score is the mean of the 6 questions. UPSIT score and the SNOT-22 
total score are the sum of all items. 
For endpoints related to sinonasal symptom diary (NC, anterior/posterior rhinorrhea, facial 
pain/pressure, loss of smell and headache), the 28-day average scores will be used for analysis 
(Table 8). 
For the three-dimensional CT volumetric measurement of the paranasal sinuses, each test (air 
volume, lateral wall thickness, volume occupied by disease, and mucosal volume), including 
location (ethmoid sinus, frontal sinus, maxillary sinus, and sphenoid sinus), laterality (right and 
left) and direction (anterior and posterior for ethmoid sinus) will be analyzed separately and as the 
mean of the left and right measurements. The total volume occupied by disease in all sinuses will 
also be summarized.  
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3.4.2 Main analytical approach  
Change from baseline to Week 24 endpoints and PGIC at Week 24 will be analyzed on the ITT 
with screening blood eosinophil count ≥ 300 cells/mm3 population comparing dupilumab to 
placebo except for the following: 
• Change from baseline to Week 24 in FEV1 and in ACQ-6 will be analyzed on the ITT with 
screening blood eosinophil count ≥ 300 cells/mm3 and with comorbid asthma subgroup in 
the dupilumab group.  
• Change from baseline to Week 24 in LMK and in sTSS will be analyzed on the ITT 
population (regardless of blood eosinophil count) in the dupilumab group.  
Handling of IEs will follow that of the primary endpoint. Otherwise, no missing data will be 
imputed. Descriptive statistics will be provided by intervention group. For endpoints comparing 
dupilumab to placebo, treatment difference (dupilumab vs placebo) and the corresponding 95% CI 
will be provided. For endpoints analyzed in the dupilumab group, 95% CI in the dupilumab group 
will be provided. The 95% CI will be constructed based on the t distribution.  
3.4.3 Exploratory analyses on the
  
Change from baseline to Week 24 in 
comparing dupilumab to placebo 
will be analyzed using the same approach as the secondary endpoints on the
populations. 
3.5 
MULTIPLICITY ISSUES  
No adjustments for multiplicity are planned for this Phase 2 study.  
3.6 
SAFETY ANALYSES  
All safety analyses will be performed on the safety population as defined in Section 2, unless 
otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned.  
• Safety data in participants who do not belong to the safety population (eg, exposed but not 
randomized) will be provided. 
3.6.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and compliance and 
summarized within the safety population.  
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Duration of IMP exposure 
Duration of IMP exposure is defined as last IMP administration date – first IMP administration 
date + 14 days, regardless of unplanned intermittent discontinuations. If the date of the last dose 
of IMP is missing, the duration of IMP will be left as missing. 
Duration of IMP exposure will be summarized quantitatively and categorically: >0 and ≤2 weeks, 
>2 and ≤4 weeks, >4 and ≤8 weeks, >8 and ≤12 weeks, >12 and ≤16 weeks, >16 and ≤20 weeks, 
>20 and ≤24 weeks, >24 and ≤28 weeks, >28 and ≤32 weeks, >32 and ≤36 weeks, >36 and ≤40 
weeks, >40 and ≤44 weeks, >44 and ≤48 weeks, >48 and ≤52 weeks, >52 weeks and ≤52 weeks + 
3 days, >52 weeks + 3 days.  
Additionally, the cumulative duration of treatment exposure (expressed in participant-years) will 
be provided. 
Treatment compliance 
A given administration will be considered noncompliant if the participant did not take the planned 
dose as required by the protocol. No imputation will be made for participants with missing or 
incomplete data. 
Percentage of treatment compliance for a participant will be defined as the number of 
administrations that the participant was compliant divided by the total number of administrations 
that the participant was planned to take from the first administration of IMP up to the actual last 
administration of IMP. 
Treatment compliance will be summarized quantitatively and categorically: <80%, ≥80%. 
3.6.2 Adverse events  
General common rules for adverse events 
All adverse events (AEs) will be coded to a lower-level term (LLT), preferred term (PT), high-
level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock. 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened or became 
serious during the treatment-emergent period 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period  
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Similarly, deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
The primary AE analyses will be on TEAEs. Pre-treatment and post-treatment AEs will be 
described separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE. 
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. Missing 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 4. 
Table 4 - 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 PTsa 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the dupilumab 300mg q2w group  
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE  
• Any severe TEAE 
• Any treatment-emergent SAE 
• TEAE leading to death 
• Any TEAE leading to permanent study intervention discontinuation  
• Any treatment-emergent AESI 
• Any treatment-emergent other AE of interest grouping 
• Any TEAE related to IMP 
The AE summaries of Table 5 will be generated with number (%) of participants experiencing at 
least one event.  
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Table 5 - Analyses of adverse events 
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
 
PT 
 
Primary and secondary SOC, HLGT, HLT and PT 
Common TEAE (≥5% in any group) 
Primary SOC and PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC and PT 
TEAE by maximal intensity 
Primary SOC and PT  
Treatment-emergent SAE 
Primary SOC and PT 
Treatment emergent SAE related to IMP as per Investigator’s 
judgment 
Primary SOC and PT 
TEAE leading to permanent intervention discontinuation 
Primary SOC and PT 
TEAE leading to deathb 
Primary SOC and PT 
COVID-19 related TEAE 
Primary SOC and PT 
Pre-treatment AE 
Overviewa 
Post-treatment AE 
Overviewa 
a Will include the following AE categories: any AEs, any serious AEs, any AEs leading to death, any AEs leading to permanent intervention 
discontinuation (pre-treatment AEs only) 
b Death as an outcome of the AE as reported by the Investigator in the AE page 
Analysis of deaths 
In addition to the analyses of deaths included in Table 5 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods 
• Deaths in non-randomized or randomized but not treated participants 
Analysis of adverse events of special interest (AESIs) and other AEs of interest 
Adverse events of special interest (AESIs) and other AEs of interest will be selected for analyses 
as indicated in Table 6. Number (%) of participants experiencing at least one event will be 
provided for each event of interest, by PT if applicable. Tables will be sorted as indicated in 
Table 4.  
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Table 6 - Selections for AESIs and other AEs of interest 
AESIs and other AEs of interest 
Criteria 
AESI 
 
Anaphylactic reaction 
Anaphylactic reaction algorithmic approach (Introductory Guide for 
Standardised MedDRA Queries (SMQs) Version 18.1): includes 
anaphylactic reaction narrow SMQ (20000021) terms and 
programmatic identification of cases based on occurrence of at least 
two preferred terms meeting the algorithm criteria occurring within 24 
hours of each other. The latter cases identified using the algorithm will 
undergo blinded medical review taking into account the timing of 
events relative to each other and to IMP administration for final 
determination of an anaphylactic reaction or not. 
Systemic hypersensitivity reactions 
SMQ [20000214] hypersensitivity narrow search and [AE corrective 
treatment/therapy = ’Y’ or Action taken with IMP = ’Drug withdrawn’ or 
Action taken with IMP = ’Drug interrupted’] followed by blinded medical 
review (documented process) for selection of relevant systemic 
hypersensitivity events 
Helminthic infections 
CMQ10544 based on HLGT as “Helminthic disorder” 
Any severe type of conjunctivitis  
CMQ10498 based on PTs (See Section 5.5)a and “Severe” ticked in 
Adverse Events eCRF page  
Any severe type of blepharitis  
CMQ10497 based on HLT as “Lid, lash and lacrimal infections, 
irritations and inflammations” and “Severe” ticked in Adverse Events 
eCRF page 
Keratitis 
CMQ10642 based on the following PTs [keratitis, allergic keratitis, 
ulcerative keratitis, atopic keratoconjunctivitis, herpes ophthalmic, 
ophthalmic herpes simplex, corneal infection] a 
Clinically symptomatic eosinophilia (or eosinophilia 
associated with clinical symptoms) b  
CMQ10641 based on HLT = Eosinophilic disorders or PT = Eosinophil 
count increased followed by blinded medical review 
Pregnancy of female participants entered in a study 
as well as pregnancy occurring in a female partner of 
a male participant entered in a study with IMP 
“Pregnancy” or “Partner Pregnancy” checked on the Pregnancy eCRF 
page as reported by the investigator 
Significant ALT elevation 
“ALT increase” and AESI answer “Yes” checked on AE eCRF as 
reported by the Investigator (ALT >5 x ULN in participants with 
baseline ALT ≤2 x ULN;  
OR ALT >8 x ULN if baseline ALT >2 x ULN) 
Symptomatic overdose with IMP 
Symptomatic Overdose is answered Yes, with Overdose of Study 
Treatment answered Yes on AE eCRF.  
Symptomatic overdose with NIMP 
Symptomatic Overdose is answered Yes, with Overdose of NIMP 
answered Yes on AE eCRF.  
Other selected AE Grouping 
 
Serious injection site reactions or severe injection site 
reactions that last longer than 24 hours  
HLT = ‘Injection site reactions’ and either with serious status, or with 
severe status and (AE end date/time - AE start date/time) ≥24 hours 
or ongoing 
Severe or serious infection 
Primary SOC = ‘Infections and infestations’ and with severe or 
serious status 
Parasitic infection 
Infection type "Parasitic" checked on eCRF “Infection Event Form” 
Opportunistic infection 
Has the AE been assessed as opportunistic infection? is answered 
Yes on eCRF "Infection Event Form” 
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AESIs and other AEs of interest 
Criteria 
Drug-related hepatic disorder 
SMQ [20000006] Drug-related hepatic disorders- narrow  
Injection site reactions  
HLT = ‘Injection site reactions’  
Malignancy 
SMQ [20000091]– Malignant or unspecified tumors narrow 
Conjunctivitis (narrow) 
CMQ10644 based on the following PTs [Conjunctivitis, Conjunctivitis 
allergic, Conjunctivitis bacterial, Conjunctivitis viral, Atopic 
keratoconjunctivitis] a 
Conjunctivitis (broad) 
CMQ10645 based on the following PTs [Conjunctivitis, Conjunctivitis 
allergic, Conjunctivitis bacterial, Conjunctivitis viral, Atopic 
keratoconjunctivitis, Blepharitis, Dry eye, Eye irritation, Eye pruritus, 
Lacrimation increased, Eye discharge, Foreign body sensation in 
eyes, Photophobia, Xerophthalmia, Ocular hyperaemia, Conjunctival 
hyperaemia] a 
Conjunctivitis 
)c 
CMQ10643 based on the following PTs [Conjunctivitis, Conjunctivitis 
allergic, Conjunctivitis bacterial, Conjunctivitis viral, Eye irritation, Eye 
inflammation, Giant papillary conjunctivitis] a 
Keratitis 
)c 
CMQ30102 based on the following PTs [keratitis, allergic keratitis, 
ulcerative keratitis, atopic keratoconjunctivitis, ophthalmic herpes 
simplex] a 
a The list of terms may be adjusted according to MedDRA version changes 
b All cases of Eosinophilia will be included in the analysis, where cases associated with clinical symptoms will be further described in the 
CSR 
c Labeling subgroup of preferred terms included in the USPI for Dupixent. 
 
The following summaries will be provided: 
• All TEAEs, by selected standardized MedDRA query (SMQ)/Customized MedDRA query 
(CMQ) and PT, showing the number (%) of participants with at least 1 PT. 
• For each AESI and other selected AE groupings,  
- 
Number (%) of participants with any TEAE  
- 
Number (%) of participants with any serious AE (regardless of treatment-emergent 
status) 
- 
Number (%) of participants with any treatment-emergent serious AE 
- 
Number (%) of participants with any AE leading to death 
- 
Number (%) of participants with any TEAE leading to permanent study intervention 
discontinuation 
- 
Number (%) of participants with any TEAE related to IMP reported by investigator 
- 
Number (%) of participants with any TEAE by maximum intensity, corrective 
treatment, and final outcome 
- 
Number (%) of participants with any TEAE adjusted by the exposure duration 
• Number (%) of participants with injection site reactions by the related injection. 
• Number (%) of participants with different number of injection site reactions. 
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In addition, AESIs reported by the investigator in eCRF will be summarized separately. 
Analysis of exposure-adjusted incidence rate 
If the cumulative duration of treatment exposure is imbalanced between dupilumab and placebo, 
then the number of participants with at least one TEAE per 100 participant-years will be provided 
for the below summaries: 
• Overview of adverse events profile  
• TEAE by primary SOC and PT 
• Common TEAE (≥5% in any group) by primary SOC and PT 
• Treatment-emergent SAE by primary SOC and PT 
• TEAE leading to permanent intervention discontinuation by primary SOC and PT 
• Treatment-emergent AESI and other selected AE grouping events by category and PT 
For participants with an event, the number of participant-years will be calculated up to the first 
event; for participants without an event, the number of participant-years will correspond to the 
length of the treatment-emergent period. 
3.6.3 Additional safety assessments  
3.6.3.1 Laboratory variables and vital signs  
The following laboratory and vital signs variables will be analyzed. They will be converted into 
standard international units. 
• Hematology:  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, red blood cell 
count, platelet count 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• Clinical chemistry: 
- 
Metabolism: glucose, total cholesterol, total protein, albumin 
- 
Electrolytes: sodium, potassium, chloride, bicarbonate 
- 
Renal function: creatinine, creatinine clearance, blood urea nitrogen, uric acid 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin 
- 
Pregnancy test: Urine pregnancy test 
• Vital signs: heart rate, systolic and diastolic blood pressure, weight, respiratory rate, 
temperature, BMI 
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Data below the lower limit of quantification (LLOQ) will be replaced by half of the LLOQ, data 
above the upper limit of quantification (ULOQ) will be replaced by ULOQ value. 
Quantitative analyses 
For laboratory and vital signs variables above, descriptive statistics for results and changes from 
baseline will be provided for each analysis window, the last value and the worst value during the 
on-treatment period. These analyses will be performed using central measurements only for 
laboratory variables.  
For all parameters, mean changes from baseline with the corresponding standard error will be 
plotted over time.  
Analyses according to PCSA 
Potentially clinically significant abnormality (PCSA) analyses will be performed based on the 
PCSA list currently in effect at Sanofi at the time of the database lock. For parameters for which 
no PCSA criteria are defined, similar analyses will be done using the normal range, if applicable.  
Analyses according to PCSA will be performed based on the worst value during the treatment-
emergent period, using all measurements (either local or central, either scheduled, nonscheduled 
or repeated). 
For laboratory and vital signs variables above, the incidence of participants with at least one 
PCSA during the treatment-emergent period will be summarized regardless of the baseline level 
and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
Additional analyses for drug-induced liver injury 
The following additional analyses will be performed for drug-induced liver injury:  
• Time to onset of the initial alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) elevation (>3 x ULN) and total bilirubin elevation (>2 x ULN) during the 
treatment-emergent period will be analyzed using Kaplan-Meier method.  
• A graph of the distribution of peak values of ALT versus peak values of total bilirubin 
during the treatment-emergent period will be provided.  
• For each liver function test (eg, ALT), participants having experienced a PCSA (eg, ALT 
>5 ULN) will be summarized using the following categories: Returned to baseline PCSA 
status (or returned to value ≤ ULN in case of missing baseline) before last IMP dose, 
Returned to baseline PCSA status after last IMP dose, Never returned to baseline PCSA 
status, No assessment after elevation. This summary will be performed by categories of 
elevation (ALT >3, >5, >10, >20 ULN). 
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3.7 
OTHER ANALYSES  
3.7.1 Other variables and/or parameters  
3.7.1.1 PK analyses  
Predose serum dupilumab concentrations at Visit 2 (Day 1), dupilumab trough levels at Week 12, 
Week 24, Week 52 and posttreatment serum dupilumab at the End of Study (EOS) visit will be 
provided. Given the variable treatment period, the EOS visit may be between 36 to 64 weeks.  
Serum concentrations of SAR231893 (REGN668) will be summarized in the PK population using 
arithmetic and geometric means, SD, standard error of the mean (SEM), coefficient of variation 
(CV), minimum, median and maximum per sampling time. If date and/or time of the drug 
injection and/or sampling is missing, then the concentration will not be taken into account. For 
drug-treated participants, where concentration values are below the LLOQ, one-half of the LLOQ 
will be used. Values will be expressed in the tables with no more than three significant figures. 
For participants in the placebo group, concentration values below the LLOQ will be taken into 
account with a plasma concentration considered equal to 0. 
3.7.1.2 Immunogenicity analyses  
Dupilumab anti-drug antibody (ADA) status (negative or titer value, if positive in the ADA assay) 
at Visit 2 (Day 1), Week 12, Week 24, Week 52 and EOS visit will be provided. Given the 
variable treatment period, the EOS visit may be between 36 to 64 weeks. The neutralizing 
antibody results for ADA positive samples will be provided. 
Incidence will be provided for the following ADA response categories. Treatment-emergent and 
treatment-boosted response will be defined based on samples collected in the on-treatment period.  
Pre-existing immunoreactivity is defined as:  
An ADA positive response in the assay at baseline with all post first dose ADA results negative, 
OR an ADA positive response at baseline with all post first dose ADA responses less than 4-fold 
over baseline titer levels. 
Treatment-emergent ADA responses are defined as:  
A positive response in the ADA assay post first dose, when baseline results are negative or 
missing. 
Treatment-emergent ADA responses are further classified as persistent, indeterminate or transient 
a) Persistent response - defined as a treatment-emergent ADA response with two or more 
consecutive ADA positive sampling time points, separated by greater than (>) 12-week 
period (84 days), with no ADA negative samples in between. 
b) Indeterminate response - defined as a treatment-emergent response with only the last 
collected sample positive in the ADA assay  
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c)
Treatment-boosted response is defined as: 
The following summary will be provided based on ADA population: 
• Number (%) of participants with pre-existing immunoreactivity 
• Number (%) of participants with treatment-emergent ADA  
• The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for participants with treatment-emergent ADA, and 
participants with persistent, indeterminate and transient ADA response 
• Number (%) of participant with transient treatment-emergent ADA  
• Number (%) of participants with persistent treatment-emergent ADA  
• Number (%) of participants with indeterminate treatment-emergent ADA  
• Number (%) of participants with treatment-boosted ADA  
• The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for participants with treatment-boosted ADA  
• The summary statistics (including number, mean, SD, median, Q1, Q3, minimum and 
maximum) of the ratio of peak post-baseline titer to baseline titer for participants with 
treatment-boosted ADA  
• Listing of ADA peak titer levels and neutralizing antibody status  
• Number (%) of participants with neutralizing antibody status  
Kinetics of treatment-emergent ADA response 
Number (%) of participants with treatment-emergent ADA positive response at each visit will be 
summarized by each intervention group. 
Plot of percentage of participants with treatment-emergent ADA positive response at each visit 
will be provided by each intervention group. 
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3.7.1.2.1 Association of Immunogenicity with Exposure, Safety and Efficacy  
The safety and efficacy analysis mentioned below will be conducted using the following 
categories: 
ADA positive participants: Participants with treatment-emergent or treatment-boosted response. 
ADA negative participants: Participants with pre-existing immunoreactivity or negative in the 
ADA assay at all time points. 
Impact of ADA on PK profile  
Potential associations between ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, indeterminate and transient response, treatment-boosted) and 
impact on serum concentration profile of dupilumab may be explored. Plot of serum concentration 
of functional dupilumab versus visit will be provided by ADA variables for each dupilumab dose 
group. Individual participant plots of dupilumab concentration according to ADA status will be 
provided. 
Impact of ADA on clinical efficacy endpoints 
Associations between the ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, treatment-boosted) and the primary efficacy endpoint may be 
explored for the dupilumab dosed group. 
Association of ADA with clinical safety endpoints 
Association of safety versus ADA status may be analyzed in the ADA population. The safety 
assessment may focus on the following events: 
• Severe injection site reactions last longer than 24 hours or serious injection site reactions 
• Hypersensitivity reactions (SMQ (20000214) hypersensitivity narrow search confirmed by 
medical review) 
• Anaphylactic reactions (SMQ (20000021) anaphylactic reaction narrow search) 
3.7.1.3 Biomarker analyses  
Blood, urine, nasal secretions and nasal brushing biomarkers will be summarized on the safety 
population. Baseline values will be the last value collected prior to the first IMP. Descriptive 
statistics (including number, mean, SD, median, Q1, Q3, min, max) of biomarkers at baseline and 
each post-baseline visit will be summarized.  
Summary plots at each visit (mean, mean change from baseline and median percent change from 
baseline) will be provided for each biomarker by intervention group. 
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3.7.1.4 Health care resource utilization and productivity  
The cumulative number of health care resource utilization and cumulative number of missed days 
of school/work will be summarized over the treatment period. Descriptive statistics (number of 
participants, mean, SD, median, minimum and maximum) will be provided.  
3.8 
INTERIM ANALYSES  
No interim analysis is planned.  
3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
Table 7 - Major statistical changes in protocol amendment(s) 
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
1 
08-Jul-2021 
Addition of a secondary objective and related endpoints 
in Part A (at Weeks 24 and 52) as follows: 
Objective: To evaluate the effect of dupilumab in the 
subgroup of participants with screening blood eosinophil 
count ≥300 cells/mm3 compared to placebo 
Endpoints: 
-Change from baseline to Weeks 24 and 52 (Part A) in 
opacification of sinuses assessed by CT scan using LMK 
score in the screening blood eosinophil count 
≥300 cells/mm3 population.  
-Change from baseline to Weeks 24 and 52 (Part A) in 
sinus total symptom score (sTSS) using the screening 
blood eosinophil count ≥300 cells/mm3 population.  
-Evaluation of other secondary endpoints listed above in 
the screening blood eosinophil count ≥300 cells/mm3 
population.  
To evaluate the effect of 
dupilumab in a subgroup of 
interest as the primary analysis 
population was changed to the 
ITT population regardless of 
eosinophil levels in Part A, per 
Health Authority request. 
 
 
The primary efficacy analysis population was changed 
from ITT population with screening blood eosinophil 
count ≥300 cells/mm3 to ITT population for Part A. 
Intercurrent event handling strategy for prohibited 
medications added in Table 7. 
Per Health Authority request for 
Part A 
 
 
Power calculations updated for Part A. Screening blood 
eosinophil count added as covariate in model-based 
analyses for Part A. 
 
Multiplicity considerations updated 
To reflect change in the primary 
efficacy analysis population 
 
 
Intercurrent event handling strategy for undergoing 
sinonasal surgery for CRSsNP prior to Week 24 was 
changed from “data after surgery will be assigned to the 
worst possible score (composite strategy)” to “Data 
To change handling of 
sinonasal surgery in the 
primary estimand to an 
approach more appropriate for 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
collected after surgery will be set to missing and the worst 
post-baseline value on or before the time of surgery will 
be used to impute missing Week 24 value (WOCF). For 
participants with no post-baseline values, the baseline 
value will be used (hypothetical strategy).” 
Sensitivity/supplementary analyses updated 
this clinical setting and to 
update supplementary analyses 
accordingly 
2 
23-Feb-2023 
Sample size determination updated.  
Primary population changed from ITT population to ITT 
population with screening blood eosinophil count ≥ 300 
cells/mm3. 
To reflect changes in the study 
primary objective and endpoint. 
 
 
Statistical hypotheses removed. 
Multiplicity consideration removed. 
Multiple imputation removed. 
Model-based analyses removed. 
Sensitivity and subgroup analyses removed. 
Use of descriptive statistics for all endpoints. 
To apply more appropriate 
analysis methods based on the 
reduced sample size. 
 
 
The intercurrent events handling strategy for taking SCS 
for any reason prior to Week 24 was changed from ’all 
data collected after SCS use will be used in the analysis’ 
to ‘data after the IE will be set to missing and the worst 
post-baseline value on or before the time of the IE will be 
used to impute missing Week 24 value (WOCF)’. 
To change handling of taking 
SCS for any reason in the 
primary estimand to an 
approach more appropriate for 
this clinical setting. 
 
 
Description of secondary analyses for proportion and 
time-to-event endpoints removed.
 
 
To reflect changes in the 
secondary objectives and 
endpoints. 
 
 
Updated the timing of analyses to only one database lock 
after all participants have completed the study. 
To reflect the removal of Part B 
and shortened treatment 
duration of Part A. 
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4 
SAMPLE SIZE DETERMINATION  
Sample size calculation was performed to ensure reasonable accuracy for the estimation of the 
primary endpoint in participants treated with dupilumab with screening blood eosinophil count 
≥300 cells/mm3. With a 1:1 randomization ratio, a standard deviation (SD) of 5 and a dropout rate 
of 10%, a sample size of approximately 30 participants (15 per arm) with screening blood 
eosinophil count ≥300 cells/mm3 will provide a half-width of approximately less than 3 for the 
2-sided 95% CI in the dupilumab group which is deemed reasonable. 
In addition, it is planned to include approximately 40 participants (20 per arm) with screening 
blood eosinophil count <300 cells/mm3. Thus, the planned total sample size is approximately 
35 participants per arm.  
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ACQ-6: 
asthma control questionnaire-6 items  
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ATC: 
anatomic category 
CI: 
confidence interval 
CLcr: 
Creatinine clearance 
CRSsNP: 
chronic rhinosinusitis without nasal polyposis  
CT: 
computerized tomography 
CV: 
coefficient of variation 
e-CRF: 
electronic case report form 
EOS: 
End of Study 
FEV1: 
forced expiratory volume 
HLT: 
high level term 
HRQoL: 
health-related quality of life 
IEs: 
intercurrent events 
IMP: 
investigational medicinal product 
INCS: 
intranasal corticosteroids  
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
LLOQ: 
lower limit of quantification 
LLT: 
lower-level term 
LMK: 
Lund-Mackay 
MedDRA: 
medical dictionary for regulatory activities 
NAb: 
neutralizing antibody 
NC: 
nasal congestion 
NES: 
Normalized Enrichment Score 
PCSA: 
potentially clinically significant abnormality 
PGIC: 
Patient Global Impression of Change 
PGIS: 
Patient Global Impression of Severity 
PK: 
pharmacokinetics 
PT: 
preferred term 
SCS: 
systemic corticosteroids 
SD: 
standard deviation 
SEM: 
standard error of the mean 
SMQ: 
standardized MedDRA query 
SNOT-22: 
Sino-Nasal Outcomes Test-22 item 
SOC: 
system organ class 
sTSS: 
sinus total symptom score 
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TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
TESAEs: 
treatment-emergent serious adverse events 
ULN: 
upper limit of normal 
ULOQ: 
upper limit of quantification 
UPSIT: 
University of Pennsylvania smell identification test 
VAS: 
visual analog scale 
WHO-DD: 
World Health Organization-drug dictionary 
WOCF: 
worst observation carried forward 
 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 3 will 
be summarized. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized. The number (%) of screen failures and reasons for screen failures will 
be provided in the screened population. 
The number (%) of participants in the following categories will be provided:  
• Randomized participants 
• Randomized but not exposed participants  
• Randomized and exposed participants 
• Participants who completed the study treatment period as per protocol  
• Participants who did not complete the study treatment period as per protocol and main 
reason for permanent intervention discontinuation.  
• Participants who completed the study period as per protocol. 
• Participants who did not complete the study period as per protocol and main reason for 
study discontinuation. 
Reasons for permanent study intervention and study discontinuation “adverse event” and “other 
reasons” will be split as related versus not related to the COVID-19 pandemic, if applicable. 
The number (%) of exposed and not randomized participants will also be summarized.  
In addition, the number (%) of participants screened, screened-failed, randomized, with 
permanent intervention discontinuation and with early study discontinuation will be provided by 
country and site.  
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Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the 
randomized population as well as displayed separately as related versus not related to the 
COVID-19 pandemic if applicable. In addition, deviations potentially impacting the primary 
endpoint analysis may be summarized. 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the randomized 
population. 
Demographic variables are: 
• Age in years as quantitative variable and in categories (18-<65, 65 - <75, 75 - <85 and ≥85 
years) 
• Gender (Male, Female) 
• Race (White, Black or African American, American Indian or Alaska Native, Asian, 
Native Hawaiian or other Pacific Island, Multiple, Not reported, Unknown) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not Reported, Unknown) 
• Region (Asia: China, South Korea; Latin America: Argentina, Chile; East Europe: 
Hungary, Russia, Ukraine; Western Countries: Belgium, Canada, Portugal, Spain, 
Sweden, USA) 
• Territory (North America: Canada, USA; European Union: Belgium, Hungary, Spain, 
Portugal, Sweden; Rest of World: Argentina, Chile, China, South Korea, Russia, 
Ukraine) 
• Weight in kg as quantitative variable 
• BMI in kg/m2 as quantitative variable and in categories (<25, ≥25-<30, ≥30 kg/m2)  
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries.  
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the participant. Medical and surgical history will be coded to a LLT, PT, HLT, HLGT, 
and associated primary SOC using the MedDRA version currently in effect at Sanofi at the time 
of database lock.  
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CRSsNP and allergic comorbidities will be summarized separately. The following comorbid 
disease will be summarized from eCRF pages which were filled in by investigators based on 
participant reporting. 
• Chronic rhinosinusitis without nasal polyps (Yes, Ongoing condition) 
• Posterior nasal drip (Yes, Ongoing condition) 
• Diminished sense of smell (Yes, Ongoing condition) 
• Nasal congestion (Yes, Ongoing condition) 
• Nasal discharge (Yes, Ongoing condition) 
• Nasal polyps (Yes, Ongoing condition) 
• Facial pain/pressure (Yes, Ongoing condition) 
• Seasonal allergic rhinitis (Yes, Ongoing condition)  
• Perennial allergic rhinitis (Yes, Ongoing condition) 
• Allergic rhinitis (Yes, Ongoing condition) 
• Allergic conjunctivitis (Yes, Ongoing condition) 
• Atopic dermatitis (Yes, Ongoing condition) 
• Epistaxis (Yes, Ongoing condition) 
• Aspirin-exacerbated respiratory disease (Yes, Ongoing condition) 
• Hives (Yes, Ongoing condition) 
• Eosinophilic esophagitis (Yes, Ongoing condition) 
• Egg allergy (Yes, Ongoing condition) 
• Fish allergy (Yes, Ongoing condition) 
• Milk allergy (Yes, Ongoing condition) 
• Peanut allergy (Yes, Ongoing condition) 
• Allery to nuts (Yes, Ongoing condition) 
• Shellfish allergy (Yes, Ongoing condition) 
• Soy allergy (Yes, Ongoing condition) 
• Flour sensitivity (Yes, Ongoing condition) 
• Gluten sensitivity (Yes, Ongoing condition) 
Prior sinonasal surgery and systemic corticosteroid history will be summarized as below. 
• Number of participants with prior sinonasal surgery and/or SCS use in the past 2 years 
before screening visit 
• Number of participants with prior sinonasal surgery  
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• Number of prior sinonasal surgeries (quantitative and in categories of 1 or ≥ 2) 
• Number of participants with prior sinonasal surgery by type 
• Time since most recent sinonasal surgery (years) 
• Number of participants with SCS use in the past 2 years before screening visit 
• Number of SCS courses in the past 2 years before screening visit (quantitative and in 
categories of 1, 2, 3, 4, ≥ 5) 
• Number of days with SCS use in the past 2 years before screening visit (quantitative and in 
categories of >0 - ≤7, >7 - ≤ 14, >14 - ≤ 21, >21 - ≤28, >28 - ≤56, >56 - ≤84, >84 - ≤112, 
>112) 
In addition, asthma history will be summarized for participants with comorbid asthma: 
• Age at asthma onset (years) 
• Time since first diagnosis of asthma (years)  
Disease characteristics at baseline  
The following baseline disease characteristics will be summarized by intervention group: 
• Age at onset of CRSsNP (years)  
• Time since first diagnosis of CRSsNP (years)  
• Baseline LMK score 
• Baseline sTSS 
• Baseline 3-dimensional CT volumetric measurement of the paranasal sinuses 
• Baseline nasal congestion/obstruction score 
• Baseline anterior/posterior rhinorrhea score 
• Baseline facial pain/pressure severity score 
• Baseline loss of smell symptom severity score 
• Baseline headache severity score 
• Baseline UPSIT score 
• Baseline SNOT-22 score 
• Baseline rhinosinusitis VAS score 
• Baseline EQ-VAS score 
• Baseline EQ-5D-5L single index score 
• Baseline PGIS score 
• Comorbid asthma (Yes, No) 
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• Baseline FEV1 (L)  
• Baseline FEV1 percent predicted (%)  
• Baseline ACQ-6 score in participants with comorbid asthma 
• Background INCS use 
• Smoking history (Never, Former, Current) 
• Frequency of alcohol drinking in the past 12 months (never, occasional, at least monthly, 
at least weekly, at least daily) and number of drinks on a typical day (1 or 2, >2) 
• Screening blood eosinophil count (109/L) 
• Screening blood eosinophil count category (<0.3, ≥0.3×109/L) 
Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock.  
• Prior medications are those the participant received prior to first IMP intake. Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment period. 
• Concomitant medications are any interventions received by the participant concomitantly 
to the IMP, from first administration of IMP to last IMP intake + 98 days. 
• Post-treatment medications are those the participant received in the period running from 
the end of the concomitant medications period up to the end of the study.  
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as post-treatment medication. If it cannot be determined whether a 
given medication was taken prior or concomitantly or post, it will be considered as prior, 
concomitant, and post-treatment medication. 
The prior and concomitant medications will be summarized for the randomized population. 
Medications will be summarized by intervention group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the 
first 3 digits of the ATC class (therapeutic category). All ATC codes corresponding to a 
medication will be summarized, and participants will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication. Therefore, participants may be counted several 
times for the same medication.  
The tables for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across intervention groups. In case of 
equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be 
used. 
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Concomitant medication received between the first IMP to last IMP +14 days and concomitant 
medication received between the first IMP to last IMP + 98 days will be summarized separately. 
The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by all other therapeutic classes based on the incidence in the dupilumab group. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used.  
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Demographic formulas 
Age at onset of CRSsNP (years): 
Year of first diagnosis of CRSsNP – Year of birth 
Time since first diagnosis of CRSsNP (years): 
(Year of randomization – Year of first diagnosis of CRSsNP) +  
(Month of randomization – Month of first diagnosis of CRSsNP)/12 
 
Time since most recent sinonasal surgery (years): 
 
(Date of randomization – Date of most recent sinonasal surgery)/365.25 if a complete date of most 
recent sinonasal is available; 
 
(Year of randomization – Year of most recent sinonasal surgery) + (Month of randomization –
Month of most recent sinonasal surgery)/12 if year and month are available; 
 
(Year of randomization – Year of most recent sinonasal surgery) if only year is available 
Age at onset of asthma (years): 
Year of first diagnosis of asthma – Year of birth 
Time since first diagnosis of asthma (years): 
(Year of randomization – Year of first diagnosis of asthma) +  
(Month of randomization – Month of first diagnosis of asthma)/12 
 
BMI is calculated as: 
Weight in kg / (height2 in meters) 
Renal function formulas  
For adults, creatinine clearance (CLcr) value will be derived using the equation of Cockroft and 
Gault: 
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CLcr (ml/min) = (140 - age) × weight (kg) × (1 - 0.15 × sex (0-M, 1-F)) / (0.814 × creatinine 
(μmol/L)) 
For participants <18 years old, CLcr value will be derived using the equation of GFR Bedside 
Schwartz 
GFR (mL/min/1.73 m²) = k × height (cm) / sCr (mg/dL), 
where the coefficient k = 0.65 for male adolescent participants or k = 0.55 for female adolescent 
participants 
CLcr will be calculated using the last weight measurement on or before the visit of the creatinine 
measurement and age at the lab sampling day. Here age is calculated as following: 
Age = age collected at screening + integer part of (lab sampling analysis day / 365.25) 
Normalization of nasal secretion and urine biomarkers 
Nasal secretion biomarkers will be normalized with total protein as the reference. Urine 
biomarkers will be normalized with creatinine as the reference. For example,  
normalized Tryptase (ug/mg) = Tryptase (ug/L) / Total protein (ug/mL) 
normalized Leukotriene E4 (ng/mg) = Leukotriene E4 (ng/mg) / Creatinine (mg /mL) 
Daily e-diary weekly scores 
For the daily efficacy endpoints (sTSS, NC, rhinorrhea, facial pain/pressure, loss of smell and 
headache), the time period used to calculate the periodical average score at each designated study 
day is summarized in Table 8. Randomization day is used as the reference day (Day 1). 
Table 8 - Periodical average of daily efficacy assessment from e-diary 
Analysis visit 
Target day 
Day range for calculating 
 periodical average score 
Week 4 
29 
2-29 
Week 8 
57 
30-57 
Week 12 
85 
58-85 
Week 16 
113 
86-113 
Week 20 
141 
114-141 
Week 24 
169 
142-169 
Week 28 
197 
170-197 
Week 32 
225 
198-225 
Week 36 
253 
226-253 
Week 40 
281 
254-281 
Week 44 
309 
282-309 
Week 48 
337 
310-337 
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Analysis visit 
Target day 
Day range for calculating 
 periodical average score 
Week 52 
365 
338-d 
EOT + 4 weeks 
29* 
2-29* 
EOT + 8 weeks 
57* 
30-57* 
EOT + 12 weeks 
85* 
58-85* 
d: planned EOT date, EOT: End of Treatment, EOS: End of Study 
* Relative to d 
Analysis windows for time points 
For the safety assessment, the reference date for the derivation of relative days of events or 
findings will be the date of first IMP administration. Selected safety variables will be summarized 
by the analysis window defined in Table 9 for the by visit descriptive analysis. All available 
values from central lab will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same number of days away from the target 
day, the latest one will be used. For procedures planned on Visit 2, if it is done on the same date 
as the first IMP injection but the performance time is missing, it will belong to the Visit 2 
window. 
Table 9 - Time window for safety endpoints 
 
 
Time windows for 
Analysis 
visit 
Target day 
Vital signs 
Laboratory  
(hematology,  
chemistry, urinalysis) 
Urine 
pregnancy 
Screening  
-28 to -14 
<-14 
<-14 
 
Baseline 
1 
-14-1- 
-14-1- 
14-1- 
Week 2 
15 
1+-49 
 
 
Week 4 
29 
 
 
1+ -42 
Week 8 
57 
 
 
43-70 
Week 12 
85 
50-126 
1+-126 
71-98 
Week 16 
113 
 
 
99-126 
Week 20 
141 
 
 
127-154 
Week 24 
169 
127-224 
127-224 
155-182 
Week 28 
197 
 
 
183-210 
Week 32 
225 
 
 
211-238 
Week 36 
253 
 
 
239-266 
Week 40 
281 
225-322 
225-322 
267-294 
Week 44 
309 
 
 
295-322 
Week 48 
337 
 
 
323-350 
Week 52 
365 
>322 
>322 
>350 
1-: up to 1st dose date/time; 1+: after 1st dose date/time; 
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For the efficacy assessment, the reference date for the derivation of relative days of events or 
findings will be the randomization day. If a participant receives IMP prior to the randomization by 
mistake, the reference date of efficacy assessment will be the date of the first IMP administration 
for that participant. For the primary analyses, all available values of scheduled measurements will 
be assigned to the appropriate visit window according to Table 10. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same number of days away from the target 
day, the latest one will be used. 
Table 10 - Time window for efficacy variables 
 
 
Time windows for 
Analysis 
visit 
Target 
day 
LMK 
/3-D 
CT 
UPSIT, 
VAS 
SNOT-22 
Spirometry 
ACQ-6 
EQ-5D-5L 
PGIS, 
HCRU/P 
PGIC 
Screening 
-28 to -14 
 
 
 
<-14 
 
 
 
 
Baseline 
1 
<1- 
<1- 
<1- 
-14-1- 
1- 
1- 
<1- 
 
Week 2 
15 
 
1+-91 
 
 
 
 
 
 
Week 12 
85 
 
 
 
1+-126 
1+-126 
 
1+-126 
1+-126 
Week 24 
169 
1+-266 
92-224 
1+-224 
127-266 
127-224 
1+-224 
127-224 
127-224 
Week 40 
281 
 
225-322 
225-322 
 
225-322 
225-322 
225-322 
225-322 
Week 52 
365 
267-d 
323-d 
323-d 
267-d 
323-d 
323-d 
323-d 
323-d 
EOS* 
NA 
 
NA 
NA 
NA 
NA 
 
 
 
d: planned EOT date, EOT: End of Treatment, EOS: End of Study 
1-: up to randomization and before 1st dose date/time; 1+: after randomization or 1st dose date/time 
* Data collected at the EOS visit will not be remapped 
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For the pharmacokinetics/pharmacodynamics variables summary, the reference date for the 
derivation of relative days of measurements will be the date of first IMP administration if the 
participant is treated with study intervention, or the randomization date if the participant is not 
treated. Pharmacokinetics /pharmacodynamics variables will be summarized by the analysis 
window defined in Table 11 for the by visit descriptive analyses. All available values of 
measurements will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same number of days away from the target 
day, the latest one will be used. For procedures planned on Visit 2, if it is done on the same date 
as the first IMP injection but the performance time is missing, it will belong to the Visit 2 
window. 
Table 11 - Time window for pharmacokinetics/pharmacodynamics variables 
 
 
Time windows for 
Analysis 
visit 
Target 
 day 
Serum 
dupilumab, 
ADA 
Blood 
biomarkers 
Urine 
biomarkers 
Nasal 
secretions 
for protein 
biomarkers 
Nasal 
brushing for 
RNA and 
cytology 
Screening 
-28 to -14 
 
 
 
 
 
Baseline 
1 
<1- 
<1- 
<1- 
<1- 
<1- 
Week 2 
15 
 
 
 
 
 
Week 12 
85 
1+-126 
1+-126 
1+-126 
1+-126 
 
Week 24 
169 
127-266 
127-266 
127-266 
127-266 
1+-266 
Week 40 
281 
 
 
 
 
 
Week 52 
365 
>266 
>266 
>266 
>266 
>266 
EOS* 
NA 
NA 
 
 
 
 
1-: up to randomization and before 1st dose date/time; 1+: after randomization or 1st dose date/time 
*PK and ADA data collected at the EOS visit will not be remapped 
 
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. Unscheduled visit measurements for efficacy data will be included in the by-visit 
summaries if they are re-allocated to scheduled visits. 
 
 
 
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5.5 
APPENDIX 5 SELECTION CRITERIA FOR AE GROUPINGS  
Table 12 - List of PTs for CMQs  
Grouping 
Preferred Term Code 
Preferred Term 
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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