A Randomized Double-blind Placebo-controlled Parallel Group Study Assessing the Efficacy and Safety of Dupilumab in Patients With Allergic Fungal Rhinosinusitis (AFRS)
Phase: PHASE3
Conditions: Allergic Fungal Rhinosinusitis
Sponsor: Sanofi

 
 
 
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Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 03  
Protocol title: 
A randomized double-blind placebo-controlled parallel 
group study assessing the efficacy and safety of 
dupilumab in patients with Allergic Fungal Rhinosinusitis 
(AFRS) 
Protocol number: 
EFC16724 
Amendment number: 03 
Compound number 
(INN/Trademark): 
SAR231893 
Dupilumab/Dupixent® 
Study phase: 
Phase 3 
Short title: 
Dupilumab in AFRS  
LIBERTY-AFRS-AIMS  
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:  
IND105379 
EudraCT: 
2020-002999-12 
NCT: 
NCT04684524 
WHO: 
U1111-1246-7549 
EUDAMED 
Not applicable 
Other: 
Not applicable 
 
Date: 
01-Mar-2023 
Total number of pages: 129 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 
All 
01 March 2023, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
23 November 2021, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
30 March 2021, version 1 (electronic 1.0) 
Original Protocol 
31 August 2020, version 1 (electronic 2.0) 
Amended protocol 03 (01 March 2023) 
This Amended Protocol 03 (Amendment 03) 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 
Given the changing dynamics during the COVID-19 pandemic period, the Sponsor has decided to 
update the primary endpoint from the proportion of subjects who undergo or plan to receive 
rescue therapy (SCS and/or surgery) to an objective endpoint that is not impacted by the pandemic 
dynamics and is clinically relevant, namely change from baseline in sinus opacifications assessed 
by computerized tomography (CT) scans using the Lund Mackay (LMK) score at Week 52. 
Consequently, the sample size is updated from 120 subjects to 62 subjects. Sinus CT scan 
opacification reflects both nasal polyps burden in the sinuses as well as the sinus mucosal 
thickening and accumulation of inflammatory secretions, including allergic fungal mucin, 
a hallmark of AFRS (1). Therefore, objective evaluation of sinus opacification (LMK) is widely 
used to evaluate disease progression and management in the sinuses and is considered a clinically 
relevant measure for the evaluation of efficacy of dupilumab in clinical signs of AFRS, a rare 
disease with a limited geographical distribution to warm and humid climates. The proportion of 
participants who undergo or plan to receive rescue therapy (SCS and/or surgery) will be assessed 
as a secondary endpoint.  
 Minor changes and clarifications and typographical errors are not mentioned in the table below. 
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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis,  
3 Objectives and 
Endpoints 
The primary objective updated from 
• To evaluate the ability of dupilumab to reduce the
need for rescue therapy with systemic corticosteroids
(SCS) or surgery for AFRS in patients with AFRS
who previously have had sino-nasal surgery
To 
• To evaluate the efficacy of treatment with dupilumab
to reduce sinus opacification in a population with
allergic fungal rhinosinusitis (AFRS)
The LMK score is a clinically relevant measure 
of efficacy in a rare disease with limited 
geographic distribution. 
The key secondary endpoint switched to primary 
endpoint as below: 
• Change from baseline in sinus opacifications
assessed by computerized tomography (CT) scans
using the Lund Mackay (LMK) score at Week 52
To align primary endpoint with change in 
primary objective. 
The primary endpoint switched to secondary endpoint 
as below: 
• Proportion of participants who receive SCS and/or
undergo/plan to undergo surgery for AFRS during the
planned study treatment period
Since the new primary endpoint is change 
from baseline in LMK score at Week 52, the 
previous primary endpoint is now a secondary 
endpoint. 
1.1 Synopsis, 
3 Objectives and 
Endpoints, 
9.4.3 Secondary 
endpoint(s) 
1.1 Synopsis,  
4.1 Overall Design 
Added text for stratification by time from last surgery to 
include ‘surgery naïve participants’ for those in 
‘≤2 years’ group 
To align with the removal of inclusion 
criterion I04. 
1.1 Synopsis,  
4.1 Overall Design, 
3.1 Appropriateness 
of Measurements, 
9.2 Sample size 
determination 
The sample size changed from 120 (60 per arm) to 
62 (31 per arm).  
The updated study power is >99% for the primary 
endpoint and 80% for the secondary endpoint using 
an alpha=0.05. 
A sample size of 62 participants would provide 
ample power for the new primary endpoint 
based on change from baseline in LMK at 
Week 52, which is a clinically relevant 
measure of efficacy. The new sample size 
would allow for sufficient power for the original 
primary endpoint of rescue therapy utilization 
as a secondary endpoint. 
Updated text to reflect switching of primary to 
secondary endpoint and vice-versa. 
1.1 Synopsis, 
9.4.2 Primary 
endpoint(s), 
9.4.3 Secondary 
endpoint(s) 
In statistical considerations, 1) primary and secondary 
endpoint switched, 2) stratification factor of disease 
pattern removed from the statistical model, 
and 3) intercurrent event of taking SCS for any reason 
changed from treatment policy to composite strategy 
(WOCF). 
The primary and secondary endpoints were 
switched, and the sample size was optimized 
based on this change. The stratification factor 
for disease pattern was removed from the 
statistical model due to only rare unilateral 
participants identified. The treatment policy was 
changed to composite strategy, an approach 
more appropriate for this clinical setting. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.2 Schema 
Schema updated with updated number of participants 
in each study arm 
To reflect the change in sample size 
1.3 Schedule of 
Activities (SoA) 
Updated Footnote ‘c’ to add more clarity in study 
completion definition. 
Clarification of study completion date to align 
with Section 4.4.  
Added below text to Footnote ‘j’ 
Questionnaires in paper form are not permitted; only 
electronic form is allowed. 
Clarification that paper documentation is not 
permitted. 
Added below text to Footnote ‘m’ 
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 for UPSIT assessment due to 
variable availability of testing materials at 
sites. 
1.3 Schedule of 
Activities (SoA), 
8.2.2 Vital signs 
Added below text to footnote ‘o’ for vital signs and 
added to the vital signs sub-section 
Height must be collected at each visit only for pediatric 
participants; collect height for adult participants at 
screening visit (V1) only. 
Clarification that height documentation for 
adults is only required at Visit 1. 
5.1 Inclusion Criteria 
Deleted the following inclusion criteria: 
I 04. History of sino-nasal surgery(ies). 
Note: Examples of sino-nasal surgery but not limited to 
include endoscopic sinus surgery (ESS) and may 
involve removal of inflamed/dysfunctional mucosa and 
may include procedures such as anterior and posterior 
ethmoidectomy, maxillary antrostomy, sphenoidotomy, 
frontal sinusotomy, and/or polypectomy. 
To accommodate variations in treatment 
paradigm per local practice. 
Updated the heading for I06 from ‘Sex’ to ‘Sex, 
contraceptive/barrier method and pregnancy testing 
requirements/breastfeeding’ and updated the WOCBP 
definition. 
Administrative/SOP updates 
5.4 Screen Failures 
Added below sentence at the end of section: 
All other screening procedures must be repeated for 
rescreening. 
Clarification that screen failed participants who 
are rescreened need repeat assessments for 
visit 1. 
8.1 Efficacy 
Assessments 
Moved the below sub-section after the sub-section for 
Three-dimensional volumetric measurement of the 
sinuses: 
8.1.2 
Proportion of participants who receive SCS 
and/or undergo/plan to undergo surgery for AFRS 
during the planned study treatment period   
In order to reflect the change in primary 
endpoints. 
8.6 
Pharmacodynamics 
Removed measurement of secreted P-glycoprotein 
Test is unable to be performed by the Sponsor 
due to assay limitations. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.4.1 General 
considerations 
Alpha level of 0.01 was changed to 0.05 and study is 
considered positive when the primary endpoint 
achieves statistical significant with 2-sided significance 
level 0.05. 
The alpha level was adjusted to support 
an optimized sample size for this rare 
condition. 
10.1.5 Dissemination 
of clinical study data 
Replaced clinicalstudydatarequest.com by vivli.org 
Administrative change. 
10.2 Appendix 2: 
Clinical Laboratory 
Tests, 
10.6 Appendix 6: 
Liver and Other 
Safety: Actions and 
Follow-Up 
Assessments 
Added below footnote in Table 9 - Protocol-required 
laboratory assessments, for clinical chemistry: 
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. 
Added this same text as note in Section 10.6 
Appendix 6 
Clarification on preference for local lab to 
perform urgent tests associated with DILI. 
10.3.2 Definition of 
SAE 
Deleted following text from list of medically important 
events: 
Cancers diagnosed during the study or aggravated 
during the study 
Correction, as cancers are already separately 
considered SAEs.  
10.7 Appendix 7: 
Clinician-Reported 
Outcomes And 
Patient-Reported 
Outcomes 
Added new appendices for following questionnaires: 
10.7.5 
Morning Diary, 
Addition of screenshots of patient reported 
outcome tools to allow clarification to sites. 
Added watermark “For Review Only” to all the 
questionnaires 
Throughout 
Updated patient to participant wherever applicable 
Formatting and typographical 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 6 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 11 
1 
PROTOCOL SUMMARY ............................................................................................................... 12 
1.1 
SYNOPSIS ..................................................................................................................................... 12 
1.2 
SCHEMA ........................................................................................................................................ 18 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 19 
2 
INTRODUCTION ............................................................................................................................ 26 
2.1 
STUDY RATIONALE...................................................................................................................... 26 
2.2 
BACKGROUND ............................................................................................................................. 27 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 29 
2.3.1 
Benefit assessment ........................................................................................................................ 29 
2.3.2 
Risk assessment ............................................................................................................................ 30 
2.3.3 
COVID-19 Benefit-risk assessment ............................................................................................... 31 
2.3.4 
Overall benefit: risk conclusion ...................................................................................................... 32 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 33 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 35 
4 
STUDY DESIGN ............................................................................................................................ 37 
4.1 
OVERALL DESIGN ........................................................................................................................ 37 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 38 
4.2.1 
Participant input into design ........................................................................................................... 38 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 38 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 39 
5 
STUDY POPULATION .................................................................................................................. 40 
5.1 
INCLUSION CRITERIA .................................................................................................................. 40 
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5.2 
EXCLUSION CRITERIA ................................................................................................................ 42 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 45 
5.4 
SCREEN FAILURES...................................................................................................................... 45 
6 
STUDY INTERVENTION AND CONCOMITANT THERAPY ........................................................ 47 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 47 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 49 
6.2.1 
Storage and handling ..................................................................................................................... 49 
6.2.2 
Responsibilities .............................................................................................................................. 49 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 49 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 50 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 51 
6.5.1 
Background treatments .................................................................................................................. 52 
6.5.2 
Prohibited medications ................................................................................................................... 52 
6.5.3 
Rescue medicine ............................................................................................................................ 53 
6.6 
DOSE MODIFICATION .................................................................................................................. 53 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 53 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 54 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 54 
7.1.1 
Definitive discontinuation ............................................................................................................... 54 
7.1.2 
Temporary discontinuation ............................................................................................................. 55 
7.1.2.1 
Rechallenge ................................................................................................................................... 56 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 56 
7.3 
LOST TO FOLLOW-UP ................................................................................................................. 57 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 58 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 59 
8.1.1 
Computerized tomography scans .................................................................................................. 59 
8.1.1.1 
Lund Mackay score ........................................................................................................................ 59 
8.1.1.2 
Three-dimensional volumetric measurement of the sinuses ......................................................... 60 
8.1.2 
Proportion of participants who receive SCS and/or undergo/plan to undergo surgery for 
AFRS during the planned study treatment period .......................................................................... 60 
8.1.3 
Nasal symptom diary, including nasal congestion/obstruction, loss of smell, and anterior 
and posterior rhinorrhea ................................................................................................................. 60 
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8.1.4 
Nasal polyps score ......................................................................................................................... 61 
8.1.5 
22-item sino-nasal outcome test .................................................................................................... 62 
8.1.6 
Rhinosinusitis severity visual analog scale .................................................................................... 62 
8.1.7 
University of Pennsylvania smell identification test ....................................................................... 62 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 64 
8.2.1 
Physical examinations ................................................................................................................... 64 
8.2.2 
Vital signs ....................................................................................................................................... 64 
8.2.3 
Electrocardiograms ........................................................................................................................ 65 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 65 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 65 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 66 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 66 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 66 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 66 
8.3.5 
Pregnancy ...................................................................................................................................... 67 
8.3.6 
Adverse event of special interest ................................................................................................... 67 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 68 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 68 
8.5 
PHARMACOKINETICS AND IMMUNOGENICITY ASSESSMENTS ............................................ 69 
8.5.1 
Systemic drug concentration and antidrug antibodies ................................................................... 69 
8.5.1.1 
Sampling time ................................................................................................................................ 69 
8.5.1.2 
Handling procedures ...................................................................................................................... 69 
8.5.1.3 
Bioanalytic method ......................................................................................................................... 70 
8.6 
PHARMACODYNAMICS ............................................................................................................... 70 
 
8.8 
BIOMARKERS ............................................................................................................................... 72 
 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 72 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 74 
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9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 74 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 74 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 75 
9.4.1 
General considerations .................................................................................................................. 75 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 76 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 77 
9.4.5 
Other safety analyses .................................................................................................................... 78 
9.4.6 
Other analyses ............................................................................................................................... 80 
9.5 
INTERIM ANALYSES .................................................................................................................... 80 
9.6 
DATA MONITORING COMMITTEE .............................................................................................. 80 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 81 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 81 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 81 
10.1.2 
Financial disclosure........................................................................................................................ 82 
10.1.3 
Informed consent process .............................................................................................................. 82 
10.1.4 
Data protection ............................................................................................................................... 83 
10.1.5 
Dissemination of clinical study data ............................................................................................... 85 
10.1.6 
Data quality assurance .................................................................................................................. 86 
10.1.7 
Source documents ......................................................................................................................... 86 
10.1.8 
Study and site start and closure ..................................................................................................... 87 
10.1.9 
Publication policy ........................................................................................................................... 88 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 88 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 90 
10.3.1 
Definition of AE .............................................................................................................................. 90 
10.3.2 
Definition of SAE ............................................................................................................................ 91 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 92 
10.3.4 
Reporting of SAEs.......................................................................................................................... 94 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 95 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 98 
10.7 
APPENDIX 7: CLINICIAN-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES .................................................................................................................................. 99 
10.7.2 
Sino-nasal outcome test .............................................................................................................. 101 
10.7.3 
Rhinosinusitis visual analog scale ............................................................................................... 102 
10.7.5 
AFRS Morning Diary .................................................................................................................... 104 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 116 
10.9 
APPENDIX 9: DEFINITION OF ANAPHYLAXIS ......................................................................... 116 
10.10 
APPENDIX 10: LIST OF OPPORTUNISTIC INFECTIONS......................................................... 117 
10.11 
APPENDIX 11: ABBREVIATIONS ............................................................................................... 118 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 120 
10.12.1 Amended protocol 01 (30 March 2021) ....................................................................................... 120 
10.12.2 Amended protocol 02 (23 November 2021) ................................................................................. 124 
11 
REFERENCES ............................................................................................................................. 126 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 33 
Table 2 - Overview of study interventions administered ............................................................................... 47 
Table 3 - Nasal congestion/obstruction symptom severity ............................................................................ 61 
Table 4 - Summary of handling procedures .................................................................................................. 69 
Table 5 - Summary of bioanalytical methods for functional dupilumab and anti-dupilumab antibodies ....... 70 
Table 6 - Populations for analyses ................................................................................................................ 74 
Table 7 - Summary of primary estimand for the primary endpoint ................................................................ 76 
Table 8 - Summary of primary estimand for the proportion secondary endpoint .......................................... 78 
Table 9 - Protocol-required laboratory assessments .................................................................................... 88 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 18 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A randomized double-blind placebo-controlled parallel group study assessing the 
efficacy and safety of dupilumab in patients with Allergic Fungal Rhinosinusitis 
(AFRS) 
Short title: 
Dupilumab in AFRS 
LIBERTY-AFRS-AIMS 
Rationale: 
Allergic Fungal Rhinosinusitis (AFRS) is a chronic disease characterized by a robust 
type 2 inflammatory response directed against colonizing fungi in the sinuses with accumulation 
of eosinophilic mucin containing fungal hyphae, which results in persistent sinus opacification 
and nasal polyp formation. This disease accounts for a small (<10%) portion of patients with chronic 
rhinosinusitis (CRS). The disease predominantly occurs in regions with warm, humid climates. 
Although all patients present with nasal polyps and there are shared type 2 driven inflammatory 
pathways underlying the 2 conditions, AFRS is distinct from chronic rhinosinusitis with nasal 
polyposis (CRSwNP) in its diagnosis, presentation, clinical course, pathophysiology, and 
management (2, 3). Unlike CRSwNP, diagnosis of AFRS requires evidence of immunoglobulin 
(Ig)E mediated inflammatory response to fungal hyphae (specific IgE serology or skin test), nasal 
polyps, characteristic computed tomography (CT) findings, eosinophilic mucin without fungal 
invasion into sinus tissue, and a positive fungal stain of sinus contents (4). Patients with AFRS have 
an indolent disease course, with slow growing opacification of sinuses due to mucin production. 
However, the disease can be severe and unlike CRSwNP, it often leads to bony erosion of the sinuses 
and even facial deformities. The disease occurs in a younger population with a mean age in the 20s to 
30s (2, 5). Patients with AFRS are more likely to have concomitant asthma than the general 
population, but the overall incidence is lower at approximately 25% (6). The disease itself is driven 
by an interplay between the presence of fungal spores and a type 2 inflammatory reaction. This 
response shares many features with CRSwNP and type 2 mediators including interleukin-4 (IL-4), 
IL-5, and IL-13 have been found to be upregulated in tissue from both diseases. However, 
molecular endotyping has also identified pathways that are distinct to AFRS, which differentiate 
AFRS from CRSwNP as a subtype of CRS demonstrating an extreme of type 2 inflammations, 
such as the ICOS, CD28, and PKCӨ pathways, which play pivotal roles in type 2 inflammatory 
effector function (7). Although there are rare cases of AFRS in children ≥6 to <12 years of age, in 
these children the disease commonly leads to facial dysmorphism. The growing facial skeleton of 
younger children may account for the higher degree of dysmorphism seen as compared to adults. 
Asymmetric disease and unilateral sinus disease are more frequent in children (above 6 years of 
age) compared with adults while incidence of bony erosion is comparable with adults (8, 9).  
Current treatment paradigms require surgical debridement via endoscopic sinus surgery (ESS) to 
remove thick mucus as well as any coexisting nasal polyps, followed by adjuvant oral 
corticosteroid taper. Patients require chronic suppression with topical corticosteroids and may 
need frequent oral steroid bursts. There is a high early recurrence rate after surgery even with 
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systemic and topical nasal corticosteroids requiring frequent systemic steroid use and repeated 
surgeries. Delayed surgery can lead to increased risk for complications as bony erosions thin the 
sinus walls. The role of antifungals remains unclear and they are currently not recommended (10). 
There remains great unmet need in identifying novel therapies that address inflammatory 
underpinnings of the disease processes, minimize the need for systemic corticosteroids (SCS) and 
their associated side effects, prevent recurrence, prevent complications and bony erosion, and 
achieve long-lasting disease control. 
Dupilumab is a fully human monoclonal antibody (mAb) directed against the interleukin 4 receptor 
alpha subunit (IL-4Rα), which is a component of IL-4 receptors Type I and Type II, as well as the 
IL-13 type II 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. Type 2 inflammation is responsible for several 
pathophysiological mechanisms including inhibition of mast cell and basophil degranulation, 
reduction in serum IgE levels, and potentially eosinophil trafficking into tissues. Dupilumab has 
demonstrated efficacy across a broad range of diseases driven by type 2 inflammation, including 
atopic dermatitis (AD), asthma, and CRSwNP.  
In the CRSwNP development program, dupilumab demonstrated a positive benefit-risk and clinically 
significant efficacy across radiological, endoscopic, and clinical symptoms of disease, resulting in 
significant reduction in sinus opacification, the need for SCS, and surgery. AFRS patients were not 
included in the previous dupilumab CRSwNP program. Both AFRS and CRSwNP are a subtype of 
CRS and share common disease characteristics, including type 2 inflammatory pattern as well as 
some elements of disease presentation, eg, sinus inflammation, nasal polyps, and symptoms like 
nasal congestion and rhinorrhea. 
Dupilumab, therefore, offers promise of significant benefit above and beyond current standard of 
care in AFRS and may provide an alternative for those patients who relapse after surgery and may 
obviate the need for repeated SCS and/or surgeries. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of treatment with dupilumab to 
reduce sinus opacification in a population with allergic 
fungal rhinosinusitis (AFRS) 
• Change from baseline in sinus opacifications assessed 
by computerized tomography (CT) scans using the Lund 
Mackay (LMK) score at Week 52 
Secondary 
• To evaluate the efficacy of treatment with dupilumab to 
reduce sinus opacification in a population with allergic 
fungal rhinosinusitis (AFRS) at Week 24 
• Change from baseline in sinus opacifications assessed 
by CT scans using the LMK score at Week 24 
• To assess the efficacy of dupilumab to reduce the need 
for rescue treatments 
• Proportion of participants who receive SCS and/or 
undergo/plan to undergo surgery for AFRS during the 
planned study treatment period   
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Objectives 
Endpoints 
• To evaluate the efficacy of treatment with dupilumab in 
improving symptoms in AFRS 
• Change from baseline in monthly average nasal 
congestion/obstruction score from the Nasal Symptom 
Diary at Week 24 and Week 52 
• Change from Baseline in the monthly average 
anterior/posterior rhinorrhea score from the Nasal 
Symptom Diary at Week 24 and Week 52 
• To evaluate the efficacy of dupilumab to reduce nasal 
polyp formation in participants with AFRS 
• Change from baseline in endoscopic nasal polyp score 
(NPS) compared with placebo at Week 24 and Week 52  
• To evaluate the efficacy of dupilumab in improving overall 
symptom severity and quality of life in AFRS 
• Change from baseline in 22-item sino-nasal outcome test 
(SNOT-22) total score at Week 24 and Week 52 
• Change from baseline in monthly average total symptom 
score (TSS) derived from the Nasal Symptom Diary at 
Week 24 and Week 52 
• Change from baseline in visual analog scale (VAS) 
rhinosinusitis at Week 24 and Week 52 
• To evaluate the efficacy of dupilumab in improving sense 
of smell in participants with AFRS 
• Change from baseline in University of Pennsylvania smell 
identification test (UPSIT) at Week 24 and Week 52 
• Change from baseline in the score of decreased/loss of 
smell using the Nasal Symptom Diary at Week 24 and 
Week 52 
• To explore the effect of dupilumab as assessed by 
three-Dimensional CT volumetric measurement of the 
paranasal sinuses  
• Change from baseline to Week 52 in three-Dimensional 
CT volumetric measurement of the paranasal sinuses 
• To evaluate the safety and tolerability of dupilumab when 
administered to participants with AFRS 
• Incidence of treatment-emergent adverse events (TEAEs) 
or serious adverse events (SAEs) through Week 52 
• To evaluate the pharmacokinetics (PK) of dupilumab in 
participants with AFRS 
• Dupilumab concentration in serum over time 
• To characterize the effect of dupilumab on total IgE and 
specific IgE 
• Percent change from baseline in total IgE in serum 
compared with placebo over the 52-week treatment 
period  
• Percent change from baseline in fungal-specific IgE in 
serum compared with placebo over the 52-week 
treatment period 
• To assess immunogenicity to dupilumab in participants 
with AFRS 
• Assessment of incidence of treatment-emergent anti-drug 
antibodies (ADA) to dupilumab over time 
Overall design: 
This is a Phase 3, multicenter, 52-week treatment, parallel-group, double-blind, randomized, 
placebo-controlled study to investigate the efficacy of dupilumab 300 mg every 2 weeks (q2w) for 
adults and adolescents/children (≥6 to <12 years) ≥60 kg, or dupilumab 200 mg q2w for 
adolescents/children ≥30 kg and <60 kg, and dupilumab 300 mg every 4 weeks (q4w) for 
adolescents/children ≥15 kg and <30 kg with signs and symptoms of AFRS. The study will 
primarily investigate the efficacy of dupilumab to reduce disease burden in the sinuses (sinus 
opacification) by radiographic imaging. In addition, the study will also evaluate efficacy of 
dupilumab to reduce the need for repeated SCS and/or surgery, nasal polyps burden, clinical 
symptoms, and explore other measures of disease activity.  
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Disclosure Statement:  
This is an interventional study with 2 arms that are blinded to both participants and Investigators. 
Number of participants: 
Approximately 62 participants (31 per arm) with AFRS with prior history of surgery will be 
randomized in a 1:1 ratio to receive either dupilumab or matching placebo. Randomization will be 
stratified first by age (adults versus adolescents/children). In adults, randomization will be stratified 
further by time from last surgery (≤2 years [including surgery naive participants], >2 years), disease 
pattern (unilateral/bilateral in the endoscopy at screening), and country. In adolescents/children, 
randomization will not be stratified further. 
Intervention groups and duration: 
Study intervention(s) 
Participants who satisfy the inclusion and exclusion criteria will be randomized (1:1) to one of the 
following treatment groups: 
• Dupilumab 300 mg q2w for all adults, 300 mg q2w for adolescents/children ≥60 kg at 
screening, 200 mg q2w for adolescents/children ≥30 kg and <60 kg at screening, 
or 300 mg q4w for adolescents/children ≥15 kg and <30 kg at screening. 
• Matching placebo.  
Duration of study period (per participant): 
• Screening period (2 to 4 weeks). 
• Randomized investigational medicinal product (IMP) intervention period (52 weeks ±3 days). 
• Follow-up period (12 weeks ±5 days).  
Investigational medicinal products: 
• Dupilumab 300 mg and placebo matching dupilumab 300 mg supplied in visually 
indistinguishable pre-filled syringes. 
• Dupilumab 200 mg and placebo matching dupilumab 200 mg supplied in visually 
indistinguishable pre-filled syringes. 
Dupilumab: 
Formulation: 
• Dupilumab 300 mg: a 150 mg/mL dupilumab solution in a pre-filled syringe to deliver 
300 mg in a 2 mL injection. 
• Dupilumab 200 mg: a 175 mg/mL dupilumab solution in a pre-filled syringe to deliver 
200 mg in a 1.14 mL injection. 
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Route of administration: subcutaneous (SC) injection 
Dose regimen: 
• One injection of 300 mg q2w for all adults and for adolescents/children weighing ≥60 kg 
at screening. 
• One injection of 200 mg q2w for adolescents/children ≥30 kg and <60 kg at screening. 
• One injection of 300 mg q4w for adolescents/children ≥15 kg and <30 kg at screening. 
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. 
• Placebo matching dupilumab 200 mg: identical formulation to the active 200 mg 
formulation without dupilumab, in a pre-filled syringe to deliver placebo in a 1.14 mL 
injection. 
Route of administration: SC injection 
Dose regimen: 
• One injection of placebo matching 300 mg q2w for all adults and for adolescents/children 
weighing ≥60 kg at screening. 
• One injection of placebo matching 200 mg q2w for adolescents/children ≥30 kg and 
<60 kg at screening. 
• One injection of placebo matching 300 mg q4w for adolescents/children ≥15 kg and 
<30 kg at screening. 
Post-trial access to study medication  
Posttrial access to study medication will not be provided. 
Statistical considerations: 
• Primary endpoint:  
- 
The primary endpoint of change from baseline in LMK score at Week 52 will be 
analyzed using an analysis of covariance (ANCOVA) model with the baseline LMK 
score, intervention group, time from last surgery (≤2 years, >2 years) and region 
(combined countries) as covariates, with intercurrent events and missing data being 
handled by a hybrid method of the worst-observation carried forward (WOCF) and 
multiple imputation. For participants who undergo/plan to undergo surgery for AFRS, 
take SCS for any reason or start prohibited biologics, data collected after these 
intercurrent events (IEs) will be excluded from analysis and the worst post-baseline 
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value on or before the IE will be assigned to the Week 52 value (ie, WOCF approach). 
For participants with no post-baseline values, the baseline value will be used 
(composite strategy). Participants who discontinue the study intervention prematurely 
are encouraged to follow the planned clinical visits and, in these participants 
(if without or before the IEs that need to be handled with composite strategy), all data 
collected after study intervention discontinuation will be included in the analysis 
(treatment policy strategy). In case there are missing data, a multiple imputation 
approach will be used to impute missing Week 52 values, and this multiple imputation 
will use all data from participants but will exclude data from participants who 
undergo/plan to undergo surgery for AFRS, take SCS for any reason or start prohibited 
biologics on or before Week 52. Each of the imputed complete data will be analyzed 
by fitting an analysis of covariance (ANCOVA) model with the baseline covariate and 
factors for intervention group, time from last surgery (≤2 years, >2 years), and region 
(combined countries). Statistical inference obtained from all imputed data will be 
combined using Rubin’s rule. Descriptive statistics including number of participants 
mean, standard error, and least squares (LS) means will be provided. In addition, 
difference in LS means and the corresponding 95% confidence intervals (CI) will be 
provided along with the p-values.  
• Secondary endpoints: 
- 
The change from baseline to Week 24 and Week 52 in the continuous secondary 
endpoints will be analyzed using the same analysis approach as for the primary 
endpoint of change from baseline in LMK score at Week 52. 
- 
The secondary endpoint of proportion of participants who receive SCS and/or 
undergo/plan to undergo surgery for AFRS during the 52-week treatment period will 
be analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by time from last 
surgery (≤2 years, >2 years) and region (combined countries). All data collected after 
study intervention discontinuation and before starting prohibited biologics will be 
included in the analysis. Participants who discontinue the study follow-up without an 
event will be considered as no event. The estimate of the odds ratio between 
dupilumab and placebo will be derived with the corresponding 95% CI and p-value.   
Data Monitoring Committee: Due to 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  
N=31
Arm A: Dupilumab SC
300 mg Q2W (for adults and adolescents/children ≥60kg) 
or 200 mg Q2W (for adolescents/children ≥30kg and <60kg),
or 300 mg Q4W (for adolescent/children ≥15kg and <30kg)
52-week treatment period
R*
Screening 
-28 to -14 days
12-week follow-up
Continue background therapy as indicated: INCS**
V2
Week 64/EOS
N=31
Arm B: Placebo SC 
Q2W (for adults and adolescents/children ≥60kg)
Q2W (for adolescents/children ≥30kg and <60kg),
Q4W (for adolescents/children ≥15kg and <30kg)
Q2W: every 2 weeks, Q4W: every 4 weeks, SC: subcutaneous, EOT: end of treatment, EOS: end of study, INCS: intranasal corticosteroids, 
R*: randomization; 
**For patients already on INCS prior to screening
V1
Week 52/EOT
 
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Procedure 
Screening 
2-4 wks  
D-28 to 
D-14 
Intervention period weeks 
Follow-up 
(Wk 64, 
12 weeks 
after 
EOT)/EOSc 
Notes 
Wk 0 
D1a 
Wk 2 
D15x 
Wk 12 
D85 
Wk 24 
D169 
Wk 36 
D252 
Wk 52 
D364 
EOTb 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Visit window: +3 days for Visit 2, 
±3 days for Visits 3 to 7, ±5 days for 
Visit 8 
Screening and baseline 
 
Informed consent/assentd 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
Recheck clinical status before 
randomization. 
Participant demography 
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 
---------------------------------------------------------------------------------------------------------------------------------------------→ 
 
Prior/Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
Check INCS as prior medication at 
screening and background 
medication during study period. 
Record rescue therapy, if applicable. 
Randomization 
 
X 
 
 
 
 
 
 
 
Log-in to IRT 
X 
X  
X 
X 
X 
X 
X 
X 
 
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Procedure 
Screening 
2-4 wks  
D-28 to 
D-14 
Intervention period weeks 
Follow-up 
(Wk 64, 
12 weeks 
after 
EOT)/EOSc 
Notes 
Wk 0 
D1a 
Wk 2 
D15x 
Wk 12 
D85 
Wk 24 
D169 
Wk 36 
D252 
Wk 52 
D364 
EOTb 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Visit window: +3 days for Visit 2, 
±3 days for Visits 3 to 7, ±5 days for 
Visit 8 
Study interventiong 
IMP administrationh 
 
----------------------------------------------------------------------------------------------→ 
 
IMP will be administered every 
14 ±3 days (q2w) for participant 
weighing ≥30 kg (measured at 
screening) or 28±3 days (q4w) for 
participant weighing <30 kg 
(measured at screening). Between 
visits at site, home administration is 
allowed after appropriate training of 
the participant (or parent/legally 
authorized representative, or 
caregiver). The planned last dose is 
at Week 50 for q2w injections and 
Week 48 for q4w injections.  
Efficacy assessmentsj  
Nasal Endoscopyi 
X 
X 
 
X 
X 
X 
X 
X 
For participant aged ≥6 to <12 years 
old, nasal endoscopy will only be 
mandatory at screening, Week 0, 
Week 24, and Week 52. 
CT scank 
X 
 
 
 
X 
 
X 
 
Initial CT scan to be done during 
screening period results should be 
available prior to randomization 
(Visit 2). Week 24 CT scan is not 
required for adolescents/children.  
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Procedure 
Screening 
2-4 wks  
D-28 to 
D-14 
Intervention period weeks 
Follow-up 
(Wk 64, 
12 weeks 
after 
EOT)/EOSc 
Notes 
Wk 0 
D1a 
Wk 2 
D15x 
Wk 12 
D85 
Wk 24 
D169 
Wk 36 
D252 
Wk 52 
D364 
EOTb 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Visit window: +3 days for Visit 2, 
±3 days for Visits 3 to 7, ±5 days for 
Visit 8 
Dispense or download 
daily diary for symptoms 
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. 
Not required for children aged ≥6 to 
<12 years.  
Nasal Symptom Diary 
(includes nasal 
congestion, loss of smell, 
anterior and posterior 
rhinorrhea; TSS derived 
from these 4 items)l 
<----------------------------------------------------------------Daily diary------------------------------------------------------------------> 
Morning assessments captured daily. 
Not required for children aged ≥6 to 
<12 years. 
22 item Sino-Nasal 
Outcome Test 
(SNOT-22)m 
 
X 
 
X 
X 
X 
X 
X 
Not required for children aged ≥6 to 
<12 years. 
Smell test (UPSIT)m 
 
X 
X 
X 
X 
 
X 
X 
Not required for children aged ≥6 to 
<12 years. 
Visual analog scale (VAS) 
for rhinosinusitism 
 
X 
X 
X 
X 
X 
X 
X 
Not required for children aged ≥6 to 
<12 years. 
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Procedure 
Screening 
2-4 wks  
D-28 to 
D-14 
Intervention period weeks 
Follow-up 
(Wk 64, 
12 weeks 
after 
EOT)/EOSc 
Notes 
Wk 0 
D1a 
Wk 2 
D15x 
Wk 12 
D85 
Wk 24 
D169 
Wk 36 
D252 
Wk 52 
D364 
EOTb 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Visit window: +3 days for Visit 2, 
±3 days for Visits 3 to 7, ±5 days for 
Visit 8 
Safety assessmentsj 
Vital signso 
X 
X 
 
X 
X 
X 
X 
X 
 
12-lead ECG  
X 
 
 
 
 
 
 
 
Local reading 
AE review 
 ---------------------------------------------------------------------------------------------------------------------------------------------→ 
 
SAE review 
 ---------------------------------------------------------------------------------------------------------------------------------------------→ 
 
Laboratory assessment 
Laboratory assessments 
(including hematology and 
biochemistry)p  
X 
X 
 
X 
X 
 
X 
X 
 
Urinalysis (urine dipstick)p 
X 
X 
 
X 
X 
 
X 
X 
 
HBV, HCV, HIV, 
TB testingq 
X 
 
 
 
 
 
 
 
TB test (performed locally if required 
and results noted in the eCRF). 
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Procedure 
Screening 
2-4 wks  
D-28 to 
D-14 
Intervention period weeks 
Follow-up 
(Wk 64, 
12 weeks 
after 
EOT)/EOSc 
Notes 
Wk 0 
D1a 
Wk 2 
D15x 
Wk 12 
D85 
Wk 24 
D169 
Wk 36 
D252 
Wk 52 
D364 
EOTb 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Visit window: +3 days for Visit 2, 
±3 days for Visits 3 to 7, ±5 days for 
Visit 8 
Pregnancy test (WOCBP 
only)r  
X 
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)s  
 
X 
  
X 
X 
 
X 
X 
 
Antidrug antibody 
sampling (ADA) s 
 
X  
 
X 
X 
 
X 
X 
 
Serum total IgE and 
fungal specific IgEt 
X 
 
 
X 
X 
 
X 
 
Only positive Allergen Specific IgE at 
screening would be retested at the 
following visits. If restrictions for 
exportation of samples, quantification 
will be done in country central lab as 
per local regulation. 
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Procedure 
Screening 
2-4 wks  
D-28 to 
D-14 
Intervention period weeks 
Follow-up 
(Wk 64, 
12 weeks 
after 
EOT)/EOSc 
Notes 
Wk 0 
D1a 
Wk 2 
D15x 
Wk 12 
D85 
Wk 24 
D169 
Wk 36 
D252 
Wk 52 
D364 
EOTb 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Visit window: +3 days for Visit 2, 
±3 days for Visits 3 to 7, ±5 days for 
Visit 8 
 ADA: anti-drug antibody; AE: adverse event; CT: computerized tomography; D: day; 
 ECG: electrocardiogram; eCRF: electronic 
case report form; EOS: end of study; EOT: end of treatment; FEF: forced expiratory flow; FEV1: forced expiratory volume; FVC: forced vital capacity; HBcAb: hepatitis B core antibody; HBsAg: hepatitis B surface 
antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HCVAb: hepatitis C virus antibody; HIV: human immunodeficiency virus; IEC: Independent Ethics Committee; Ig: immunoglobulin; IMP: investigational medicinal 
product; IRB: Institutional Review Board; INCS: intranasal corticosteroids; IRT: Interactive response technology; NPS: Nasal Polyp Score; PK: pharmacokinetics; 
 
; PRO: Patient-Reported outcome; 
; SAE: serious adverse event; SC: subcutaneous; SNOT-22: 22-item sino-nasal outcome; TB: tuberculosis; 
TSS: total symptom score; UPSIT: University of Pennsylvania smell identification test; VAS: visual analog scale; V: Visit; Wk: Week; WOCBP: women of childbearing potential.  
a All assessments at Visit 2, (Day 1) are to be conducted pre-IMP dose with the exception of the assessment of local tolerability of SC injections. Note: Under particular circumstances, that might require additional 
time, such as eosinophilic mucin collection or skin testing performed during the screening, the screening period can be extended to a maximum of additional 14 days (maximum of 42 ±3 days). 
b Participants who discontinue the study treatment prematurely (prior to completing the 52-week treatment period) will perform the 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.  
c If a participant discontinues treatment period prematurely before Week 40 but completes follow-up to Week 52, he/she will be considered to have completed the study. 
d Consent to be obtained for optional procedures (whole blood DNA and whole blood RNA sampling and serum/plasma sampling for archival; HIV test if specific consent locally required, spirometry for children). 
e Past medical history including allergic comorbidities (asthma, aspirin sensitivity, allergic rhinitis etc). Surgeries will be assessed including type and dates of sino-nasal 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 eCRF. Fungal stain assessment (positive/negative/not done). 
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 
AE or 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 In case of emergency (eg, natural disaster, pandemic) remote visit (except for Baseline, Week 24 and Week 52) could be considered (eg, Home nursing, Telehealth) 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 lab tests and clinical assessment procedures can be considered to be 
conducted locally per local regulation requirement. 
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h Refer to Section 4 Study Design for details on treatment arms. IMP will be administered after completion of all scheduled clinical assessments and sample collections at the visit or at home. 
i 
Nasal endoscopy (including use of decongestants before the procedure): The participant will be considered eligible based on a V1 central reading followed by a V2 local reading of NPS score of 2 out of 4 for 
unilateral polyps or 3 out of 8 for bilateral polyps.  
j 
Assessments/procedures should be conducted in the following order: Patient-Reported outcome (PRO), Investigator assessments, safety and laboratory assessments (including sample collection for ADA, PK, 
biomarker, and optional archival serum/plasma, DNA and RNA), and administration of IMP. Questionnaires in paper form are not permitted; only electronic form is allowed. 
k CT scan should be performed during screening period before first administration of IMP, at V5 (Week 24 if accepted per local EC requirement) and at V7 (Week 52), and central reading will be used for comparison 
baseline (BL) to Week 52 for the primary analysis and at EOT. 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. If participant need to have CT scan around the time of surgery the next scheduled CT scans per protocol do not 
need to occur after a surgery for AFRS. In any case participants may not have more than 3 CT scans during the study. 
l 
Electronic diary is used for daily recording of nasal symptoms: 1) nasal congestion/obstruction 2) anterior rhinorrhea (runny nose), 3) posterior rhinorrhea (post nasal drip), and 4) loss of sense of smell, scored 
using a 0-3 categorical scale where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms). This device is dispensed at V1 and information is downloaded from this device on 
the other indicated days. 
o Vital signs, including blood pressure (mm Hg), pulse (beats per minute), respiratory rate (breaths per minute), body temperature (degrees Celsius), body weight (kg), and height (cm) will be measured at the 
screening and randomization visits (V1 and V2) and subsequent visit pre-specified in the flow-chart. Vital signs will be measured prior to receiving IMP at the clinic visits in the semi-supine or sitting position using 
preferably the same arm at each visit. Height must be collected at each visit only for pediatric participants; collect height for adult participants at screening visit (V1) only. 
p Refer to Section 10.2 and central laboratory manual for collection details. China will use the urine sample analysis (not dipstick). 
q Clinical laboratory testing at V1 includes hepatitis screen covering HBsAg, HBcAb total, HCVAb and HIV screen (anti-HIV-1 and HIV-2 antibodies). In case of results showing HBsAg (negative), and HBcAb total 
(positive), an HBV DNA testing will be performed and confirmed negative prior to randomization. In case of results showing HCV Ab (positive), an HCV RNA will be performed and should be confirmed negative 
prior to randomization. 
r 
Only for women of childbearing potential: Serum pregnancy test at V1 and urine pregnancy tests at V2 and every 4 weeks thereafter. A negative result must be obtained between V1 and V2 prior to randomization 
visits. Urinary test could be performed at home with or without the assistance of a home care provider after appropriate training. In case of positive urine test, the study treatment will be withheld and a serum 
pregnancy test to confirm the pregnancy should be performed as soon as possible. Pregnancy will lead to definitive treatment discontinuation in all cases.  
s At indicated time points serum dupilumab concentration and ADA samples will be collected and archived prior to administration of investigational product. Blood samples for PK and ADA assessment may be 
collected in case a suspected SAE. In response to AEs of special interest like anaphylaxis or hypersensitivity additional ADA samples may be collected at or near the event based on the medical judgment of the 
Investigator and/or Sponsor representative. Pharmacokinetic and ADA samples will be collected unless restricted due to local regulation. However, the PK and ADA samples will be collected for safety assessment 
in the event of an SAE. Samples for ADA will only be collected for analysis in the event of any SAE for participants from China sites. 
t 
For sites that cannot send fungal specific IgE to central lab to test timely, additional local 
 tests or skin test may be needed to meet participant’s eligibility.  
x For participants ≥15 kg to <30 kg at screening and injection every 4 weeks, Visit 3 will be at Week 4. Parent/legally authorized representative, or caregiver injection training will be performed at this visit. 
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2 
INTRODUCTION  
Allergic fungal rhinosinusitis is a type 2 mediated disease characterized by thick mucus, 
opacification of the sinuses, and nasal polyps. Dupilumab is a fully human monoclonal antibody 
directed against the IL-4Rα, which is a component of IL-4 receptors Type I and Type II, as well 
as the IL-13 type II receptor. The binding of dupilumab to IL-4Rα results in blockade of IL-4 and 
IL-13 intracellular signaling.  
As a targeted/specific immunomodulatory agent, dupilumab is expected to selectively inhibit 
type 2 inflammations 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 CRS and by blocking the activity of 
these cytokines, dupilumab has been shown to be an effective treatment for CRSwNP including 
improved sinus opacification, reduction in nasal polyp burden and improved symptom scores.  
2.1 
STUDY RATIONALE  
Allergic fungal rhinosinusitis is a chronic disease of the sinuses characterized by a type 2 
inflammatory response to the presence of fungal hyphae. There is a great unmet need to identify 
a therapy that can suppress disease progression and potentially limit the need for recurrent surgery 
or oral corticosteroid exposure. This indolent disease is chronic and is associated with a gradual 
progression, thick mucus and nasal polyps. Current treatment paradigms require endoscopic nasal 
sinus surgery including debridement of mucus and polypectomy, followed by a tapering schedule 
of adjuvant oral corticosteroids. The disease is chronic in nature, and can recur despite surgery, 
particularly with continued exposure to fungal spores in endemic areas. Patients with recurrence 
will need rescue therapy, including a short course of oral corticosteroids and even repeat surgery.  
Allergic fungal rhinosinusitis is driven by a type 2 inflammatory response in the presence of 
fungal spores, and therefore is highly likely to respond to dupilumab treatment. The presence of 
type 2 inflammation is evidenced by polyp formation as well as responsiveness to corticosteroids. 
Molecular profiling has demonstrated elevations in type 2 inflammatory markers including IL-4, 
IL-5 (promoter of eosinophil survival, differentiation and taxis), and IL-13, eosinophil cationic 
protein (eosinophil activation product), eotaxins (eosinophil chemoattractants), P-glycoprotein 
(marker of eosinophilia, that correlates with Lund Mackay [LMK] score) and immunoglobulin E 
(IgE) from the nasal mucosa and local secretions (11, 12) as well as overexpression of 
eosinophilia-related genes (13). Whole gene microarray analysis from ethmoid mucosa has 
demonstrated an overexpression of type 2 inflammatory genes among patients with AFRS.  
Dupilumab is a fully human monoclonal antibody directed against the IL-4Rα, which is 
a component of IL-4 receptors type I and type II, as well as the IL-13 type II receptor. 
The binding of dupilumab to IL-4Rα results in blockade of IL-4 and IL-13 intracellular signaling. 
As a targeted/specific immunomodulatory agent, dupilumab is expected to selectively inhibit 
type 2 inflammations and is designed to achieve the desired therapeutic effect without the side 
effects typically associated with the use of less selective immunosuppressants.  
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Both IL-4 and IL-13 signaling pathways are implicated in CRS, asthma and other atopic diseases 
and by blocking the activity of these cytokines, dupilumab has been shown to be an effective 
treatment for CRSwNP, a type 2 inflammatory process. This includes 2 successful Phase 3 studies 
of 24- and 52-weeks duration, in which 300 mg q2w of dupilumab used on top of topical 
corticosteroids (mometasone furoate nasal spray) in patients with CRSwNP demonstrated 
a positive benefit-risk and clinically significant efficacy across radiological, endoscopic, and 
clinical symptoms of disease, resulting in significant reduction in need for SCS and surgery (14). 
Therefore, given the high degree of overlap between the immunologic drivers for mucus 
production and nasal polyp formation, considering both AFRS and CRSwNP are a subtype of 
CRS and share common disease characteristics, including type 2 inflammatory pattern, as well as 
some elements of disease presentation, eg, sinus inflammation, nasal polyps, and symptoms like 
nasal congestion and rhinorrhea it is anticipated that dupilumab will have a similar impact on 
disease burden in patients with AFRS. 
Dupilumab, therefore, offers promise of significant benefit above and beyond current standard of 
care in AFRS and may provide an alternative for those patients who relapse after surgery and may 
obviate the need for repeated SCS and/or surgeries. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of dupilumab is 
provided in the Investigator’s Brochure (IB). 
2.2 
BACKGROUND  
Disease Background and Unmet Medical Need 
Allergic fungal rhinosinusitis is a disease driven by a type 2 inflammatory response to fungal 
spores that presents with a chronic and indolent course, mucous and nasal polyp formation in the 
sinuses and nasal cavity (2).  
Allergic fungal rhinosinusitis is present worldwide, predominantly identified in regions with 
warm and humid climates such as the Southeastern United States (US) (15), and has also been 
described globally including Japan (16), Turkey (17), Saudi Arabia (18), and India (19). Although 
the disease is characterized by CRS, and all patients must have nasal polyps as part of the 
diagnostic criteria, AFRS represents a distinct disease that is driven by dynamic interplay between 
fungal spores and host defenses. The disease occurs in a younger population with a mean age in 
the 20s to 30s (2, 5). There may be a greater predominance of African Americans and some 
reports suggest a greater predominance among individuals with lower socioeconomic status (20). 
Patients with AFRS are more likely to have concomitant asthma than the general population, but 
the overall incidence is lower at approximately 25% (6). AFRS typically presents in young adults 
in their late teens and twenties, however there are rare case reports of AFRS in children between 
6 to 12 years of age (9).   
More often the presentation of AFRS is subtle and indolent. Patients typically complain of nasal 
airway obstruction developed gradually (1). Nasal discharge typically has a thick mucoid 
peanut-butter like appearance. Without timely intervention, possible complications in patients 
with AFRS can include visual disturbances, proptosis, facial deformity, and intracranial sequelae. 
The incidence of bony erosion in AFRS has been reported to be between 20% to 90% (21). 
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The CT findings can be distinctive and may include the presence of unilateral disease, 
hyperdensities, bony demineralization of the sinuses, and bone erosion of the sinuses. CT scans of 
the sinuses in AFRS patients typically show near-complete opacification with heterogeneous 
radiodensity (hyperdensities) of the soft tissue of the sinuses (21). Although there are rare cases of 
AFRS in children ≥6 to <12 years of age, in these children the disease commonly leads to facial 
dysmorphism in children. The growing facial skeleton of younger children may account for the 
higher degree of dysmorphism seen as compared to adults. Asymmetric disease and unilateral 
sinus disease are more frequent in children (above 6 years of age) compared with adults while 
incidence of bony erosion is comparable with adults (8, 9).   
Allergic fungal rhinosinusitis is a disease marked by type 2 inflammation driven by dynamic 
interaction of fungal hyphae locked within thick sinus mucus and type 2 inflammatory responses. 
Patients have elevated serum IgE antifungal antibodies and eosinophils, and the inflammatory 
mucus is characterized by the presence of eosinophils (21). Patients with AFRS have notably 
higher levels of serum IgE antifungal antibodies than CRSwNP (3, 21). Molecular phenotyping 
has demonstrated that the epithelium of patients with AFRS shares many common overexpressed 
genes with CRSwNP (13). This includes type 2 inflammatory genes, including those involved 
with IgE and eosinophil chemotaxis and activation, such as eotaxin-3 (22). Large scale gene 
expression profiling including tissue from patients with CRSwNP and AFRS has demonstrated 
shared overexpression of type 2 inflammatory pathways including those involved with IL-4, IL-5, 
and IL-13 (13). However, molecular endotyping has also identified pathways that are distinct to 
AFRS, which differentiate AFRS from CRSwNP as a subtype of CRS demonstrating an extreme 
of type 2 inflammation such as the iCOS, CD28 and PKCӨ signaling pathways, which play 
pivotal roles in type 2 inflammatory effector function (7). 
Allergic fungal rhinosinusitis is identified by distinct diagnostic criteria that were developed by 
Bent and Kuhn (4). This includes the presence of nasal polyps and characteristic CT opacification, 
as well as the presence of IgE mediated inflammatory response to fungal hyphae as characterized 
by specific IgE positivity or skin prick testing, as well as sheets of eosinophils presence in sinus 
mucus. Aspergillus species are the most commonly identified fungi. Other funguses include 
Bipolaris and Curvularia (3). In 1999, Ponikou showed that treating mucus with a reducing agent, 
dithiothreitol (DTT), could release fungi trapped within the mucin. Using this technique, his group 
showed positive fungal cultures from nasal secretions collected from 96% of chronic 
rhinosinusitis (CRS) patients and 100% of patients without CRS. Fungal staining has high 
variability (10-100% false positive rate) and low specificity. In practice this means that a negative 
fungal stain does not rule out the diagnosis of AFRS, while saprophytic fungal growth is not 
necessarily diagnostic of AFRS. This uncertainty is reflected in the fact that fungal culture is only 
considered supportive evidence in the Bent and Kuhn diagnostic criteria in contrast to the other 
four criteria which are key for the diagnosis (CT, polyps, elevated specific IgE, and eosinophilic 
mucin). Therefore, fungal culture is used as supportive evidence. However, the remainder of the 
Bent and Kuhn criteria is necessary for making the diagnosis of AFRS (23).  
Except for the mildest cases, AFRS usually requires surgical intervention, followed by 
a prolonged course of adjuvant medical therapy (21). Medical therapy alone is regularly 
ineffective in alleviating symptoms and surgical intervention, alone or in combination with 
medical therapy is required (3). The large majority of patients will undergo surgical ESS with 
mucus debridement followed by adjuvant therapy including oral corticosteroid taper over 2 weeks 
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to 6 months with or without chronic topical (intranasal) corticosteroids (3, 21, 24). Recurrence can 
occur, and risk factors may include inadequate full debridement at the time of surgery or 
noncompliance with/inability to tolerate topical and oral corticosteroids (25). Overall recurrence 
rates after surgery are reported to range from 10% to 100% (3). The median interval for revision 
surgery in AFRS was much shorter than CRSwNP (2 versus 7 years) (26). Postoperative oral 
corticosteroids help decrease disease recurrence (21). However, even in AFRS patients treated 
with postoperative systemic steroids and with topical steroid, approximately 10% to 30% of 
patients experience disease recurrence within 6 months to 1 year after surgery (27, 28, 29). 
Despite the widespread acceptance of these treatment modalities, the optimal dose, duration, and 
tapering regimen of postoperative oral corticosteroids have not been addressed. A short-term oral 
corticosteroid rescue therapy can be considered for acute exacerbation. In the pediatric population, 
early efforts should be made to transition from a systemic regimen of corticosteroids to intranasal 
topical steroid therapy to avoid the side effects of systemic steroids (9). Multiple repeated oral 
corticosteroid rescue or long-term use of oral corticosteroids can cause significant side effects, 
including psychosis, insomnia, weight gain, poor control of glucose level, high blood pressure, 
Cushing’s syndrome, adrenal insufficiency, osteoporosis, glaucoma, etc (24). Patients who 
continue to have progressive disease have increased risk for erosion of the bony sinuses, which 
can lead to facial deformities as well as increase the complexity and risk at the time of endoscopic 
surgery. The role of antifungals remains unclear and they are currently not recommended (10). 
There are currently no therapies that are approved specifically for the treatment of AFRS. There 
remains great unmet need in identifying novel therapies that address inflammatory underpinnings 
of the disease processes, minimizes the need for SCS and surgery and their associated side effects, 
prevents recurrence, prevents complications and bony erosion, and achieve a long-lasting disease 
control. 
2.3 
BENEFIT/RISK ASSESSMENT  
The Sponsor also recognizes that the “Coronavirus Disease 2019” (COVID-19) pandemic may 
have an impact on the conduct of clinical studies. The Sponsor will monitor the situation closely 
and ensure the integrity of the study conduct and data (see Section 8).  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AE) of dupilumab are available in the IB.  
2.3.1 Benefit assessment  
Dupixent (dupilumab) is authorized for marketing in over 50 countries worldwide including the 
US, European Union (EU) (Centralized Procedure), Japan, China, Canada, and Australia for adult 
atopic dermatitis (AD) indication. Dupilumab is also authorized in the US, EU, and other 
jurisdictions for the adolescent AD indication, and in the US, EU, Japan and other jurisdictions for 
the adult and adolescent asthma indication. Dupilumab also has approval for its chronic 
rhinosinusitis with nasal polyposis (CRSwNP) indication in the US, EU, and Japan. For the latest 
information, please refer to the current IB. 
Allergic fungal rhinosinusitis usually requires surgical intervention, followed by a prolonged course 
of adjuvant medical therapy. Recurrence rates are high after surgery. There are currently no therapies 
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that are approved specifically for the treatment of AFRS. There remains great unmet need in the 
treatment of AFRS. Considering this unmet medical need and the known mechanism of dupilumab, 
the Sponsor is proposing to develop dupilumab for AFRS for the following reasons: 
• AFRS is a type 2 inflammatory disease. Dupilumab has demonstrated efficacy across a broad 
range of diseases driven by type 2 inflammation, including AD, asthma, and CRSwNP. 
• Dupilumab demonstrated significant efficacy in reducing sinus opacification, symptoms, 
and nasal polyp burden in CRSwNP, a disease that shares clinical and molecular features 
with AFRS. 
• Dupilumab demonstrated reduction in proportion of patients requiring rescue with SCS 
and/or surgery in the CRSwNP development program. Given that surgery and SCS use are 
common with AFRS and are accompanied by well-established risks, there is a potential for 
benefit in reducing their use in AFRS. 
• Patients with AFRS were excluded from the dupilumab CRSwNP registrational studies. 
Dupilumab, therefore, offers promise of significant benefit above and beyond current standard of 
care in AFRS and may provide an alternative for those patients who relapse after surgery and may 
obviate the need for repeated SCS and/or surgeries. 
2.3.2 Risk assessment  
No tissue targets or specific hazards to humans were identified in nonclinical general and 
reproductive toxicology studies. 
Dupilumab has an extensive safety database. As of 28 March 2020, a total of 10 191 participants 
were enrolled into the development program for dupilumab and are included in the safety 
population: 382 as healthy volunteers, 4405 from AD studies, 3614 from asthma studies, 782 from 
CRSwNP studies, 232 from eosinophilic esophagitis (EoE) studies, 103 from the grass allergy 
study, 145 from peanut allergy studies, 511 from the chronic obstructive pulmonary disease 
(COPD) study, 5 from PN studies, and 12 from the CSU study. The number of participants 
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 sales figures and using the World Health Organization’s defined daily dose for 
dupilumab of 21.4 mg/day, the cumulative post-marketing exposure to dupilumab is estimated to 
be 161 582 patient years (01 January 2017 to 31 March 2020).  
Dupilumab was generally well tolerated in all populations tested in clinical development programs 
consistent with a favorable benefit/risk profile. The adverse drug reactions (ADRs) identified to 
date for dupilumab include injection site reactions, conjunctivitis (including allergic and 
bacterial), oral herpes, herpes simplex, blepharitis, 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 further details). More significant serious allergic reactions were very rare. 
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Importantly, no increased overall infection risk was observed in participants treated with 
dupilumab. 
Systemic hypersensitivity is established as an important identified risk with dupilumab. As protein 
therapeutics, all monoclonal antibodies are potentially immunogenic. Rare serious and systemic 
hypersensitivity reactions have been observed in the dupilumab program including serum 
sickness/serum sickness-like reaction in the adult AD program and anaphylaxis related to 
dupilumab in the adult asthma clinical trials.  
The important potential risk for dupilumab is “eosinophilia associated with clinical symptoms in 
asthma patients.” The observed increase in eosinophil count is transient, which is consistent with 
the current understanding of the mechanism of action of dupilumab. In dupilumab asthma studies, 
a small number of patients with asthma experienced serious systemic eosinophilia presenting with 
clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic 
granulomatosis with polyangiitis, conditions which are often treated with SCS therapy. These 
events have been seen in other drug development programs for severe asthma and usually, but not 
always, have been associated with the reduction of oral corticosteroid therapy suggesting possible 
unmasking of these conditions with tapering of corticosteroids during dupilumab therapy. 
The association of dupilumab treatment 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 
participants, 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. 
To date, the safety profile has been similar among adult, adolescent and child ≥6 to <12 years old 
participants in asthma and AD populations and adult participants with CRSwNP. While long-term 
data are still accumulating, data from randomized, placebo-controlled trials and open-label 
extension studies to date, have not identified any new safety concern in these populations. It is 
anticipated that dupilumab in patients with AFRS will have a favorable safety profile as observed 
across other type 2-driven immunological disorders.  
2.3.3 COVID-19 Benefit-risk assessment  
Dupilumab has shown clinical benefit in several type-2 driven immunological disorders, such as 
AD, asthma, and chronic rhinosinusitis with nasal polyposis. In asthma and AD, clinical benefit 
has also been established in certain pediatric patients (asthma in adolescents and AD in 6 to 
18 years old) and a similar benefit-risk profile to adults has been observed. 
To date, more than 8000 patients have been treated with dupilumab during the clinical 
development program in several indications, of which AD, asthma, and chronic rhinosinusitis 
with nasal polyposis are licensed in some countries.  
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Currently, as sufficient data in patients with COVID-19 who are being treated with dupilumab is 
not available. Thus, the safety and efficacy of dupilumab in COVID-19 patients are unknown. 
During the course of the clinical trial program, respiratory infections including viral infections 
were monitored and these events are not listed as adverse drug reactions with dupilumab. 
The target population of EFC16724 is patients with uncontrolled AFRS 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 EFC16724 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, CRSwNP), where 
type 2 inflammation is the underlying driver of the disease process. 
Based on the aforementioned potential benefits to patients participating in EFC16724, the Sponsor’s 
assessment is that the benefit-risk remains favorable for patients to participate in this trial.  
2.3.4 Overall benefit: risk conclusion  
Based on the evidence to support the potential therapeutic benefit in AFRS, a patient population 
with an unmet medical need, considering the favorable benefit/risk profile across multiple 
indications, and the extensive available safety database, the Sponsor is proposing to conduct 
a Phase 3 program with dupilumab for the treatment of patients with AFRS. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of treatment with dupilumab to 
reduce sinus opacification in a population with allergic 
fungal rhinosinusitis (AFRS) 
• Change from baseline in sinus opacifications assessed 
by computerized tomography (CT) scans using the Lund 
Mackay (LMK) score at Week 52 
 
Secondary 
• To evaluate the efficacy of treatment with dupilumab to 
reduce sinus opacification in a population with allergic 
fungal rhinosinusitis (AFRS) at Week 24 
• Change from baseline in sinus opacifications assessed 
by CT scans using the LMK score at Week 24 
• To assess the efficacy of dupilumab to reduce the need 
for rescue treatments 
• Proportion of participants who receive SCS and/or 
undergo/plan to undergo surgery for AFRS during the 
planned study treatment period  
• To evaluate the efficacy of treatment with dupilumab in 
improving symptoms in AFRS 
• Change from baseline in monthly average nasal 
congestion/obstruction score from the Nasal Symptom 
Diary at Week 24 and Week 52 
• Change from baseline in the monthly average 
anterior/posterior rhinorrhea score from the Nasal 
Symptom Diary at Week 24 and Week 52 
• To evaluate the efficacy of dupilumab to reduce nasal 
polyp formation in participants with AFRS 
• Change from baseline in endoscopic nasal polyp score 
(NPS) compared with placebo at Week 24 and Week 52  
• To evaluate the efficacy of dupilumab in improving overall 
symptom severity and quality of life in AFRS 
• Change from baseline in 22-item sino-nasal outcome test 
(SNOT-22) total score at Week 24 and Week 52 
• Change from baseline in monthly average total symptom 
score (TSS) derived from the Nasal Symptom Diary at 
Week 24 and Week 52 
• Change from baseline in visual analog scale (VAS) 
rhinosinusitis at Week 24 and Week 52 
• To evaluate the efficacy of dupilumab in improving sense 
of smell in participants with AFRS 
• Change from baseline in University of Pennsylvania smell 
identification test (UPSIT) at Week 24 and Week 52 
• Change from baseline in the score of decreased/loss of 
smell using the Nasal Symptom Diary at Week 24 and 
Week 52 
• To explore the effect of dupilumab as assessed by three-
Dimensional CT volumetric measurement of the 
paranasal sinuses  
• Change from baseline to Week 52 in three-Dimensional 
CT volumetric measurement of the paranasal sinuses 
• To evaluate the safety and tolerability of dupilumab when 
administered to participants with AFRS 
• Incidence of treatment-emergent adverse events 
(TEAEs) or serious adverse events (SAEs) through 
Week 52 
• To evaluate the PK of dupilumab in participants with 
AFRS 
• Dupilumab concentration in serum over time 
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Objectives 
Endpoints 
• To characterize the effect of dupilumab on total IgE and 
specific IgE 
• Percent change from baseline in total IgE in serum 
compared with placebo over the 52-week treatment 
period  
• Percent change from baseline in fungal-specific IgE in 
serum compared with placebo over the 52-week 
treatment period 
• To assess immunogenicity to dupilumab in participants 
with AFRS 
• Assessment of incidence of treatment-emergent anti-drug 
antibodies (ADA) to dupilumab over time 
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3.1 
APPROPRIATENESS OF MEASUREMENTS  
The primary objective of this study is to evaluate the efficacy of dupilumab through reduction in 
sinus opacification. This study will evaluate the efficacy of dupilumab in a patient population who 
have significant disease burden in the sinuses and nasal cavity (LMK ≥9 out of 12 for unilateral or 
≥12 out of 24 for bilateral and NPS ≥2 out of 4 for unilateral or ≥3 out of 8 for bilateral). AFRS is 
identified by distinct diagnostic criteria that were developed by Bent and Kuhn (4). This includes 
the presence of nasal polyps and characteristic CT opacification. For AFRS, CT scans are used 
clinically to evaluate the disease severity and progression. The CT findings in this disease can be 
distinct and may include the presence of hyperdensities, bony demineralization of the sinuses, and 
bone erosion of the sinuses. Computed tomography scans of the sinuses in AFRS patients 
typically show near-complete opacification with heterogeneous radiodensity (hyperdensities) of 
the soft tissue of the sinuses (21). Both mucus accumulation and mucosal thickening contribute 
significantly to sinus opacification (30). Therefore, sinus opacification is considered as one of the 
key disease signs to be observed in this study. Computed tomography imaging quantified based 
on the degree of sinus opacification provides visualization of mucin involvement in the sinuses, 
which may not be detectable through other measurements. Lund Mackay score will be used to 
quantify the degree of opacification of each sinus on CT scan. The change from baseline in sinus 
opacifications assessed by CT scans using the LMK score at Week 52 is selected as the primary 
endpoint for the study. The LMK scoring system has been validated in previous studies (31, 32, 
33). In the CRSwNP development program for dupilumab, sinus CT scan was a key secondary 
endpoint used to assess sinus disease burden, in which significant improvement in the CT LMK 
score of sinus opacification was observed. Importantly, in dupilumab CRSwNP studies, 
improvement in LMK was accompanied by improvement in measures of symptoms including 
nasal congestion (NC), loss of smell and total symptom score. Computed tomography imaging 
will be read by control blinded reviewers.  
The need for SCS or surgery at Week 52 is a secondary endpoint. Patients with AFRS typically 
have a high relapse rate after surgery requiring several SCS bursts as rescue to control the disease 
and many patients require repeat surgery. The need for frequent SCS and/or sino-nasal surgery is 
an important part of disease burden. Reducing the need for SCS and repeat surgery will decrease 
the risk of SCS associated side effect and surgery complications. In the CRSwNP program, 
dupilumab dramatically reduced the proportion of participants requiring SCS use and the 
proportion of participants who required surgery. To date there is no other alternative treatment for 
these patients other than another course of SCS or another surgery. Therefore, reducing 
occurrence of systemic steroids use and/or surgery will also reflect the disease status 
improvement. 
Clinically, AFRS can present long-term subjective symptoms of nasal obstruction and congestion, 
reduction in or loss of the sense of smell, and anterior and posterior rhinorrhea. The presence or 
absence of polyps is confirmed by performing endoscopy. These symptoms can greatly impact 
patient’s QoL. Thus, the secondary endpoints of this study include changes from baseline at 
Week 24 and Week 52 assessed by the patient Nasal Symptom Diary in which key subjective 
symptoms will be recorded as the monthly average of nasal congestion/obstruction score, 
anterior/posterior rhinorrhea score, and decreased/loss of smell (UPSIT) and in addition a monthly 
average of total symptom score (TSS) derived from these 4 items; other secondary endpoints are 
the endoscopic nasal polyp score (NPS) used to evaluate the efficacy of dupilumab to reduced 
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nasal polyp burden. The visual analog scale (VAS) will be completed by each participant to assess 
specifically rhinosinusitis severity at Week 24 and Week 52. Three-dimensional CT volumetric 
measurement of the sinuses will also be used to explore the disease (volume of air, thickness of 
mucosa, and lateral wall) across all individual sinuses as an exploratory secondary endpoint. In 
addition, 
  
 Reduction in serum IgE level may be a biomarker for the control of 
type 2 inflammation. Based on previous research, increase in total serum IgE level of 10% or 
more in patients with AFRS after surgery might be helpful to detect recurrence of sinus disease 
and predict the need for recurrent sinus surgery (34). Therefore, change in total IgE and 
fungal-specific IgE will be measured as secondary endpoints.  
The proposed study design and endpoints will answer important clinical questions regarding the 
ability of dupilumab to reduce the need of SCS rescue therapy and surgery, objective signs of the 
disease, and symptoms reported by patients, which are the most relevant clinical practice 
assessments and reflect current standard of care. Forced expiratory volume (FEV1) and asthma 
control questionnaire 6-item version (ACQ-6) questionnaire will be used in AFRS patients with 
asthma for lung function and symptom improvement.  
Other efficacy assessments based in Patient-Reported Outcomes (PRO) including health-related 
quality of life (HRQoL ) using the specific HRQoL 22-item sino-nasal outcome test (SNOT-22) 
instrument will also be measured to evaluate the potential real life benefit.  
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 3, multicenter, 52-week treatment, parallel-group, double-blind, randomized, 
placebo-controlled study to investigate the efficacy of dupilumab 300 mg q2w for adults and 
adolescents/children (≥6 to <12 years) ≥60 kg, or dupilumab 200 mg q2w for adolescents/children 
≥30 kg and <60 kg, dupilumab 300 mg q4w for adolescents/children ≥15 kg and <30 kg with 
signs and symptoms of AFRS. The study will primarily investigate the efficacy of dupilumab to 
reduce disease burden in the sinuses (sinus opacification) by radiographic imaging. In addition, 
the study will also evaluate efficacy of dupilumab to reduce the need for repeated SCS and/or 
surgery, nasal polyps burden, clinical symptoms, and explore other measures of disease activity.  
Approximately 62 participants (31 per arm) with AFRS who satisfy the inclusion and exclusion 
criteria will be randomized in a 1:1 ratio to receive either dupilumab or matching placebo:  
• Dupilumab 300 mg q2w for all adults, 300 mg q2w for adolescents/children ≥60 kg at 
screening, or 200 mg q2w for adolescents/children ≥30 kg and <60 kg at screening, or 
300 mg q4w for adolescents/children ≥15 kg and <30 kg at screening. 
• Matched placebo. 
Randomization will be stratified first by age (adults versus adolescents/children [≥6 years old]). 
In adults, randomization will be stratified further by time from last surgery (≤2 years [including 
surgery naive participants], >2 years), disease pattern (unilateral/bilateral in the endoscopy at 
screening), and country. In adolescents/children, randomization will not be stratified further. 
Duration of study period (per participant): 
• Screening period (2 to 4 weeks): to determine a participant’s eligibility and continue with 
his/her own background intranasal corticosteroids (INCS) prior to randomization. 
• Randomized IMP intervention period (52 weeks ±3 days): to randomize the participants 
into a treatment arm and treat with dupilumab or placebo dose regimen. 
• Follow-up period (12 weeks ±5 days): to continue to collect data for PK, immunogenicity, 
safety, and efficacy after the participant has completed the randomized IMP intervention 
period. 
The total duration of study participation for participants that complete the randomized treatment 
period and posttreatment follow-up is approximately 68 weeks. The schedule of the visits is 
described in the specific flow-chart in Section 1.3. 
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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The study is designed as a randomized, double-blind, placebo-controlled and parallel-group study 
to evaluate the efficacy and safety of dupilumab on top of current standard of care background 
therapy in the treatment of AFRS, utilizing multiple objective and subjective outcome measures.  
To be eligible, participants need to have a confirmed diagnosis of AFRS based on well-accepted 
Bent and Kuhn criteria (4). The proposed inclusion criteria will identify participants with AFRS 
demonstrated to have high disease burden and significant symptoms by high CT LMK score 
(≥9 out of 12 for unilateral polyps or ≥12 out of 24 for bilateral polyps), and NPS score (≥2 out of 
4 for unilateral polyps or 3 out of 8 for bilateral polyps). Adolescents can be treated much like an 
adult with similar disease processes (35). AFRS in children is similar to adults with 50% of them 
presenting unilateral nasal polyposis versus about 30% in adults. Thus, the current entry criteria 
are suitable to include the population (age ≥6 years) in the study (36).  
As currently there is no approved medication specifically for AFRS, a placebo-controlled design 
is appropriate and provides for the most robust assessment of the efficacy and safety of dupilumab 
in the target participant population. Dupilumab or matched placebo will be added on top of 
background standard treatment as applicable, based on clinical consensus (3, 10). Participants will 
continue to take their background therapy as they do prior to the study. Rescue medications and/or 
surgery for AFRS deemed necessary by Investigators will be allowed, which mirrors the expected 
future therapeutic paradigm of dupilumab in this population in clinical practice.  
The 52-week treatment duration is considered sufficient for efficacy evaluation based on the 
efficacy results from pivotal dupilumab studies in CRSwNP. Dupilumab 300 mg q2w 
demonstrated statistically significant and clinically meaningful improvement across all primary 
and multiplicity-adjusted secondary outcome measures at Week 24 and at Week 52. Early 
beneficial effect was seen from Week 2 to Week 4, followed by a progressive improvement 
through 52 weeks. The 52-week duration is also appropriate to evaluate safety considering the 
extensive safety experience with the related condition of CRSwNP. The posttreatment 12-week 
follow-up period is based on the expected PK of dupilumab after the last dose, ie, the time for 
systemic concentrations to decline to non-detectable levels in most 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 PK, safety and efficacy of dupilumab, the selected dosing regimens for this 
study are dupilumab 300 mg q2w for adults and for adolescents/children ≥60 kg, 200 mg q2w for 
adolescents/children ≥30 kg and <60 kg, and 300 mg q4w for adolescents/children ≥15 kg and 
<30 kg.  
These dose regimens are expected to achieve concentrations in serum that saturate the 
target-mediated clearance pathway and have demonstrated similar efficacy in adult and adolescent 
participants with asthma and AD, and in adults with CRSwNP. The PK of dupilumab has been 
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found to be consistent across populations of participants with AD, asthma, and CRSwNP, as well 
as healthy volunteers. In prior studies with dupilumab, body weight has been the only covariate 
identified with a meaningful impact on dupilumab PK. 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 and have an acceptable safety 
profile in adult and adolescent participants with moderate-to-severe AD, moderate-to-severe 
asthma, and adult participants with CRSwNP. Consistent with the observed PK and 
pharmacodynamics (PD) profile of nasal polyps response (gradual development of response 
during the treatment period as well as slow offset of response during off-treatment period) in 
participants with CRSwNP, PK/PD simulation of co-primary endpoints of NPS and nasal 
congestion showed minimal difference in the development of treatment effect and steady-state 
response of NPS and nasal congestion in the presence and absence of the loading dose of 600 mg 
on Day 1 in participants with CRSwNP. Therefore, as in the pivotal CRSwNP program, 
no loading dose is included in the present study for AFRS participants.  
Three hundred (300) mg q2w with a loading dose of 600 mg for adolescents/children ≥60 kg, 
200 mg q2w with a loading dose of 400 mg for adolescents/children ≥30 kg to <60 kg OR 300 mg 
q4w with a loading dose of 600 mg for adolescents/children ≥15 kg to <30 kg are the approved 
dosing regimens for AD. These dosing regimens in adolescents/children achieved steady-state 
trough concentration similar to 300 mg q2w in adult participants with AD. Given the lack of 
significant sustained difference at the steady state PK and PD profiles observed between 
CRSwNP participants who had loading dose and participants who did not have loading dose, in 
this study, 2-tiered weight-based dosing regimens without a loading dose are included for AFRS 
adolescent/child participants, to achieve comparable PK exposure to 300 mg q2w AFRS adult 
participants in both adolescent weight groups.  
The collective PK/PD, clinical efficacy, and safety data of dupilumab across diverse disease 
populations suggest that the selected dose regimens for this study will be efficacious and safe for 
the treatment of adult and adolescent/child (≥6 to <12 years) AFRS 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 at Week 64. 
If a participant discontinues treatment period prematurely before Week 40 but completes 
follow-up to Week 52, 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 6 years of age at the time of signing the informed consent.  
Note: For those countries where local regulations do not permit enrollment of children 
aged ≥6 to <12 years, the recruitment will be restricted to those who are ≥12 years of age 
(or the minimum legal age for adolescents in the country of the investigational site). For 
those countries where local regulations do not permit enrollment of children aged ≥6 to 
<12 years of age and adolescents, the recruitment will be restricted to those who are 
≥18 years of age. 
Type of participant and disease characteristics 
I 02. Participants with the diagnosis of AFRS adapted from criteria by Bent and Kuhn (meeting 
all): 
a) IgE mediated inflammatory response to fungal hyphae (specific IgE serology or skin 
test)  
Evidence of sensitization to fungus by skin testing (at screening or documented 
historical positive skin test in the previous 12 months), or positive fungal-specific IgE 
in serum at screening. 
b) Nasal polyposis confirmed by nasal endoscopy at screening. 
c) Characteristic CT signs to be performed during screening period and can include any 
of the below signs as assessed by central reader: 
o hyperdensities 
o bony demineralization 
o bone erosion of sinus 
d) Eosinophilic mucin/mucus identified within 5 years prior to screening or at screening 
with or without positive fungal stain.  
e) Criterion deleted as per Amended Protocol 01. 
I 03. AFRS patients with the following: 
a) An endoscopic NPS of at least 2 out of 4 for unilateral polyps or 3 out of 8 for bilateral 
polyps at Visit 1 (central reading) and Visit 2 (local reading) and, 
b) Sinus opacification in CT scan with an LMK score of 9 for patients with unilateral 
polyps or 12 for patients with bilateral polyps during screening period and, 
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I 04. Criterion deleted in Amended Protocol 03. 
Weight  
I 05. Body weight ≥15 kg at screening. 
Sex, contraceptive/barrier method and pregnancy testing requirements/breastfeeding 
I 06. Male and/or female 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
o 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 an acceptable contraceptive method as described in 
Appendix 4 (Section 10.4) of the protocol during the study (up to 12 weeks after 
the last dose of study intervention). 
➢ A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) on Day 1 before the first dose of study intervention. 
➢ If a urine test on Day 1 cannot be confirmed as negative (eg, an ambiguous result), 
a serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive. 
o Additional details can be found in Appendix 4 (Section 10.4) of the protocol. 
o 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 07. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of 
the protocol which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. In countries where legal age of majority 
is above 18 years, a specific ICF must also be signed by the participant’s legally authorized 
representative. For adolescents (≥12 to <18 years) and for children (≥6 to <12 years), both 
the adolescent/child and the parent/legally authorized representative must sign the specific 
ICF/assent form. 
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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. Patients with conditions/concomitant diseases making them non-evaluable at Visit 1 or for 
the primary efficacy endpoint such as:  
o Antrochoanal polyps.  
o Nasal septal deviation that would occlude at least one nostril.  
o Acute sinusitis, nasal infection or upper respiratory infection within 2 weeks prior to 
Visit 1 (patient can be rescreened after resolution of symptoms).  
o Ongoing rhinitis medicamentosa.  
o Eosinophilic granulomatous polyangiitis (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. Patients with nasal cavity malignant tumor and benign tumors (eg, papilloma, 
hemangioma, etc).  
E 03. Known of fungal invasion into sinus tissue.  
E 04. 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 05. Histories 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 06. Severe concomitant illness(es) that, in the Investigator’s judgment, would adversely affect 
the patient’s participation in the study. Examples include, but are not limited to participants 
with short life expectancy, participants with uncontrolled diabetes (hemoglobin A1c ≥9%), 
participants with cardiovascular conditions (eg, Class III or IV cardiac failure according to 
the New York Heart Association classification), severe renal conditions (eg, participants 
on dialysis), hepato-biliary conditions (eg, Child-Pugh class B or C), neurological 
conditions (eg, demyelinating diseases), active major autoimmune diseases (eg, lupus, 
inflammatory bowel disease, rheumatoid arthritis, etc), other severe endocrinological, 
gastrointestinal, metabolic, pulmonary, or lymphatic diseases. The specific justification for 
participants excluded under this criterion will be noted in study documents (chart notes, 
electronic case report forms [eCRFs], etc).  
E 07. Known or suspected history of 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.  
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E 08. Patients with active TB or 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 patient 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 ethic boards. 
E 09. 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 10. History of malignancy within 5 years before Visit 1, except completely treated in situ 
carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal 
cell carcinoma of the skin.  
E 11. Known or suspected alcohol and/or drug abuse.  
E 12. History of systemic hypersensitivity or anaphylaxis to dupilumab or any of its excipients. 
E 13. Planned major surgical procedure during the patient’s participation in this study. 
E 14. Patient 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 15. Treatment with commercially available dupilumab within 12 months, participation in prior 
dupilumab clinical trial, or  discontinued dupilumab use due to adverse event. 
E 16. Patients who are treated with intranasal corticosteroid drops; intranasal steroid emitting 
devices/stents; nasal spray using exhalation delivery system, such as Xhance™, during 
screening period. 
E 17. Patients who are on INCS spray unless they have received stable dose for at least 4 weeks 
prior to Visit 1. 
E 18. Patients who have undergone sinus intranasal surgery (including polypectomy) within 
6 months prior to Visit 1.  
E 19. For patients receiving systemic antifungals for AFRS treatment at screening: unwilling to 
stop antifungal therapy at screening.  
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E 20. Patients who have taken: 
o Biologic therapy/systemic immunosuppressant to treat inflammatory disease or 
autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary 
biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc) within 4 weeks 
before Visit 1 or 5 half-lives, whichever is longer. 
o Any investigational mAb within 5 half-lives or within 6 months before Visit 1 if the 
half-life is unknown. 
o Anti-IgE therapy (omalizumab) within 4 months prior to Visit 1. 
E 21. 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: 
o Patient for whom administration of live (attenuated) vaccine can be safely postponed 
will be eligible to enroll into the study. 
o Patients who have their vaccination preponed can enroll in the study only after a gap of 
4 weeks following administration of the vaccine. 
E 22. Leukotriene antagonists/modifiers unless patient is on a continuous treatment for at least 
30 days prior to Visit 1.  
E 23. Initiation of allergen immunotherapy within 3 months prior to Visit 1 or a plan to begin 
therapy or change its dose during the screening or treatment period. 
E 24. Patients received SCS during screening period. 
E 25. Either intravenous immunoglobulin therapy and/or plasmapheresis within 30 days prior to 
Screening Visit (Visit 1). 
Noncompliance to completion of the e-diary 
E 26. Participants who do not demonstrate at least the following for acceptable compliance: 
Completing the e-diary for any 4 mornings in the 7 days immediately preceding Baseline 
Visit (Visit 2). 
Diagnostic assessments 
E 27. Patients with any of the following result at the Screening Visit (Visit 1): 
o Positive (or indeterminate) hepatitis B surface antigen (HBsAg) or,  
o Positive total hepatitis B core antibody (HBcAb) and a negative hepatitis B surface 
antigen (HBsAg) with a positive hepatitis B virus (HBV) DNA or, 
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o Positive hepatitis C virus antibody (HCVAb) with a positive hepatitis C virus (HCV) 
RNA. 
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 trial site or other individuals directly involved in 
the conduct of the study or immediate family members of such individuals (in conjunction 
with Section 1.61 of the International Council for Harmonisation [ICH] Good Clinical 
Practice [GCP] Ordinance E6). 
E 32. Any specific situation during study implementation/course that may raise ethical concerns. 
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. 
5.3 
LIFESTYLE CONSIDERATIONS  
No restrictions are required. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
reasons, eligibility criteria, and any 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’s 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. 
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If certain dynamic laboratory tests do not meet the eligibility criteria at screening period, these 
laboratory assessments may be repeated, at the discretion of the Investigator, if it is judged to be 
likely to return to 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 90 days old. If the rescreening is performed 
outside of the 90 days window, the CT scan must be repeated. All other screening procedures 
must be repeated for rescreening. 
 
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6 
STUDY INTERVENTION AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
ARM name 
Dupilumab 
Placebo 
Intervention name 
Dupilumab 200 mg or Dupilumab 300 mg 
Placebo 
Type  
Biological 
Other 
Dose formulation 
Dupilumab 200 mg:  
A 175 mg/mL dupilumab solution in 
a pre-filled syringe to deliver 200 mg in 
1.14 mL. 
or 
Dupilumab 300 mg:  
A 150 mg/mL dupilumab solution in 
a pre-filled syringe to deliver 300 mg in 2 mL. 
Placebo matching dupilumab 200 mg will 
be supplied as an identical formulation to 
the active 200 mg formulation without 
dupilumab, in a pre-filled syringe to deliver 
placebo in 1.14 mL. 
or 
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) 
200 mg or 300 mg 
0 mg 
Dosage level(s) 
One injection of 200 mg q2w for 
adolescents/children ≥30 kg and <60 kg at 
screening 
or 
One injection of 300 mg q2w for all adults 
and for adolescents/children weighing ≥60 kg 
at screening 
or 
One injection of 300 mg q4w for 
adolescents/children ≥15 kg and <30 kg at 
screening 
One injection of placebo matching 200 mg 
q2w for adolescents/children ≥30 kg and 
<60 kg at screening 
or 
One injection of placebo matching 300 mg 
q2w for all adult participants and for 
adolescents/children weighing ≥60 kg at 
screening 
or 
One injection of placebo matching 300 mg 
q4w for adolescents/children ≥15 kg and 
<30 kg at screening 
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 
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The IMP will be administered every 14 ±3 days (q2w) or 28 ±3 days (q4w) during the 52-week 
treatment period (with the last IMP administration at Week 50 for q2w administrations and at 
Week 48 for q4w administrations). 
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 parent/legally authorized representative, or 
caregiver). The Investigator or delegate will prepare and inject the first dose of IMP at Visit 2, in 
front of the participant (or parent/legally authorized participant representative/caregiver). The 
participant (or parent/legally authorized representative/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) different 
training ways (eg, training remotely with instruction provided by phone) can be performed (and 
will be documented in the participant’s study file). If the participant (or parent/legally authorized 
representative/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.  
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits 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. The 
monitoring period may be extended as per country-specific or local site-specific requirements. 
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 their healthcare provider or emergency services. 
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 or q4w injections. Injections in the upper arms could be done only by 
a trained person (parent/legally authorized representative/caregiver trained by Investigator or 
delegate) or health care professional but not the participants themselves.  
For doses not given at the study site, diaries will be provided to record information related to the 
injections. The diary will be kept as source data in the participant’s study file. 
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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 interventions must 
be stored in a secure, environmentally controlled, and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the 
Investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
6.2.2 Responsibilities  
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.7). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for Direct to Patient 
shipment, for which a courier company has been approved by the Sponsor), allow the IMP to be used 
other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
The randomized intervention kit number list is generated centrally by Sanofi and IMPs are 
packaged in accordance with this list. The randomization and intervention allocation are 
performed centrally by an IRT. The IRT generates the participant randomization list and allocates 
the intervention number and the corresponding intervention kits to the participants according to it. 
Before the study is initiated, the telephone number and call-in directions for the interactive voice 
response system and/or the log in information and directions for the interactive web response 
system will be provided to each site. 
Participants will be randomized in a 1:1 ratio treatment arm described in Table 2.  
The randomization will be stratified by age (adults versus adolescents/children) first. In adults, 
randomization will be further stratified by time from last surgery (≤2 years, >2 years), disease 
pattern (unilateral/bilateral in the endoscopy at screening), and country. In adolescents/children, 
randomization will not be further stratified.  
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At screening (Visit 1), the Investigator or designee will contact the IRT system to receive the 
participant number. If a participant who had previously failed screening is approached for 
rescreening, a new ICF/assent form 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 whether the treatment was administered or not (ie, participant registered 
by the IRT). A participant cannot be randomized more than once in the study. 
Study intervention will be dispensed at the study visits summarized in Schedule of Activities (SOA) 
(see Section 1.3). Returned study intervention should not be re-dispensed to the participants. 
Methods of blinding 
Dupilumab 300 mg/200 mg and matching placebo matching dupilumab 300 mg/200 mg will be 
provided in identically matched 2 mL/1.14 mL pre-filled syringes that are visually indistinguishable 
for each dose. Syringes and box will be labeled with a treatment kit number. While these are 
double-blind with regard to the treatment with either dupilumab or placebo, they are not blinded to 
weight-based dose levels, due to the different volume size (2 mL versus 1.14 mL) of the dose level of 
dupilumab (300 mg/matching placebo or 200 mg/matching placebo) that will be used for the 
different weight categories for adolescents/children. In addition, in children, the study is not blinded 
to dose regimen due to the different frequency of IMP administration (q4w versus q2w). 
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 case report form, as applicable. 
If the code is broken at the site level, the participant must permanently withdraw from IMP 
administration. 
6.4 
STUDY INTERVENTION COMPLIANCE  
• 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 to 
Patient process, the intervention units can be returned by the carrier (if defined in the 
contract). 
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- 
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 electronic case report form (eCRF). 
- 
The monitor in charge of the study then checks the eCRF data by comparing them with 
the IMP which he/she has retrieved and intervention log forms. 
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 e-diary and 
used/unused kits/pre-filled syringes during the site visits and documented in the source documents 
and eCRF. Changes 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. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the eCRF. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest that the participant is receiving 
at the time of screening 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/Sponsor representative should be contacted if there are any questions regarding 
concomitant or prior therapy. 
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6.5.1 Background treatments  
Participants that are using background INCS must have a stable dose regimen for at least 1 month 
at the time of V1. From the time of screening throughout the study treatment period, they should 
not change their background medications.  
Intranasal corticosteroids other than nasal spray such as, drops, stents, or devices are not allowed 
as background treatment. 
6.5.2 Prohibited medications  
The following concomitant treatments are not permitted during the screening period and the study 
treatment period:  
• Intravenous immunoglobulin (IVIG) therapy. 
• 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 systemic steroids are prohibited during screening and study treatment period 
except that a short term (<2 weeks) oral corticosteroids are allowed only in study treatment 
period as rescue medication (see rescue medication in Section 6.5.3). 
• Live, attenuated vaccines.  
• Other monoclonal antibodies (biological immunomodulators), including but not limited to 
anti-IgE, anti-IL-5 and anti-TNF, etc.  
• Systemic antifungals and antibiotics are prohibited during screening and study treatment 
period except for rescue use (see rescue medication in Section 6.5.3).  
Permitted concomitant medication 
The following treatments are allowed:  
• Intranasal normal saline. 
• Short-acting β2-adrenergic receptor agonists (SABA), long-acting β2-adrenergic receptor 
agonists (LABA), and long-acting muscarinic acetylcholine receptor antagonists (LAMA).  
• Methylxanthines (eg, theophylline, aminophyllines). 
• Inhaled corticosteroids. 
• Systemic antihistamines. 
• Leukotriene antagonists/modifiers are permitted during the study, only for participants 
who were on a continuous treatment for ≥30 days prior to Visit 1.  
• Allergen immunotherapy in place for ≥3 months prior to Visit 1 is permitted and the dose 
should be kept stable during screening and study treatment period.  
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• 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 for example lidocaine are allowed before nasal brushing or before 
endoscopy.  
• Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Sponsor/Sponsor representative if required. 
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 requiring medical intervention, the Investigator may 
consider rescue treatment with: 
• Systemic antibiotics (up to 2 weeks) in case of acute infection. 
• Short term courses (prednisone or prednisolone up to 2 weeks) of oral corticosteroids for 
AFRS or short courses of oral corticosteroids to treat other serious coexisting diseases 
(such as asthma exacerbation). 
• Short term (≤4 weeks) systemic antifungal treatment based on participant’s tolerability.  
• Intranasal corticosteroids spray (initiation of INCS spray or change in dosing of 
a background INCS spray during the study period). 
• Sino-nasal surgery for AFRS (8 weeks of IMP treatment is recommended prior to surgery 
to allow onset of treatment effect). For participants who undergo or are planned for 
surgery for AFRS, the Investigator may decide to continue IMP up to the time of surgery 
or end of treatment whichever date comes first. At the time of surgery, the participants will 
be permanently discontinued from study treatment. 
Note: It is recommended if a participant must use SCS as per the Investigator’s decision, the site 
should make every effort to perform clinical assessments (including an endoscopy, if it is needed) 
before starting treatment with SCS. If a participant needs to have CT scan around the time of 
surgery the next scheduled CT scan per protocol does not need to occur after surgery for AFRS. 
In any case, participants may not have more than 3 CT scans during the study. All this 
information collected will be recorded in dedicated eCRF pages.  
6.6 
DOSE MODIFICATION  
No IMP dose modification is allowed. This is also applicable for adolescent participants who 
become adult during the study or participants who change weight band during the study. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
Sponsor will not be responsible for intervention after the EOS Visit. Intervention after the EOS 
Visit will be at the discretion of the Investigator or treating physician. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively 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 they decide to do so, at any time 
and irrespective of the reason, or this may be the Investigator’s decision. All efforts should be 
made to document the reasons for treatment discontinuation, and this should be documented in the 
eCRF. 
Participants must be withdrawn from the study treatment (ie, from any further IMP) for the 
following reasons: 
• At their own request or at the request of their legally authorized representative (legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective participant to the participant’s 
involvement 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 they are treated with the specific prohibited medications mentioned in Section 6.5.2. 
• Sino-nasal surgery. 
• If they miss 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 request 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 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). 
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• Serum alanine aminotransferase (ALT) >3 upper limit of normal (ULN) and Total 
Bilirubin >2 ULN (see Section 10.6). 
• Serum ALT >5 ULN if baseline ALT ≤2 ULN or ALT >8 ULN if baseline ALT >2 ULN 
(see Section 10.6). 
Any abnormal laboratory value 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 52-week 
treatment period) will perform, as soon as possible, the early termination visit with all assessments 
normally planned for the end of treatment (EOT) Visit (Visit 7) (refer Section 8.1.1) including 
a pharmacokinetics sample, if appropriate, to assure a complete clinical assessment in close 
temporal proximity to the premature termination of study treatment is available. 
In addition, and to allow assessment of participant outcomes over the stipulated study period, 
participants will be asked and encouraged to complete all remaining study treatment visits, and 
participate in all assessments according to the visit schedule with a ±3 day 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 status of AFRS 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. 
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. 
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Temporary intervention discontinuation decided by the Investigator corresponds to at least 1 dose 
not administered to the participant. Following a temporary interruption or missed dose, the 
treatment should be reinitiated at the next scheduled administration, maintaining the planned dose. 
If 2 consecutive IMP doses have been missed, the study treatment will be definitively 
discontinued (see Section 7.1.1). Investigator must contact the participant to instruct not to take 
any subsequent injection. 
7.1.2.1 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(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 
parent(s)/caregiver(s)/legally authorized representative(s) decide to do so, 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). See SoA for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
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. 
Participants who have withdrawn from the study cannot be rerandomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused.  
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7.3 
LOST TO FOLLOW-UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, 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/assent form 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. 
• Assessments/procedures should be conducted in the following order: daily symptoms of 
nasal congestion; loss of smell and rhinorrhea; SNOT-22; VAS rhinosinusitis;
 and administration of IMP. Note:
 
• PRO questionnaires should be completed by the participants (not applicable for children 
aged ≥6 and <12 years) 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. 
• Participants under 18 years of age will have a caregiver or a tutor. 
• Adolescents completing the PRO questionnaires may be helped by their parents/caregivers 
for the reading and the understanding of the instructions, a word or a question of the 
questionnaires if they encounter difficulties to answer. However, adolescents (not 
applicable for those aged ≥6 and <12 years) should answer the question themselves; 
parents/caregivers should not influence nor interpret their child's answer. 
Parents/caregivers should not select any of the response choices on behalf of their child; 
only help on transcribing accurately the answers will be allowed. 
• 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 230 mL for 
adults, 195 mL for adolescents, and 87 mL for children with weight ≥20 to <30 kg or 
71 mL for children with weight ≥15 to <20 kg. Repeat or unscheduled samples may be 
taken for safety reasons or for technical issues with the samples. 
• In light of the public health emergency related to COVID-19 (or in case of any other 
pandemic requiring public health emergency), the continuity of clinical study conduct and 
oversight may require implementation of temporary or alternative mechanisms, eg, phone 
contact, virtual visits, online meetings, use of local clinic or laboratory locations, and 
home visits by skilled staff. Implementation of such mechanisms may differ country by 
country, depending on country regulations and local business continuity plans. 
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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 in response to COVID-19 are to be documented 
as being related to COVID-19 and will remain in effect only for the duration of the public 
health emergency. 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 Computerized tomography scans  
For both LMK scores, three-dimensional volumetric measurement of the sinuses 
 the same acquisitions (sequences) will be used for centralized imaging data assessments 
and scoring by an independent physician reviewer for the imaging data 
8.1.1.1 Lund Mackay score  
Computerized tomography scans using the LMK scores allows the assessment of sinus 
opacification.  
The CT scan LMK staging system represents the most widely established method of sinus CT 
scoring in clinical trials. Lund Mackay 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 (31, 32, 33).   
Computed tomography scans should be performed anytime during the screening period before 
first administration of IMP at Visit 2 (baseline CT data), at Visit 5 (Week 24), and Visit 7 
(Week 52). 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 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), these countries will be 
exempted from all the planned study CT scans until approval from these committees is received. 
A 3-month window is required between 2 CT scans in screening period if a participant needs to be 
rescreened. 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 
(Visit 7). Week 24 CT scan is not required for adolescents/children. In any case, participants may 
not have more than 3 CT scans during the study. If a participant needs to have CT scan around the 
time of surgery the next scheduled CT scan per protocol does not need to occur after surgery for 
AFRS. 
The CT scan will be performed locally and centrally reviewed in a pre-specified manner as 
described in the Image Acquisition Standards (IAS) and Image Interpretation Standards (IIS) and 
the SoA (Section 1.3).  
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8.1.1.2 Three-dimensional volumetric measurement of the sinuses  
This method is used to calculate: (37)  
• 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. 
8.1.2 Proportion of participants who receive SCS and/or undergo/plan to undergo 
surgery for AFRS during the planned study treatment period  
Systemic corticosteroids use 
Use of systemic steroids for rescue treatment of AFRS or for another reason will be captured by 
the Investigator (or designee) on the appropriate page(s) of the eCRF page and the date and dosing 
information (daily dose, duration, INN). The reason for SCS use will be also captured. 
Surgery (actual or planned) for AFRS 
For participants who undergo or plan to have surgery for AFRS, the reason (worsening signs 
and/or symptoms during the study), the expected and real surgery date, the type and outcome of 
surgery will be recorded in a specific eCRF page. If surgery: 
• Is performed during the study treatment period, participant and Investigator may decide to 
continue IMP up to the time of surgery or EOT whichever date comes first. At the time of 
surgery, participants will be permanently discontinued from study treatment and assessed as 
soon as possible using the procedures normally planned for the EOT Visit and will be 
instructed to return to the study site as described in Section 1.3.  
• Is performed during the follow-up the participants will be assessed according to the 
procedures normally planned for the EOS Visit and will be instructed to return to the study 
site as described in Section 1.3. 
• Date is scheduled after the planned end of study; a follow-up contact(s) will be scheduled 
around the time of planned surgery to document the surgery date and outcome. 
8.1.3 Nasal symptom diary, including nasal congestion/obstruction, loss of smell, and 
anterior and posterior rhinorrhea  
The Nasal Symptom Diary is designed to assess the severity of CRS nasal symptoms on daily 
basis. These symptoms include nasal congestion/obstruction, loss of smell, anterior rhinorrhea and 
posterior rhinorrhea (38). Each of the individual items of the diary are scored from 
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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. (Table 3). 
Table 3 - Nasal congestion/obstruction symptom severity  
Scale 
Symptoms 
0 
No symptoms 
1 
Mild symptoms (symptoms clearly present, but minimal awareness and easily tolerated) 
2 
Moderate symptoms (definite awareness of symptoms that is bothersome but tolerable) 
3 
Severe symptoms (symptoms that are hard to tolerate, cause interference with activities or daily living) 
The TSS is a composite score (ranging between 0 and 9) consisting of the sum of the following 
symptoms assessed daily in the morning: nasal congestion/obstruction, decreased/loss of sense of 
smell, rhinorrhea (average of anterior/posterior nasal discharge). Higher scores on the TSS 
indicate greater symptom severity. 
The psychometric properties of nasal congestion as an individual item, including validity, reliability 
and ability to detect changes have been demonstrated in adult patients with CRSwNP. Within-
person (responder definition) meaningful threshold has been determined in the CRSwNP population 
as follows: -0.48 to -1.14 for NC, -0.88 to -1.00 for loss of smell, and -1.15 to -3.60 for TSS. 
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 reviewing as well as compliance to 
background/rescue therapy and overall e-diary compliance. The site should follow-up with the 
participant as appropriate.  
The Nasal Symptom Diary will be administered electronically.  
Participants will complete the Nasal Symptom Diary as described in the SoA (Section 1.3). 
8.1.4 Nasal polyps score  
The bilateral endoscopy NPS allows the assessment of nasal polyp formation. Polyps on each side 
of the nose will be graded based on polyp size scores: 0 = no polyps; 1 = small polyps in the 
middle meatus not reaching below the inferior border of the middle turbinate; 2 = polyps reaching 
below the lower border of the middle turbinate; 3 = large polyps reaching the lower border of the 
inferior turbinate or polyps medial to the middle turbinate, 4 = large polyps causing complete 
obstruction. The total score is the sum of the right and left nostrils, ranging from 0 to 8.  
The NPS grading score is a recognized tool that is widely used to assess nasal polyps in clinical 
development programs (14, 39, 40, 41). 
Clinicians will perform the measure as described in the SoA (Section 1.3). 
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8.1.5 22-item sino-nasal outcome test  
The SNOT-22 is a PRO questionnaire designed to assess the impact of CRS on participants 
HRQoL (42). 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 (42). 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 (42). 
The SNOT-22 is provided in Appendix 7 (Section 10.7.2).  
Participants will complete the SNOT-22 as described in the SoA (Section 1.3). 
8.1.6 Rhinosinusitis severity visual analog scale  
The rhinosinusitis VAS is used to evaluate the overall severity of the rhinosinusitis (38). 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 VAS is provided in Appendix 7 (Section 10.7.3). 
Participants will complete the rhinosinusitis severity VAS as described in the SoA (Section 1.3). 
8.1.7 University of Pennsylvania smell identification test  
The University of Pennsylvania smell identification test (UPSIT) (UPSIT 40 odorant test) 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 1 odorant per page. Above each odorant 
strip is a multiple-choice question with 4 alternative words to describe the odor and 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. Participants can be classified based on their score (43). UPSIT 
will be translated and culturally adapted according to industry practice in order to account for the 
different cultural contexts of participants and thus easing identification of the odorant depending 
on degree of smell loss. 
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Clinician will administer and score the UPSIT that will be completed by the participant as 
described in the SoA (Section 1.3). If UPSIT is planned on the same day as nasal endoscopy and 
the endoscopy is conducted under local anesthetic, the assessments with UPSIT must be 
performed before anesthetics use to ensure that the effect of anesthetics will not interfere with 
UPSIT interpretation. 
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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 exam), 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 AE. 
8.2.2 Vital signs  
• Vital signs will be measured in a semi-supine or sitting position after 5 minutes rest and 
will include body 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. 
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• Body weight (kg) will be measured at screening (Visit 1), randomization (Visit 2), and all 
following visits as specified in SoA (Section 1.3). Height must be collected at each visit 
only for pediatric participants; collect height for adult participants at screening visit (V1) 
only. 
8.2.3 Electrocardiograms  
A simple 12-lead electrocardiogram (ECG) will be obtained for screening purpose only as defined 
in SoA (Section 1.3). 
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 which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study 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/Sponsor representative. 
- 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified, and the Sponsor notified. 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA (Section 1.3).  
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7).  
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8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the ICF/assent form until the EOS visit at the time 
points specified in the SoA (Section 1.3). 
All SAEs and adverse events of special interest (AESI) will be recorded and reported to the 
Sponsor or designee immediately and under no circumstance should this exceed 24 hours, as 
indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all 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 a SAE is essential so that legal 
obligations and ethical responsibilities toward 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.  
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• Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows: 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 
7 days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days. 
- 
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor. 
• An Investigator who receives an Investigator safety report describing a SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether 
an event meets the criteria for a SUSAR, and therefore, is expedited to regulatory 
authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until 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 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 screens in the eCRF. 
AESIs for this study include:  
• Anaphylactic reactions. 
• Systemic hypersensitivity reactions. 
• Helminthic infections. 
• Any severe type of conjunctivitis or blepharitis.  
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• 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 a 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. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria. 
- 
In the event of pregnancy in a female participant, IMP should be discontinued. 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
• Significant ALT elevation 
- 
ALT >5 × ULN in participants with baseline ALT ≤2 × ULN; 
OR 
- 
ALT >8 × ULN if baseline ALT >2 × ULN. 
• Symptomatic overdose (serious or nonserious) with IMP 
- 
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 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). 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/Sponsor representative immediately. 
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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/Sponsor representative (determined on a case-by-case basis). 
5. Document appropriately in the eCRF. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
Sponsor/Sponsor representative based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS AND IMMUNOGENICITY ASSESSMENTS  
8.5.1 Systemic drug concentration and antidrug antibodies  
8.5.1.1 Sampling time  
Blood samples will be collected for the assessment of functional dupilumab and anti-dupilumab 
antibodies in serum as specified in the SoA (Section 1.3). Special procedures for the collection, 
storage, and shipping of serum are described in separate operational manuals. The date of 
collection should be recorded in the eCRF. 
8.5.1.2 Handling procedures  
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of handling procedure for samples used in the determination of 
systemic drug concentration and anti-drug antibodies (ADA) is provided in Table 4.  
Table 4 - Summary of handling procedures  
Sample type 
Functional dupilumab 
Anti-dupilumab antibody 
Matrix 
Serum 
Serum 
Blood sample volume 
2 mL 
2 mL 
Anticoagulant 
None 
None 
Blood handling procedures 
See Operational Manual 
See Operational Manual 
Serum aliquot split 
2 aliquots 
2 aliquots 
Storage conditions 
<6 months: below -20°C 
<24 months: below -80°C (preferred) 
<6 months: below -20°C 
<24 months: below -80°C (preferred) 
Serum shipment condition 
In dry ice 
In dry ice 
 
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8.5.1.3 Bioanalytic method  
Serum PK and ADA samples will be assayed using validated methods as described in Table 5. 
Table 5 - Summary of bioanalytical methods for functional dupilumab and anti-dupilumab 
antibodies  
Analyte 
Functional dupilumab 
Anti-dupilumab antibody 
Matrix 
Serum 
Serum 
Analytical technique 
ELISA 
Electro-chemiluminescence 
Site of bioanalysis 
Regeneron 
Regeneron 
ELISA: enzyme-linked immunosorbent assay. 
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 or hypersensitivity, PK and ADA samples 
may be collected at or near the onset of the event based on the medical judgment of the 
Investigator and/or Sponsor representative. 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/assent form.  
8.6 
PHARMACODYNAMICS  
Several types of samples will be collected to quantify the following PD biomarkers: 
For timing of PD sample collection refer to SoA (Section 1.3).  
More detailed information on the collection, handling, transport, and preservation of samples 
(eg, minimum volumes required for blood collection and for aliquots for each biomarker assay) 
will be provided in a separate laboratory manual.  
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Assay methodologies are briefly summarized below:  
• Plasma/serum biomarkers:  
Total and 
fungal-specific IgE will be measured with a quantitative method (eg, Phadia ImmunoCAP) 
approved for diagnostic testing. 
Some procedures for PD assessments specific to sites in China are described in the laboratory manual. 
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8.8 
BIOMARKERS  
Pharmacodynamic and pharmacogenetics biomarkers are described in Section 8.6 and Section 8.7. 
An optional collection of serum/plasma samples that will be archived for other biomarker research 
is also part of this study: 
• The archived samples may be used for research purposes related to respiratory diseases 
such as AFRS or inflammatory diseases (eg, exploratory biomarkers of disease or drug 
effect), pathway biology, additional drug safety assessments or development and 
validation of bioassay methods beyond those defined in the present protocol. 
• Samples (including unused samples or leftover samples after testing) may also be used for 
research to develop methods, assays, prognostics and/or companion diagnostics related to 
dupilumab, disease process, pathways associated with disease state, and/or mechanism of 
action of the study intervention. 
• Samples may be stored for a maximum of 15 years (or according to local regulations) 
following the last participant’s last visit for the study at a facility selected by the Sponsor 
to enable further analysis. 
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/parent(s)/legally authorized 
representative (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 
either to the drug, the mechanism of action, and the disease or its associated conditions.
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). 
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All study participant data and samples will be coded such that no participant direct identifiers will 
be linked to them. Coded data and samples may be transferred to a Sponsor site (or a 
subcontractor site), which may be located outside of the country where the study is conducted. 
The Sponsor adopts safeguards for protecting participant confidentiality and personal data 
(see Section 10.1.4). 
The samples will be stored for a maximum of 15 years after the end of the study. 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  
The following null and alternative hypotheses will be tested for dupilumab versus placebo: 
• H0: No treatment difference between dupilumab and placebo. 
• H1: There is a treatment difference between dupilumab and placebo. 
9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 6): 
Table 6 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF/assent 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. 
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 
treatment 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 first dose of the study treatment. 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 treatment. Participants will be analyzed 
according to the intervention actually received. 
ADA: antidrug antibody; ICF: informed consent form; IRT: interactive response technology; ITT: intent-to-treat; PK: pharmacokinetic 
Endpoints not required for children aged ≥6 to <12 years will be analyzed using the ITT 
population in adults and adolescents (≥12 to <18 years).  
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will be developed and finalized prior to database lock and will 
describe the participant populations to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the most important endpoints including the primary and secondary endpoints. 
9.4.1 General considerations  
All comparisons will be of dupilumab (300 mg q2w and 300 mg q4w and 200 mg q2w) versus 
placebo. 
The baseline value is defined generally as the last available value before randomization. For 
endpoints collected on the daily Nasal Symptom Diary, baseline is defined as the average of the 
scores in the 7 days prior to randomization.   
For efficacy analyses, a multiplicity-controlled hierarchical testing is proposed to control the 
overall type-I error rate for testing the primary and select secondary efficacy endpoints at an alpha 
of 0.05. The detailed hierarchical testing procedure will be defined in the study SAP. The study is 
considered positive when the primary endpoint achieves statistical significance with 2-sided 
significance level 0.05. 
Data collected regarding the impact of the COVID-19 or other pandemics on the participants will 
be summarized (eg, discontinuation due to COVID-19). Any additional analyses and methods 
required to investigate the impact of COVID-19 or other pandemics pandemic requiring public 
health emergency on the efficacy (eg, missing data due to COVID-19) and safety will be detailed 
in the SAP. 
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9.4.2 Primary endpoint(s)  
The primary estimand for the primary endpoint of change from baseline in LMK score at Week 52 
is the composite/treatment policy strategy, as described in Table 7.  
Table 7 - Summary of primary estimand for the primary endpoint  
Endpoint 
Category  
Estimands 
Endpoints Population 
Intercurrent event(s) handling strategy 
and missing data handling 
Population-level 
summary 
Objective: To evaluate the efficacy of treatment with dupilumab to reduce sinus opacification in a population with allergic 
fungal rhinosinusitis (AFRS) 
Primary 
endpoint 
Change from 
baseline in 
LMK score at 
Week 52 
 
ITT 
The following intercurrent events will be handled 
with a composite strategy; data after the IE will be 
excluded and the worst post-baseline value on or 
before the start of the IE will be assigned to the 
Week 52 value (WOCF); for participants with no 
post-baseline values, the baseline value will be 
used. 
• 
Undergo/plan to undergo surgery for AFRS 
prior to Week 52  
• 
Taking SCS for any reason prior to Week 52 
• 
Starting prohibited biologics prior to Week 52 
The following IEs will be handled with the treatment 
policy strategy (without IEs that need to be handled 
with composite strategy).  All assessments after 
starting such IE will be included. 
• 
Discontinuing the study intervention 
• 
Taking antifungals or other prohibited/rescue 
medications 
In addition, the missing data imputation rules are as 
follows: 
• 
For missing data, a multiple imputation 
approach will be used to impute missing 
Week 52 values, and this multiple imputation 
will use all data from participants excluding 
participants who undergo/plan to undergo 
surgery for AFRS on or before Week 52. 
ANCOVA model with 
intervention group, 
time from last surgery 
(≤2 years, >2 years), 
region (countries 
combined), and 
relevant baseline 
measurement as 
covariates is used. 
Statistical inference 
obtained from all 
imputed data by 
ANCOVA model will 
be combined using 
Rubin’s rule. 
 
The primary endpoint of change from baseline in LMK score at Week 52, will be analyzed using 
an analysis of covariance (ANCOVA) model with the baseline LMK score, intervention group, 
time from last surgery (≤2 years, >2 years) and region (combined countries) as covariates, with 
intercurrent events and missing data being handled by a hybrid method of the worst-observation 
carried forward (WOCF) and multiple imputation. For participants who undergo/plan to undergo 
surgery for AFRS, take SCS for any reason or start prohibited biologics, data collected after these 
IEs will be excluded from analysis and the worst post-baseline value on or before the IE will be 
assigned to the Week 52 value (ie, WOCF approach). For participants with no post-baseline 
values, the baseline value will be used (composite strategy). Participants who discontinue the 
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study intervention prematurely are encouraged to follow the planned clinical visits and, in these 
participants (if without or before the IEs that need to be handled with composite strategy), all data 
collected after study intervention discontinuation will be included in the analysis (treatment policy 
strategy). In case there is missing data, a multiple imputation approach will be used to impute 
missing Week 52 values, and this multiple imputation will use all participants excluding 
participants who undergo/plan to undergo surgery for AFRS, take SCS for any reason or start 
prohibited biologics on or before Week 52. Each of the imputed complete data will be analyzed 
by fitting an ANCOVA model with the baseline covariate and factors for intervention group, time 
from last surgery (≤2 years, >2 years), and region (combined countries). Statistical inference 
obtained from all imputed data will be combined using Rubin’s rule. Descriptive statistics 
including number of participants mean, standard error, and LS means will be provided. 
In addition, difference in LS means and the corresponding 95% CI will be provided along with 
the p-values. 
Subgroup analyses 
To assess the consistency in treatment effects across different subgroup levels, subgroup analyses 
will be performed for the primary efficacy endpoint with respect to age group, gender, region, and 
other factors that will be specified in the SAP. 
9.4.3 Secondary endpoint(s)  
Statistical analysis methods for the secondary efficacy endpoints listed in Table 1 are presented 
below.  
The primary estimand for the secondary endpoint of proportion of participants who receive SCS 
and/or undergo/plan to undergo surgery for AFRS during the 52-week treatment period is the 
/treatment policy/while before rescue strategy, as described in Table 8. 
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Table 8 - Summary of primary estimand for the proportion secondary endpoint  
Endpoint 
Category 
Estimands 
 
Endpoints 
Population 
Intercurrent event(s) 
handling strategy and 
missing data handling 
Population-level 
summary  
Secondary objective: To assess the efficacy of dupilumab to reduce the need for rescue treatments 
Secondary endpoint  
Proportion of 
participants 
who receive 
SCS and/or 
undergo/plan 
to undergo 
surgery for 
AFRS during 
the 52-week 
treatment 
period. 
ITT 
The following IEs will be handled with 
a treatment policy strategy 
(if without/before taking prohibited 
biologics): 
• 
Discontinuation of study 
intervention 
• 
Taking antifungals or other 
prohibited/rescue medications 
The following IE will be handled with 
a while before rescue strategy, All 
data before starting prohibited 
biologics will be included in the 
analysis. 
• 
Starting prohibited biologics 
In addition, the missing data 
imputation rules are as follows: 
• 
Discontinuing the study follow-up 
without an event prior to 
discontinuation: Participant will 
be considered as no event. 
Cochran-Mantel-Haenszel 
(CMH) test stratifying by 
time from last surgery 
(≤2 years, >2 years), and 
region (combined 
countries). The estimate of 
the odds ratio between 
dupilumab and placebo will 
be derived. 
This secondary endpoint will be analyzed using a CMH test stratifying by time from last surgery 
(≤2 years, >2 years) and region (combined countries). All data collected after study intervention 
discontinuation and before starting prohibited biologics will be included in the analysis. 
Participants who discontinue the study follow-up without an event will be considered as no event. 
The estimate of the odds ratio between dupilumab and placebo will be derived with the 
corresponding 95% CI and p-value. 
The change from baseline to Week 24 and Week 52 in the continuous secondary endpoints will be 
analyzed using the same analysis approach as for the primary endpoint of change from baseline in 
LMK score at Week 52.  
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. The baseline value is defined generally as the last available 
value before first dose of IMP. 
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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. 
Proportion of participants with at least 1 treatment-emergent adverse event (TEAE), 
treatment-emergent SAE, TEAE leading to death, and TEAE leading to permanent treatment 
discontinuation will be tabulated by treatment group. In addition, TEAEs will be described 
according to maximum intensity and relation to the study intervention. Serious AEs and AEs 
leading to study discontinuation that occur outside the treatment-emergent period will be 
summarized separately. 
Incidence of each type of AESI and other AE groupings will be tabulated by treatment group. For 
each type of AESI, the following analysis will be generated. 
A summary of the number (%) of participants with 
• Any TEAE. 
• Any SAE (regardless of treatment-emergent status). 
• Any treatment-emergent SAE. 
• Any AE leading to death. 
• Any TEAE leading permanent treatment 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 deaths 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. 
Results and change from baseline for the laboratory parameters will be summarized by treatment 
group for baseline and each post baseline time point, endpoint, minimum and maximum value. 
Summary statistics will include number of participants, mean, standard deviation, median, Q1, 
Q3, minimum, and maximum. 
The following definitions will be applied to laboratory parameters. 
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests. 
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• PCSA criteria will determine which participants had at least 1 PCSA during the 
on-treatment period, taking into account all evaluations performed during the on-treatment 
period, including unscheduled or repeated evaluations. The number of all such participants 
will be the numerator for the on-treatment PCSA percentage.  
The proportion of participants who had at least 1 incidence of PCSA at any time during the 
treatment-emergent period will be summarized by treatment group. Shift tables showing changes 
with respect to the baseline status will be provided. 
9.4.6 Other analyses  
Pharmacokinetic, immunogenicity, PD, and biomarker exploratory analyses will be described in 
the SAP finalized before database lock. The population PK and PD analyses might be presented 
separately from the main clinical study report (CSR). 
9.5 
INTERIM ANALYSES  
There is no interim analysis planned as part of this study. 
A primary database lock will be performed when all randomized participants have completed their 
treatment phase. Final analyses in the CSR will be based on all data collected up to this database 
lock. 
The database will be updated at the end of the study for all participants to include the 
posttreatment follow-up information and updates for the events previously ongoing at the time of 
the primary lock. Additional data between this database lock and last participant completing last 
visit will be summarized in a CSR addendum. 
9.6 
DATA MONITORING COMMITTEE  
Due to extensive clinical development and post-marketing safety profile for the 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 GCP Guidelines. 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]). 
• The protocol, protocol amendments, ICF/assent form, 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 
o The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
o The participant in a clinical trial 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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o 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/assent form 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/assent was 
obtained before the participant was enrolled in the study and the date the written 
consent/assent was obtained. The authorized person obtaining the informed consent/assent 
must also sign the ICF/assent form. 
• In case of ICF/assent form amendment while the participants are still included in the 
study, they must be re-consented to the most current version of the ICF(s)/assent form. 
Where participants are not in the study anymore, teams in charge of the amendment must 
define if those participants must or not re-consent or be informed of the amendment 
(eg, if the processing of personal data is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s)/assent form must be provided to the participant or the participant’s 
legally authorized representative.  
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Participants who are rescreened are required to sign a new ICF/assent form. 
The ICF contains 2 separate sections that address the use for research of participants’ data and/or 
samples (remaining mandatory samples or new samples collected for optional research). Optional 
exploratory research must be detailed in the section “Optional tests/procedures” and future 
research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each option is 
subject to an independent consent and must be confirmed by ticking a checkbox in CSICF Part 3. 
The Investigator or authorized designee will explain to each participant the objectives of the 
exploratory research and why data and samples are important for future research. 
Participants/parent(s)/legally authorized representative will be told that they/their children 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/parent(s)/legally 
authorized representative's agreement to allow any remaining specimens to be used for 
exploratory research. Participants/parent(s)/legally authorized representatives 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. The study Sponsor, Sanofi is 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 ICF/assent form.  
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• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• 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. 
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• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical trials and results on publically 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”. 
10.1.6 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/assent form, pertaining to the conduct of 
this study must be retained by the Investigator for 25 years after the signature of the final 
study report unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the Sponsor. No records may be transferred to another location or party 
without written notification to the Sponsor.  
10.1.7 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
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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. 
10.1.8 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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10.1.9 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 9 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 involvement in the study. 
Table 9 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
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Laboratory assessments 
Parameters 
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) 
 
Creatinine phosphokinase 
 
Alkaline phosphatase 
 
Total bilirubin 
 
Albumin 
 
Total protein 
Routine urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
by dipstickc   
• Microscopic examination (if blood or protein is abnormal)d 
Other screening tests 
Highly sensitive serum (at screening) or urine (at other time points) hCG pregnancy test 
(as needed for WOCBP)e.  
Serologyf: HBsAg, HBcAb total, HCVAb, HIV screen (Anti-HIV-1 and HIV-2 antibodies);  
Tuberculosis test (performed locally if required). 
All study-required laboratory assessments will be performed by a central laboratory, with 
the exception of TB test, urine pregnancy test, and routine urinalysis. 
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 China will use urine sample (not dipstick). 
d In case the urine dipstick test result is abnormal, a urine sample should be sent into the central laboratory for microscopic examination. 
e After screening local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
f 
In case of results showing HBsAg (negative), and HBcAb total (positive), an HBV DNA testing will be performed and confirmed negative prior 
to randomization. In case of results showing HCVAb (positive), an HCV RNA testing will be performed and should be confirmed negative 
prior to randomization.   
For children aged ≥6 to <12 years, laboratory assessments are based on the child’s weight and are 
detailed in the laboratory manual. 
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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. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
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• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease); however, if local health authority requirements supersede this it will be 
reported per local health authority requirements. 
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. 
- 
Is a congenital anomaly/birth defect 
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e) 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. 
o 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. This list is illustrative and not derived from safety 
concerns specific to dupilumab:  
➢ 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 
➢ 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’s representative 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 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 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 in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
- 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
➢ Females on hormone replacement therapy (HRT) and whose menopausal status is 
in doubt will be required to use one of the non-estrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment. 
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 
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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 
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. 
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• 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 8.3.5. 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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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS  
 
*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. 
*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: CLINICIAN-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES  
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10.7.2 Sino-nasal outcome test  
 
 
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10.7.3 Rhinosinusitis visual analog scale  
 
 
 
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10.7.5 AFRS Morning Diary  
 
 
 
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10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.9 
APPENDIX 9: DEFINITION OF ANAPHYLAXIS  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death”. 
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 
• Non-TB mycobacteria 
• Pneumocystis pneumonia 
This list is indicative and not exhaustive.
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10.11 APPENDIX 11: ABBREVIATIONS  
ADA: 
anti-drug antibodies  
ADR: 
adverse drug reaction 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AFRS: 
allergic fungal rhinosinusitis 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
CI: 
confidence interval 
CMH: 
Cochran-Mantel-Haenszel 
COPD: 
chronic obstructive pulmonary disease 
COVID-19: 
Coronavirus Disease 2019 
CRF: 
case report form 
CRS: 
chronic rhinosinusitis 
CRSwNP: 
chronic rhinosinusitis with nasal polyposis  
CSICF: 
Core Study Informed Consent Form  
CSR: 
clinical study report 
CT: 
computed tomography 
DILI: 
drug-induced liver injury 
eCRF: 
electronic case report form 
ELISA: 
enzyme-linked immunosorbent assay 
EoE: 
eosinophilic esophagitis 
EOS: 
end of study 
EOT: 
end of treatment  
ESS: 
endoscopic sinus surgery  
EU: 
European Union  
GDPR: 
General Data Protection Regulation 
HBcAb: 
hepatitis B core antibody 
HBsAg: 
hepatitis B surface antigen  
HBV: 
hepatitis B virus 
HCV: 
hepatitis C virus  
HCVAb: 
hepatitis C virus antibody 
HIV: 
human immunodeficiency virus 
HRQoL: 
health-related quality of life 
HRT: 
hormone replacement therapy  
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IB: 
investigator’s brochure  
ICF: 
informed consent form  
ICH: 
International Council for Harmonisation 
IEC: 
Independent Ethics Committee 
Ig: 
immunoglobulin 
IL: 
interleukin 
IMP: 
investigational medicinal product 
INCS: 
intranasal corticosteroids  
IRB: 
Institutional Review Board 
IRT: 
interactive response technology  
LMK: 
Lund Mackay 
LS: 
least squares 
mAb: 
monoclonal antibody  
NMPA: 
National Medical Products Administration 
NPS: 
nasal polyp score 
PCSA: 
potentially clinically significant abnormality  
PD: 
pharmacodynamics 
PK: 
pharmacokinetics 
PRO: 
patient-reported outcome  
PT: 
preferred term 
q2w: 
every 2 weeks  
q4w: 
every 4 weeks  
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SCS: 
systemic corticosteroids 
SNOT-22: 
22-item sino-nasal outcome test  
SOA: 
Schedule of Activities  
SOC: 
system organ class  
TB: 
tuberculosis 
TEAE: 
treatment-emergent adverse event 
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 
 
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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 (30 March 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. 
OVERALL RATIONALE FOR THE AMENDMENT  
This amendment institutes changes in response to Health Authorities feedback following review 
of the protocol and the overall pediatric development plan. The enrolment of study participants 
was extended to children aged ≥6 years old. The study assessments and the investigational 
medicinal products (IMP) were adapted to this population and are reflected in this amendment. 
The inclusion criteria were modified to allow more suitable criteria for participant enrolment, 
while maintaining the necessary inclusion/exclusion criteria to achieve the scientific aims of the 
study and maintain patient safety. 
Minor changes and typographical errors are not mentioned in the table below. 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Rationale, overall design, number of participants 
and intervention groups and duration subsections 
were revised to include children aged ≥6 years 
old and an additional dose regimen for 
adolescents/children ≥15 kg and <30 kg of 
300 mg q4w at screening. 
Statistical considerations: The redundant listing of 
the primary endpoint of the proportion of patients 
who received systemic corticoids (SCS) and/or 
undergo/plan to undergo surgery for AFRS during 
the planned study period was removed.  
Statistical considerations: an intercurrent event 
handling strategy for prohibited biologics and 
other prohibited medications was added. 
Statistical considerations: Added disease pattern 
(unilateral/bilateral in endoscopy at screening) as 
a factor in the statistical analysis model.   
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger pediatrics, the age of 
participants was revised to be at least 6 years old and 
the dosage of IMP was selected to be 300 mg q4w for 
adolescents/children ≥15 kg and <30 kg. 
This redundant listing of the primary endpoint was 
removed as the repetition of the primary endpoint was 
unnecessary. 
 
 
As per Health Authorities request to propose intercurrent 
event handling strategies for prohibited biologic use and 
other prohibited medications.   
To account for this new randomization stratification 
factor. 
1.2 Schema 
Figure 1 was modified to include children aged 
≥6 to <12 years. Dosing for adolescents/children 
≥15 kg and <30 kg was selected to be 300 mg 
q4w.  
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger pediatrics, the age of 
participants was revised to be at least 6 years old and 
the dosage of IMP was selected to be 300 mg q4w for 
adolescents/children ≥15 kg and <30 kg. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
activities (SoA) 
Some notes were modified to include specific 
information related to participants aged ≥6 to 
12 years old.  
 
 
Medical history: Footnote e was modified to 
record fungal stain assessment. 
 
Nasal endoscopy assessment will be performed 
only at screening, Week 0, Week 24, and 
Week 52 for children aged ≥6 to <12 years old.  
 
Nasal endoscopy: Footnote i for nasal polyp score 
(NPS) ≥3 for both unilateral and bilateral disease 
was modified to NPS score ≥2 out of 4 for 
unilateral polyps or 3 out of 8 for bilateral polyps.  
CT scan note and footnote k: The information 
requiring performing a CT scan within 48 hours 
prior to the use of SCS was removed. 
Addition of footnote x related to Visit 2 for q4w 
administrations. 
Specified assessments will not be conducted in children 
(aged less than 12 years old); while they remain 
appropriate for adolescents and adults, as clinical 
assessments done by patients themselves, they are not 
suitable for the younger pediatric group. 
Fungal stain assessment as supporting evidence is 
optional, so the criterion was combined with criterion 
I02 d. However, the information is recorded in medical 
history.  
To reduce the frequency of an invasive procedure in 
children aged ≥6 to <12 years old, nasal endoscopy at 
Week 12 and Week 36 will not be performed in this age 
group.  
To allow the enrolment of patients with unilateral AFRS, 
specific criteria for NPS for this subgroup were updated. 
 
 
As per Health Authorities request, the CT scan to be 
performed between Week 36 and Week 52 in case of 
SCS use was removed. 
This footnote was added for q4w administrations and 
IMP training. 
2.2 Background 
Rationale for background information was added 
for children aged ≥6 to <12 years. 
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger pediatrics, the age of 
participants was revised to be at least 6 years old. 
3.1 
Appropriateness 
of 
measurements 
Inclusion criteria related to NPS ≥3 for both 
unilateral and bilateral disease was modified to 
NPS score ≥2 out of 4 for unilateral polyps or 
3 out of 8 for bilateral polyps and Lund Mackay 
(LMK) ≥12 for both unilateral and bilateral 
disease was modified to LMK ≥9 for patients with 
unilateral polyps or ≥12 for patients with bilateral 
polyps. 
To allow the enrolment of patients with unilateral AFRS, 
specific criteria for NPS and LMK for this subgroup were 
updated. 
4.1 Overall 
design  
Study design and dosage of dupilumab was 
updated to include children aged ≥6 years old. 
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger pediatrics, the age of 
participants was revised to be at least 6 years old and 
the dosage of IMP was selected to be 300 mg q4w for 
adolescents/children ≥15 kg and <30 kg. 
4.2 Scientific 
rationale for 
study design 
Inclusion criteria related to NPS of ≥3 out of 
8 was modified to NPS score ≥2 out of 4 for 
unilateral polyps or 3 out of 8 for bilateral polyps 
and LMK ≥12 out of 24 was modified to LMK 
≥9 out of 12 for unilateral polyps or ≥12 out of 
24 for bilateral polyps. 
To allow the enrolment of patients with unilateral AFRS, 
specific criteria for NPS and LMK for this subgroup were 
updated. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
4.3 Justification 
for dose 
Information on dosing and exposures for 
dupilumab derived from previously conducted AD 
studies in children was added to justify the dosing 
for children used in this study. 
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger pediatrics, the age of 
participants was revised to be at least 6 years old and 
the dosage of IMP was selected to be 300 mg q4w for 
adolescents/children ≥15 kg and <30 kg as per 
dupilumab AD studies with the same population. 
5.1 Inclusion 
criteria 
I 01. Participant age modified from ≥12 years 
to ≥6 years. 
I 05. Body weight modified from ≥30 kg to ≥15 kg. 
 
I 02.e) was removed and combined with inclusion 
criterion I 02.d). A footnote was added in the 
Schedule of Activity - Medical History to record 
this information. 
 
 
 
 
 
 
I 03.a) Endoscopic NPS of at least 3 out of 
8 (either unilateral or bilateral polyps) was 
modified to NPS score ≥2 out of 4 for unilateral 
polyps or 3 out of 8 for bilateral polyps. 
I 03.b) LMK score at inclusion was modified to 
include either LMK score of 9 unilateral sinus 
opacification or 12 bilateral sinus opacification. 
I 07. Addition of a specific Assent Form for 
children aged ≥6 to <12 years. 
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger pediatrics, the age of 
participants was revised to be at least 6 years old.  
Fungal staining has high variability (10-100% false 
positive rate) and low specificity. In practice this means 
that a negative fungal stain does not rule out the 
diagnosis of AFRS, while saprophytic fungal growth is 
not necessarily diagnostic of AFRS. This uncertainty is 
reflected in the fact that fungal culture is only considered 
supportive evidence in the Bent and Kuhn diagnostic 
criteria in contrast to the other four criteria which are key 
for the diagnosis (elevated specific IgE, polyps, CT, and 
eosinophilic mucin). 
To allow the enrolment of patients with unilateral AFRS, 
specific criteria for NPS and LMK for this subgroup were 
updated. 
 
To allow the enrolment of patients with unilateral AFRS, 
specific criteria for NPS and LMK for this subgroup were 
updated. 
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger pediatrics, a specific 
Assent Form should be used for these children. 
5.2 Exclusion 
criteria 
E 02 blood boil example was removed and 
replaced by hemangioma. 
E15 was modified to provide a more precise 
description of prior dupilumab use that leads to 
exclusion. 
Blood boil is not the correct medical term for the 
condition. 
Precision concerning prior dupilumab use was added in 
the exclusion criterion. 
6.1 Study 
Intervention(s) 
administered 
Addition of a new dosing regimen for dupilumab 
and matching placebo for adolescents/children 
≥15 kg and <30 kg. 
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger pediatrics, the age of 
participants was extended to be at least 6 years old. The 
dosing for these children was added. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
6.3 Measures to 
minimize bias: 
Randomization 
and blinding 
Added children to the adolescent stratification 
factor. 
 
 
 
Added another stratification factor in adults of 
disease pattern (unilateral/bilateral in endoscopy 
at screening). 
Code breaking: The sentence “Investigator could 
decide at his/her discretion to contact the Sponsor 
to discuss the situation in case of unblinding 
participant’s intervention assignment” was 
removed 
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger children, the age 
stratification was clarified to include children with 
adolescents.  
To ensure treatment balance within disease pattern. 
 
 
As per EMA GCP Inspectors Working Group (GCP IWG) 
and the Clinical Trial Facilitation Group (CTFG), the 
responsibility to break the treatment code in emergency 
situations resides solely with the Investigator. 
Consequently, the Sponsor can't require or insist on 
being involved in the decision to unblind, stall or delay in 
any way the unblinding of trial subject treatment in 
emergency situations. 
6.5.3 Rescue 
medicine 
Information related to use of SCS during the 
specific period from Week 36 to Week 52 was 
removed. 
As per Health Authorities request, the CT scan to be 
performed between Week 36 and Week 52 in case of 
SCS use was removed. 
8 Study 
assessments 
and procedures 
PRO assessment order was added. 
 
Blood sample volume was specified for children 
PRO assessment order was added to be consistent with 
footnote in SoA. 
Based on Health Authorities input regarding overall 
pediatric development plan and their recommendation to 
extend the inclusion to younger children, the age of 
participants was extended to be at least 6 years old. The 
blood sample volume for these children was added. 
8.1.2.1 Lund 
Mackay score 
Information related to use of SCS during the 
specific period from Week 36 to Week 52 was 
removed. 
As per Health Authorities request, the CT scan to be 
performed between Week 36 and Week 52 in case of 
SCS use was removed. 
9.3 Populations 
for analysis 
The following was added: PRO endpoints will be 
analyzed using the ITT population in adults and 
adolescents. 
PRO questionnaires are not applicable for children aged 
≥6 and <12 years. 
9.4.1 General 
considerations 
for Statistical 
Analysis 
Added clarification that all primary and select 
secondary efficacy endpoints in the multiplicity 
hierarchical testing procedure will be performed at 
an alpha of 0.01 level. 
As per Health Authorities request to clarify that the 
multiplicity plan will conform to the same overall alpha of 
0.01. 
9.4.2 Primary 
endpoint(s) and 
9.4.3 Secondary 
endpoint(s) 
Removed the estimand from the endpoint column 
in Table 7 and Table 8 and added an intercurrent 
event handling strategy for prohibited biologics 
and other prohibited medications. 
 
Added disease pattern (unilateral/bilateral in 
endoscopy at screening) as a factor in the 
statistical analysis model. 
As per Health Authorities request to clarify the strategy 
is associated with the intercurrent event and not the 
endpoint, and to propose intercurrent event handling 
strategies for prohibited biologic use and other 
prohibited medications.   
To account for this new randomization stratification 
factor.  
10.2 Appendix 2: 
Clinical 
laboratory tests 
HBcAb IgM and IgG were removed 
Only HBcAb total test is performed at Central Laboratory 
whereas HBcAb IgM and IgG tests are not performed at 
Central Laboratory. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
10.4 Appendix 4: 
Contraceptive 
guidance and 
collection of 
pregnancy 
information 
For male participants with partners who become 
pregnant, the sentence “this applies to male 
participants who receive dupilumab” was 
removed. 
As the study is double-blinded, this sentence is not 
accurate. 
10.12.2 
Amended protocol 02 (23 November 2021)  
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  
The primary purpose of the amendment is to institute changes to allow more flexible criteria for 
participant enrolment, while maintaining the necessary inclusion/exclusion criteria to achieve the 
scientific aims of the study and maintain patient safety.  
Inclusion/exclusion criteria were modified in order to be more in line with the current clinical 
practice of investigators in terms of diagnosis and management of patients with allergic fungal 
rhinosinusitis (AFRS).  
Additional changes including statistical analysis of the secondary endpoint(s) are presented in the 
table below. The Sponsor changed the handling of surgery for AFRS or starting prohibited 
biologics from worst possible score to worst observation carried forward to better reflect the 
clinical scenario of treatment failure. 
Minor changes and clarifications and typographical errors are not mentioned in the table below. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 
Schedule of 
activities (SOA) 
Footnote a: Extension of the screening period 
from 28 days ±3 days to a maximum of 
42 ±3 days in case of particular circumstances to 
allow patients to complete study procedures 
(eg, skin testing, mucin collection). 
To allow adequate time for certain test results to be 
available, ie. fungal sensitization by skin testing or 
eosinophilic mucin present in sinus tissue. 
Section 5.1 Inclusion 
criteria 
Removal of “without fungal invasion” from 
Inclusion criteria 02 B&K criteria d: 
d) Eosinophilic mucin/mucus without fungal 
invasion into sinus tissue (identified within 5 years 
prior to screening or at screening) with or without 
positive fungal stain. 
Patients with known or risk factors for fungal 
invasion are already excluded from participating in 
the study with the following exclusion criteria: E03, 
E05, E06, and E07, therefore, an additional 
inclusion criteria for histological proof of fungal 
invasion into sinuses is not deemed necessary to 
exclude these patients from the study. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion 
criteria 
Revision of inclusion criterion I04 previously 
reported as “Prior sino-nasal surgery(ies) for 
AFRS” to “History of sino-nasal surgery(ies)” with 
addition of a note providing examples of sino-
nasal surgery. 
The AFRS disease process evolves with time and 
due to the similarity of symptoms patients may 
undergo sino-nasal intervention for CRS or nasal 
polyps and the diagnosis of AFRS based on Bent 
Kuhn criteria is only made post-surgically based on 
histopathology. Therefore, a modification in this 
criteria is made, to allow enrollment of patients who 
may not have in the historical sino-nasal surgical 
report specified "surgery for AFRS" (eg. for the first 
surgery) but for whom a histopathological diagnosis 
of AFRS was made at or after surgery and before 
randomization in the study. 
Section 5.4 Screen 
failures 
Extension of the duration of validity of the screening 
CT scan to 90 days in case of rescreening if the 
rescreening is performed outside of the 90 days 
window, the CT scan must be repeated. 
To avoid re-exposing patients to radiation in case of 
rescreening, given that CT scan images are not 
likely to change significantly during a 3-month 
period.  
Section 8.1.7 
Addition of the following text: If UPSIT is planned 
on the same day as nasal endoscopy and the 
endoscopy is conducted under local anesthetics 
the assessment with UPSIT must be performed 
before anesthetics use to ensure that the effect of 
anesthetics will not interfere with UPSIT 
interpretation. 
Instruction added to avoid any impact of the 
anesthetics on the UPSIT assessment. 
Section 9.4.3 
Secondary 
endpoint(s) and 
1.1 Synopsis 
Change of intercurrent event handling strategy for 
undergoing surgery for AFRS or starting 
prohibited biologics: “data collected after surgery 
or starting prohibited biologics will be excluded 
and the worst possible score (eg, 24 for LMK) will 
be assigned to the Week 52 value” changed to 
“data collected after surgery or starting prohibited 
biologics will be set to missing and the worst post-
baseline score value on or before surgery or 
starting prohibited biologics will be used to impute 
the missing Week 52 value (ie worst observation 
carried forward [WOCF] approach). For 
participants with no post-baseline values, the 
baseline value will be used (composite strategy).” 
To change the intercurrent event handling strategy 
for surgery for AFRS or use of prohibited biologics 
to include each patient's own worst data in order to 
better reflect the clinical scenario of treatment 
failure.  
Section 10.2 
Appendix 2 Clinical 
Laboratory tests and 
Section 1.3 
Schedule of 
activities (SOA) 
Revision of the footnote e in the Table 9-Protocol-
required laboratory assessments and the footnote 
q in the Schedule of Activities to remove HBsAb 
test and to precise wording for the testing. 
Clarification on hepatitis DNA/RNA assessments. 
Removal of HBsAb assessment from the entire 
protocol, as only HBsAg and HBcAb results are 
used for the assessment of HBV DNA. 
Removal of the wording “false positivity” for 
patients with positive HBcAb or HCVAb and 
negative DNA/RNA as this wording is not 
appropriate for antibodies status. 
Section 10.12 
Appendix 12: 
Protocol amendment 
history 
The overall rationale and table with summary of 
changes for Amended protocol 01 were moved 
from the Cover page to Section 10.12. 
This is aligned with Sanofi procedures. 
 
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11 
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4. Bent JP, Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg. 
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