Clinical trial NCT05545072
Conditions: Allergic Fungal Rhinosinusitis
Sponsor: Emory University
Start date: 2023-10-26; Completion date: 2024-07-10
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to find a more effective treatment for allergic fungal rhinosinusitis (AFRS). Most people suffering from nasal polyps have elevated levels of white blood cells called eosinophils that are involved in inflammation of the air passages. Despite appropriate treatment with oral/topical corticosteroids, saline irrigations, and surgery, nasal polyps return frequently within months of surgery. Participants will be administered a placebo or dupilumab every two weeks for 52 weeks.

Detailed description:
Allergic fungal rhinosinusitis (AFRS) is a severe form of eosinophilic nasal polyposis with critically inadequate treatment options for the 10% of chronic rhinosinusitis subjects affected by the disease. Occlusive eosinophilic mucus and severe nasal polyposis present in early adulthood, with an unrelenting course marked by sinus expansion and pressure-induced dehiscence of the surrounding orbit and skull base. Despite appropriate therapies with oral/topical corticosteroids, saline irrigations, and comprehensive sinus surgery, nasal polyps aggressively recur, frequently within months of surgery. Medical options beyond topical and systemic steroids are limited. Neither antifungal nor allergen immunotherapy is beneficial. Due to persistent sinonasal inflammation, patients with AFRS receive an average of three corticosteroid bursts per year and revision sinus surgery every 42 months.

Certain proteins made by the body, called interleukins, appear to play a major role in the survival and activation of eosinophils. Antibodies are proteins naturally produced by your body that find foreign substances, such as bacteria, fungi, viruses, and other substances that enter your body and make them inactive. Dupilumab is an antibody made in the laboratory that has been made to block specific interleukins from activating the eosinophils. This research is being done to find out if the medication dupilumab is effective and safe when used to treat patients with AFRS following recommended sinus surgery. Dupilumab is already approved for the treatment of atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis (CRSwNP); however, it is not approved to treat AFRS.

Patients who meet the eligibility criteria will be enrolled in this randomized, double-blind study and will go through four periods: a run-in period, surgery period, randomized treatment period, and post-treatment period. During the run-in period, patients will perform twice daily saline irrigations followed by intranasal corticosteroid spray (INCS) for 2 to 6 weeks before planned sinus surgery. Saline irrigations/INCS and sinus surgery will be completed by the standard of care (SoC). Patients who continue to meet eligibility criteria following surgery will be randomized to receive a placebo or dupilumab subcutaneously every 2 weeks. Participants will receive 26 doses of the investigational medical product (IMP), via either study personnel or home administration, to maintain a 2-week treatment schedule. Participants will receive IMP directly from the central pharmacy, with compliance assessments via reminder text messages on the day of each scheduled home administration, as well as monthly phone calls and injection device collection at recurring 3-month study visits. Participants will then be monitored on daily saline irrigation and INCS spray for 12 weeks to evaluate potential disease recurrence after discontinuation of IMP. An end-of-study visit will be conducted 12 weeks after the treatment period at Week 64.

Arms: arm 1: Participants receiving dupilumab for 52 weeks following surgery for allergic fungal rhinosinusitis (AFRS). arm 2: Participants receiving a placebo to match dupilumab for 52 weeks following surgery for allergic fungal rhinosinusitis (AFRS).
Interventions: intervention 1: Dupilumab intervention 2: Placebo intervention 3: Intranasal Corticosteroid Sprays (INCS)
Intervention descriptions: intervention 1: Dupilumab will be administered subcutaneously at a dose of 300 milligrams (mg) in a 2 milliliter (mL) solution every 2 weeks until the end of treatment (EOT) at Week 52. Participants will receive a total of 26 doses. intervention 2: A placebo to match dupilumab will be administered subcutaneously every 2 weeks until the end of treatment (EOT) at Week 52. Participants will receive a total of 26 doses. intervention 3: All participants will undergo standardized background therapy with intranasal corticosteroid sprays (INCS) per standard of care (SoC). This will continue throughout the entire study. Participants either receive fluticasone propionate or mometasone furoate.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Title: S-I: Add-on Dupilumab for AFRS as Postoperative Therapy (ADAPT)
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PROTOCOL TITLE:   S-I: A randomized, 52-week treatment double-blind, placebo-controlled 
efficacy and safety study of dupilumab 300 mg every other week after endoscopic sinus surgery 
in patients with allergic fungal rhinosinusitis (AFRS) on a background therapy with intranasal 
corticosteroid spray
Short: Add-on Dupilumab for AFRS as Postoperative Therapy (ADAPT)
EMORY PRINCIPAL INVESTIGATOR:
, MD
Assistant Professor, Rhinology and Skull Base Surgery Division
Department of Otolaryngology – Head & Neck Surgery 
Emory University School of Medicine 
EXTERNAL (NON-EMORY) COLLABORATORS                                                                  
, Associate Professor of Otolaryngology McGovern Medical School 
at the University of Texas Health Science Center at Houston, Department of Otolaryngology- 
Head & Neck Surgery
The University of Texas IRB will review the engagement in human participants research 
activities. 
SPONSOR INVESTIGATOR:
Office of the Clinical Director
VERSION: 3.7.3
FUNDING SOURCE: Sanofi 


Protocol Title: S-I: Add-on Dupilumab for AFRS as Postoperative Therapy (ADAPT)
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REVISION HISTORY
Revision #
Version Date
Summary of Changes
2.1
07 Dec 2019
Protocol formatting
Format of entire protocol updated to reflect current standards of 
practice
Table 1. Schedule of Activities – CT sinus scan
Timing of post-treatment CT scan adjusted from EOS to EOT
Table 1. Schedule of Activities - Pregnancy Test
Frequency of urine pregnancy testing increased to facilitate testing 
during each study visit prior to IMP administration (5 per subject).
Section 13. Safety Definitions, Reporting, And Monitoring
Required subject safety activities included.
2.2
15 Oct 2020
Statistical methods
Stratification strategy updated with removal of asthma
Blinded central reader introduced
10.1 Study Database
Introduction of Microsoft OneDrive as a central data repository
12.1 Objective measures of disease
Introduction of blinded central reader to determine mLK scores
13.1 Missing data handling
Introduction of multiple imputation approach
13.6 Primary Analysis
Strategy for handling of intercurrent events is further described
13.7 Secondary and Exploratory Analysis
Revision surgery during follow-up will be considered a treatment 
failure
14.3 Recording and Reporting Adverse Events
Reporting expectations are clarified, to include 24-hour notification
2.3
02 Mar 2021
6.1 Overall Design
Background medication changed from Budesonide irrigations to 
standard of care intranasal corticosteroid sprays (INCS), as chosen 
by the treating physician
8.1.2 Non-Investigational Products
Background medication changed from Budesonide irrigations to 
standard of care intranasal corticosteroid sprays (INCS), as chosen 
by the treating physician
8.3.5 Rescue Therapy
Topical corticosteroid irrigations allowed as rescue per treating 
physician
2.4
12 Nov 2021
Table 1: Schedule of Activities
Defined frequency of pregnancy testing and assessment of subject 
compliance
4.6.3 Accountability
Westat included as external study monitor with defined monitoring 
plan


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4.8 Pharmacy
Belmar Pharma Solutions included as dispensing pharmacy
8. Study Timelines
Updated timeline for study milestones
16.2 Database Set-up and Management
Inclusion of FDA Part 11 compliance
17.1 Obligations of Sponsor-Investigator
Inclusion of 21 CFR 312
17.4.3 Evaluation of Causality
Defined IND Safety Reporting
3.0
28 Dec 2021
Protocol Formatting
Clarification provided to define protocol mandated study activities 
versus those completed per standard of care (sinus surgery, nasal 
saline irrigations, topical corticosteroid sprays)
1.0 Study Summary
Addition of reminder text messages the day of scheduled IMP 
injections.
Table 4: Investigational study treatments
Clarification of Placebo
4.6 Preparation/handling/administration/accountability
Description of central pharmacy and delivery of study drug, as well 
as internal monitoring for drug receipt and subsequent use / disposal
Appendix C: Data and Safety Monitoring Board Charter
DSMB Charter included
Appendix E: List of Study Vendors
Reference list of study vendors included
3.1
31 Jan 2022
15.4.1 Evaluation of Severity 
Addition of Common Terminology Criteria for Adverse Events 
(CTCAE) to evaluate AE event severity
3.2
17 Feb 2022
Title: 
Added S-I
1. Study Summary
Addition of SNOT-22 and ACT in the table
6. Data Specimen Banking
Changed “mandatory” to “optional”
7.1 Inclusion Criteria
Added the language that non-English speakers will be included
7.1.5 Reproduction
Added men criteria


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3.3
31 May 2022
28 Jun 2022
3. Study Objectives and Endpoints 
Addition of co-primary endpoint
15.3 Recording and Reporting Adverse Events
Added details for clarification
Copied a section about FDA reporting (that was initially under 15.4 
Evaluation of Severity and Causality)
14.6 Primary Analysis
Added specific details about

the statistical model

analysis for subject with unilateral disease

plan for Type I error control
3.4
14 Jul 2022
14.11 Safety evaluation plan
Added
1. Study Summary
Removed Randomization from visit 3 and added it to surgery 
period.
Clarified Surgery period length: 7 days ± 4 weeks  
Study design is summarized in Figure 1 
Updated the Figure with correct running timeframe
4.1 Overall Design
Clarified that randomization is before visit 3 (week0)
15.7 Monitoring Table 2
Added to this version
3.5
9 Aug 2022
2. Background
Added more details on dupilumab mechanism of action and 
rationale.
4.6.2 Administration
Clarified that participants who prefer to get injection at the clinic 
can do so.
13. Compensation
Clarified how compensation will be done at study visit
3.6
7 Mar 2023
Appendix D: List of Study Personnel
Addition of 
Removal of 
5.2.1 Objective measures of disease 
Incentive Spirometry:  
Removed “Incentive” to reflect the correct procedure 
6. Data Specimen Banking
Renamed this section “Data Specimen collection and Banking” to 
clarify that the specimen is not only for banking. Rearranged the 
section to explain the required collection first and then the optional.
Appendix E: List of Study Vendors
Changed Westat contact person to Michele Snyder
3.7
21 Mar 2023
Investigators
Added 
 as PI of Emory site.


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Changed 
 (S-I) address to the NIH site
Across the protocol
Added the fourth site: NIH and changed the number of sites from 
three to four, and the number of participants per site from 44 to 33.
Removed RSDI to be consistent with the SoA
3.7.1
1 Sep 2023
Across the protocol
Removed Vanderbilt as a site and changed the number of sites from 
four to three, and the number of participants from 33 to 44.
Clarified that study visits and dosing of IMP can be within 7 days 
of planned date in line with prescribing package information for 
dupilumab for CRSwNP.
Formatting adjustments. Subjects updated to participants 
Standardized treatment for nasal polyps to daily include saline 
irrigations and INCS spray.
Standardized that pregnancy test will be done until visit 8
Table 1. 
Clarified that CT scan is per SoC and can be up to 6 months before 
surgery.
Clarified that randomization occurs post-operatively
4.5.3 Postoperative care / 7.1.4 Sinus Surgery
Post operative pain regimen at discretion of treating physician.
Oral steroid regimen specified to be prednisone. 
Removed from section 7.1.4 (duplicated information) 
4.7 Randomization and blinding 
Randomization, blinding, and emergency unblinding provided by 
study data team
6. Data Specimen Collection and Banking
Clarified that routine laboratory monitoring is not planned but can 
be obtained for SoC if needed
7.2.1. Exclusion Criteria
Removed mucocele as exclusion criteria as this frequently seen in 
AFRS.
3.7.2
9 Oct 2023
Schema
Updated the schema to reflect the changes made to the protocol
3.7.3
2 Apr 2024
Across the protocol
Asthma Control Test (ACT) was replaced by Asthma Control 
Questionnaire (ACQ) throughout the protocol.
4.1 Overall Design
Protocol clarified to allow enrollment of participants within 2 
weeks of surgery if they have been on background therapy for a 
minimum of 2 weeks and meet all other eligibility criteria.


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Table of Contents
1.
Study Summary ........................................................................................................................8
2.
Background ............................................................................................................................15
3.
Study Objectives and Endpoints.............................................................................................16
4.
Study Intervention/Investigational Agent ..............................................................................17
5.
Procedures Involved...............................................................................................................22
6.
Data Specimen Banking .........................................................................................................24
7.
Inclusion and Exclusion Criteria ............................................................................................24
8.
Local Number of Participants.................................................................................................27
9.
Recruitment Methods .............................................................................................................28
10. Withdrawal of Participants.....................................................................................................28
11. Risk to Participants.................................................................................................................28
12. Potential Benefits to Participants ...........................................................................................28
13. Compensation to Participants.................................................................................................29
14. Data Management and Confidentiality...................................................................................29
15. Provisions to Monitor the Data to Ensure the Safety of Participants.....................................33
16. Provisions to Protect the Privacy Interest of Participants ......................................................40
17. Informed Consent...................................................................................................................40
18. Setting.....................................................................................................................................40
19. Appendix ................................................................................................................................41
20. Resources Available...............................................................................................................58
21. Multi-Site Research monitoring .............................................................................................58
22. References ..............................................................................................................................59


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1. Study Summary
Table 1: Schedule of Activities
Run-
in 
Surgery Randomized Treatment period 
EOT EOS 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
Week 
W-6 W-1 
W0 2,4,6,8,10b
 
12 14,16,18,20,22b 24 
26,28,30,32, 
34b
36 
38,40,42,44,46,48,
50b
52 
64 
Day ± 7
 
D-42 
 
 
D-7g 
 
D0 
 
D84
 
 
 
 
D168 
 
D252 
D364
 
D448
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion 
and 
exclusion 
criteria 
X 
 
X
 
 
 
 
 
 
 
 
 
Patient 
Demography
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical / 
surgery history 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Urine Pregnancy 
Testc 
X 
 
X 
 
X 
 
X 
 
X 
 
X
X
Transfer 
diagnostic nasal 
endoscopy to 
online 
repository 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 


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Determination of 
mLK endoscopic 
scored 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Spirometrye 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 SNOT-22 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 ACQ
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CT sinus scan 
Xi 
 
 
 
 
 
 
 
 
 
X 
 
Randomizationf 
 
X 
 
 
 
 
 
 
 
 
 
 
Collect 
peripheral
bloodh 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Sinus mucus 
sampleh 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Ethmoid sinus 
tissue 
 
X 
 
 
 
 
 
 
 
 
 
 
Treatment: 
IMP: 
Dupilumab/ 
placebo 
injectionb 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Record 
concomitant 
medications
X 
X
X 
 
X 
 
X 
 
X 
 
X 
X 
Text reminder 
for IMP self-
administrationb 
 
 
 
X, X, X, X, 
X 
 
X, X, X, X, X 
 
X, X, X, X, 
X 
 
X, X, X, X, X, X, 
X 
 
 
Assessment 
of IMP 
compliance 
(phone 
call)b 
 
 
 
X, X 
 
X, X 
 
X, X 
 
X, X, X 
 
 


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Assessment 
of IMP 
compliance 
(device 
collection)b 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Record planned 
surgery for NP, 
OCS use and 
other rescue 
medications 
|-----------------------------------------------------------------------X----------------------------------------------------------------------------|
a Patients who discontinue treatment early will be assessed as soon as possible using the procedures normally planned for the EOT 
Visit.
b Patients will self-administer investigational drugs between study visits (v3-8). Compliance will be ensured by reminder text 
messages the day of each home injection, monthly phone calls and collection of injection materials at following study visits.
c Urine pregnancy test completed by all WOCBP, (i.e., post-pubescent, premenopausal females).
d Determination of mLK endoscopic scores will be completed by a blinded, central reader for all study sites.
e Lower airway assessments completed for participants with medical history of comorbid asthma (~25% of study cohort).
f Patients will be randomized once pathology report is available post-operatively to confirm presence of fungus.
g Surgery period can be extended to 4 weeks to accommodate operating room availability, unforeseen personal events, or other 
occurrences that delay randomization.
h Optional, only in participants that consent to collection and banking of these materials.
i If not previously obtained within prior 6 months. 
ACQ: Asthma Control Questionnaire, AE: Adverse Event, CT: Computed Tomography, IMP: Investigational Medical Product, mLK: 
Modified Lund Kennedy Endoscopic Score, NP: Nasal Polyp, OCS: Oral Corticosteroid, SAE: Serious Adverse Event, SNOT-22: 22-
item SinoNasal Outcomes Test, WOCBP: women of childbearing potential


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Project Title
S-I A randomized, 52-week treatment double-blind, placebo-controlled efficacy and 
safety study of dupilumab 300 mg every other week after endoscopic sinus surgery in 
participants with allergic fungal rhinosinusitis (AFRS) on a background therapy with 
intranasal corticosteroid spray
Short: Add-on Dupilumab for AFRS as Postoperative Therapy (ADAPT)
Project Design
Multicenter, randomized, double-blind, placebo-controlled study comparing the 
efficacy of dupilumab to placebo in allergic fungal rhinosinusitis (AFRS) participants 
after sinus surgery on a background treatment with intranasal corticosteroid spray 
Study periods: 
The clinical trial consists of 4 periods:
1. Run-in period (2 weeks + 4 weeks):
All participants will enter a run-in period of 2-6 weeks receiving saline 
irrigations and INCS spray daily. All oral steroids and antibiotics as well as 
corticosteroid rinses will be stopped. 
2. Surgery period (7 days + 4 weeks):
Patients will undergo surgery as scheduled. Sinonasal mucus, peripheral blood 
and ethmoid tissue will be collected from all participants at the time of surgery.
3. Randomized treatment (52 weeks ± 7 days):
Patients will be randomized to one of the following treatments: 

Arm A: dupilumab 300 mg subcutaneous (SC) q2w until Week 52

Arm B: placebo given SC q2w until Week 52
4. Posttreatment period (12 weeks ± 3 days):
After completing 52 weeks of treatment with IMP (or following early 
discontinuation of IMP or  discontinuation from the study), participants will be 
instructed to 

Return to the study site for the last scheduled visits for physical 
examination, nasal endoscopy, NPS, PROs (SNOT-22 and ACQ), FEV1 
measurement in those with asthma and safety.

Continue on stable dose of INCS spray during the posttreatment period. 

Report any adverse event (AE).
Co-Primary 
Objectives
a) Determine the efficacy of dupilumab in controlling sinonasal 
inflammation and preventing nasal polyp recurrence after complete sinus 
surgery for AFRS, as measured by change in the mLK score
b)  Evaluate the effect of dupilumab on oral corticosteroid utilization 
following complete sinus surgery for AFRS
Secondary 
Objectives
To evaluate the effect of dupilumab on:

Prevention of revision surgery for AFRS

Secondary objective measures of sinonasal inflammation following sinus 
surgery using the NPS and LMS

Lower airway dysfunction following sinus surgery in the subgroup of 
participants with asthma (~25%) 

Upper and lower airway, disease-specific, health-related quality of life, as 
measured by ACQ and SNOT-22 

Reducing utilization of rescue medications for acute exacerbations of CRS 
following sinus surgery


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Research 
Interventions / 
Interactions
Dupilumab 300 mg will be administered SC every 2 weeks with an EOT at week 52. 
Matching placebo will be administered SC at the same time points. Patients will 
receive a total of 26 doses of IMP. Patients will receive IMP directly from the central 
pharmacy, with compliance assessments via reminder text messages the day of each 
scheduled home administration, as well as monthly phone calls and injection device 
collection at recurring 3-month study visits (W0, 12, 24, 36). Self-administration of 
IMP will be completed at home to maintain a 2-week treatment schedule (W2, 4, 6, 8, 
10, 14, 16, 18, 20, 22, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50). Pregnancy testing 
in WOCBP will be completed during each study visit (W0, 12, 24, 36, 52, 64).
All participants will undergo standardized background therapy with intranasal 
corticosteroid sprays (INCS) per standard of care (SoC). This will be continued 
throughout the entire study. The systemic bioavailability of INCS varies from <1% to 
up to 40-50%, which is why we will standardize the dose of INCS. Participants will 
either receive fluticasone propionate or mometasone furoate at the following dosages 
below.
INCS
Frequency
Total Daily Dosage
Fluticasone 
propionate
2 sprays (50mcg) in 
each nostril once 
daily
200mcg 
Mometasone 
furoate
2 sprays (50mcg) in 
each nostril twice 
daily
400mcg
Study 
Population
Allergic Fungal Rhinosinusitis
Sample Size
This study will be completed at 3 North American sites. A total of 132 participants will 
be randomized.
Study 
Duration for 
individual 
participants
The total duration of the study (per subject) is expected to be approximately 71 weeks:

Run-in period (2-6 weeks*)

Surgery period (7 days + 4 weeks)

Randomized treatment period (52 weeks ± 7 days)

Posttreatment period (12 weeks ± 3 days)
*Participants may be consented & enrolled at any time during run-in or presurgical 
period, provided the failure of appropriate medical therapy has been documented as 
outlined in the inclusion criteria
Study Specific 
Abbreviations
/ Definitions
Abbreviation 
or Term
Definition
ACQ
Asthma Control Questionnaire
AE
Adverse event
AERD
Aspirin exacerbated respiratory disease
AM
Morning
AFRS
Allergic Fungal Rhinosinusitis


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BID
Twice a day
CFR
Code of Federal Regulations
CRSwNP
Chronic Rhinosinusitis with nasal polyps
CT
Computed tomography
EDC
Electronic Data Capture
FU
Follow-up
GCP
Good clinical practice
ICF
Informed consent form
IMP
Investigational medicinal product
INCS
Intranasal corticosteroids
IP
Investigational product
IPD
IP discontinuation
IRB
Institutional Review Board
LMS
mLK
Lund-Mackay score
Modified Lund Kennedy Endoscopic Score
SNOT-22
SoC
SinoNasal Outcome Test, 22 item
Standard of Care
WOCBP
Women of childbearing potential 
Funding 
Source 
Sanofi


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Schema
Arm A: Dupilumab 300 mg q2week to Week 52
Arm B: Placebo q2week to Week 52
Background Therapy: Intranasal Corticosteroid Spray per Standard of Care
Run-In
Post-
Treatment
Period
V1
Week-6
V2
Surgery
Week-1
V3 (D0/W0)
+/- 7 days
IMP Initiation
V7/EOT
Week 52
+/- 7 days
V8/EOS
Week 64
+/- 7 days


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2. Background
Allergic fungal rhinosinusitis (AFRS) is a severe form of eosinophilic nasal polyposis with 
critically inadequate treatment options for the 10% of chronic rhinosinusitis participants affected 
by the disease. Occlusive eosinophilic mucus and severe nasal polyposis presents in early 
adulthood, with an unrelenting course marked by sinus expansion and pressure-induced 
dehiscence of the surrounding orbit and skull base. Despite appropriate therapies with 
oral/topical corticosteroids, saline irrigations and comprehensive sinus surgery, nasal polyps 
aggressively recur, frequently within months of surgery. Medical options beyond topical and 
systemic steroids are limited. Neither antifungal nor allergen immunotherapy are beneficial. Due 
to persistent sinonasal inflammation, patients with AFRS receive an average of three 
corticosteroid bursts per year and revision sinus surgery every 42 months.
Rationale
In addition to the activation of type 2 inflammatory mediators found in other CRSwNP 
phenotypes, AFRS is uniquely characterized by an exaggerated activation of the adaptive 
immune response with serum IgE levels often above 1000 kU/L and defined by an upregulation 
of fungal specific IgE levels [1]. Marked eosinophilic inflammation is found throughout the 
upper airway, and the degree of mucosal eosinophil infiltration has been repeatedly reported as a 
potent predictor of poor surgical outcomes. We therefore hypothesize that dupilumab, a human 
monoclonal antibody that targets the type-2 inflammatory cascade, is a safe and effective 
treatment for nasal polyps as add-on therapy following endoscopic sinus surgery.
AFRS represents an extreme form of type 2 inflammation. In a study of immune profiling in 130 
participants with different CRS subtypes [2], inflamed sinus mucosa from AFRS participants 
demonstrated increased local IgE levels when compared to other subtypes, including CRSwNP. 
While all subtypes demonstrated increased levels of canonical type 2 inflammatory markers, 
only AFRS demonstrated markedly increased IL-4 levels. Other studies have also reproduced 
increased mucosal levels of allergen-specific IgE when compared to other CRS subtypes that 
was not limited to fungal antigens. 
The same authors more recently sought to describe the gene expression variations in AFRS that 
distinguish it from CRSwNP [3]. In a cohort of 86 patients (37 AFRS, 34 CRSwNP, 15 healthy 
controls), AFRS tissue demonstrated nearly 3,000 unique gene expression variations, while 
CRSwNP only demonstrated 30. These unique gene expression variations in AFRS were 
strongly linked with T helper 2 inflammation, co-stimulatory signaling, and T-cell receptor 
signaling. 
Recent Phase III trials with dupilumab have excluded AFRS given the above uniqueness of 
AFRS from other CRSwNP phenotypes and its regional geographic distribution, despite the 
exaggerated levels of type-2 inflammatory mediators such as IL-4 and IL-13. In addition, all 
trials to date have included patients who were at least 6 months removed from a prior sinus 
surgery. However, the efficacy of the combination of sinus surgery followed by dupilumab has 
yet to be evaluated in AFRS and exemplifies an attractive treatment regimen for this highly 
recalcitrant disease. 


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IMP Mechanism of Action 
Dupilumab is a humanized monoclonal antibody that binds to the alpha-subunit of IL4 and IL13 
receptors, two key mediators of type-2 inflammation. This represents the first and only dual 
inhibitor of IL-4 and IL-13. Receptor binding reduces expression of these proinflammatory 
markers, ultimately leading to decreased total and specific IgE, eosinophil activation, and 
trafficking.
3. Study Objectives and Endpoints 
3.1 Primary Objectives 
Co-Primary objectives
Endpoint/variable(s)
Change from baseline at 52 weeks both within 
and between treatment and placebo arms

Determine the efficacy of dupilumab in 
controlling sinonasal inflammation and 
preventing nasal polyp recurrence after 
complete sinus surgery for AFRS

Endoscopic modified Lund-Kennedy 
(mLK) score

Evaluate the effect of dupilumab on 
oral corticosteroid utilization following 
complete sinus surgery for AFRS

Incidence of oral corticosteroid utilization 
per participant
3.2 Secondary Objectives 
Secondary objectives
Endpoint/variable(s)
Change from baseline at 52 weeks both within 
and between treatment and placebo arms
To evaluate the effect of dupilumab on:

Prevention of revision surgery for AFRS

Prevalence of revision sinus surgery for 
recurrent nasal polyps, and comparison of 
survival curves

Secondary objective measures of sinonasal 
inflammation following sinus surgery

Endoscopic nasal polyp score (NPS)

CT generated Lund-MacKay score

Lower airway dysfunction following 
sinus surgery in the subgroup of 
participants with
asthma (~25%)

Spirometry

Upper and lower airway, disease-specific, 
health-related quality of life

22-item sinonasal outcomes test (SNOT-22)

Asthma Control Questionnaire (ACQ)

Reducing utilization of rescue medications 
for acute exacerbations of CRS following 
sinus surgery

Prevalence of oral / topical corticosteroid 
utilization per treatment cohort

Incidence of oral / topical antibiotic 
utilization per subject

Prevalence of oral / topical antibiotic
utilization per treatment cohort
Other secondary objectives
Endpoint/variable(s)
Change from end of treatment (EOT) to end of 


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3.3 Safety Objectives
Safety objective
Endpoint/variable(s)

Assess the safety of dupilumab after sinus 
surgery

Continual reporting of events of special 
interest (ESIs) and serious adverse events 
(SAEs)

Physical examination
3.4 Exploratory Objectives
Exploratory objectives
Endpoint/variable(s)

Generation of novel AFRS biobank to support 
future study of predictive biomarkers 
associated with positive clinical outcomes 
following IMP

Exploratory biomarker parameters:
-
Serum and plasma
-
Whole blood
-
Nasal secretions
-
Nasal polyp biopsies
4. Study Intervention/Investigational Agent 
4.1 Overall Design
This is a multi-center, randomized, double-blinded, placebo-controlled, parallel group study to 
evaluate the efficacy of dupilumab 300mg administered subcutaneously (SC) every 2 weeks 
versus placebo in participants with AFRS following planned sinus surgery.
132 participants will be randomized to receive dupilumab 300mg SC or matching placebo while 
on a background of intranasal corticosteroid sprays twice daily. Patients will be stratified by 
study site and by baseline comorbid asthma status (yes vs no). ~25% of the randomized 
participants will have comorbid asthma.
Eligible participants will enter a screening/run-in period on twice daily nasal saline irrigations 
followed by INCS spray for 2-6 weeks prior to planned sinus surgery. Participants may be 
consented and enrolled at any time during this 2-6 week run-in period, provided the failure of 
appropriate medical therapy has been documented as outlined in the inclusion criteria. Eligible 
participants already on study background therapy for at least two weeks may be consented and 
enrolled during the pre-surgery period. 
Both saline irrigations/INCS and sinus surgery will be completed per standard of care (SoC) and 
not according to the study protocol. Patients who continue to meet eligibility criteria following 
surgery will be randomized 1:1 before Visit 3 (Day 0) when they receive placebo or dupilumab 
300mg SC every 2 weeks. Patients will receive a total of 26 doses of IMP, via either study 
study (EOS)
To evaluate the effect of dupilumab on:

Objective measures of sinonasal 
inflammation following sinus 
surgery

Endoscopic modified Lund-Kennedy 
(mLK) score

Endoscopic nasal polyp score (NPS)

Upper and lower airway, disease-specific, 
health-related quality of life

22-item sinonasal outcomes test (SNOT-22)

Asthma Control Questionnaire (ACQ)


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personnel (Visit 3-6 at W0, 12, 24 and 36) or home-administration (W2, 4, 6, 8, 10, 14, 16, 18, 
20, 22, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50) to maintain a 2-week treatment schedule. 
Patient compliance will be recorded via text messages the day of scheduled home administration, 
as well as monthly phone calls and collection of used syringes during scheduled study visits 
(Visit 4-7 at W12, 24, 36 and 52). An EOT visit will be conducted at Week 52 (Visit 7). Patients 
will then be monitored on daily saline irrigation and INCS spray for 12-weeks to evaluate 
potential disease recurrence after discontinuation of IMP. An EOS visit will be conducted at 
Week 64 (Visit 8).
Participants will return to their respective study site for dosing visits (Visit 3-6), EOT and EOS 
for evaluation of efficacy and safety. Collection of optional blood and nasal secretions for 
exploratory biomarker analysis will be completed at study visits 1, 3, 4, 5, 7 and 8. Nasal polyp 
tissues will be collected at time of surgery (Visit 2).
Sinus surgery will be completed per SoC. Study protocol will determine cohort assignment (use 
of IMP versus placebo) with all other SoC interventions allowed throughout the entire study. 
Physician prescribed SoC medications for the treatment of nasal polyps include INCS sprays and 
nasal saline irrigations. Rescue medications are allowed per the treating physician’s discretion.
Rescue medications (topical/oral corticosteroids, topical/oral antibiotics, or revision sinus 
surgery) will be allowed as deemed clinically necessary for the treatment of an acute 
exacerbation of CRS (AECRS) by the treating physician. See Table 3 for standardized criteria to 
diagnose AECRS [1]. If at any point a subject meets discontinuation criteria, an early 
discontinuation visit will be performed (see Section 8.1- Discontinuation of study treatment).
Table 3: Diagnostic Criteria for AECRS
AECRS may be diagnosed if all of the following are present:
- Duration of symptoms >7 days
- Total SNOT-22 score increased >9 from baseline
- Objective evidence of sinonasal inflammation by nasal endoscopy or CT scan
AECRS; Acute exacerbation of chronic rhinosinusitis
4.2 Scientific Rationale for Study Design
This study is designed to evaluate the safety and efficacy of fixed dose dupilumab (300mg) 
administered SC every 2 weeks, on top of intranasal corticosteroid spray in participants 
undergoing sinus surgery for medically recalcitrant nasal polyps in AFRS. The population is 
composed of participants with ongoing chronic symptoms despite appropriate medical 
management who elect to undergo sinus surgery per SoC. The randomized, placebo- controlled 
design allows for determination of IMP efficacy in preventing recurrence of severe sinonasal 
disease. 
The sample size (n=132) and 52-week treatment duration are appropriate to capture maintenance 
effects while providing 1-year treatment safety data in the intended study population. Following 
completion of the treatment phase, all participants will enter an additional 12-week observation 
period to demonstrate durability of response and provide off-treatment safety data.


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4.3 Justification for Dose
The dupilumab dose and regimen will be consistent with the product insert for the treatment of 
nasal polyps, i.e., 300mg by SC injection every two weeks. No dose adjustment for the AFRS 
nasal polyp endotype is warranted.
4.4 End of Study Definition
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study. A subject is considered to have completed the study when he/she has completed their last 
scheduled visit.
4.5 Treatments administered
4.5.1 Investigational products
Table 4: Investigational study treatments
Treatment 1
Treatment 2
Treatment name:
Dupilumab
Placebo^
Dosage formulation:
150 mg/mL in pre-filled
syringe to deliver 300 mg in 2 
mL
Pre-filled syringe to deliver 
2 mL
Route of administration:
Subcutaneous
Subcutaneous
Dosage regimen:
Every 2 weeks during 
treatment period
Every 2 weeks 
during treatment 
period
Provider:
Sanofi
Sanofi
^ Placebo contains vehicle and other non-pharmacoactive components contained in Dupilumab 
IMP
4.5.2 Non-investigational products
All enrolled participants will receive a background of INCS spray and nasal saline irrigations as 
prescribed by their treating physician per SoC. 
4.5.3 Postoperative care
All participants will undergo the following standardized post-operative care:

Intraoperative packing: hemostatic packing only with either Chitogel, Merogel, Nasopore 
or PosiSepX dressings. No steroid eluting packing will be used.

Saline irrigations 2-3 times per day and once or twice daily INCS spray

Pain medication: at discretion of treating physician

Oral steroids, prednisone 30 mg x 4 days, 20 mg x 4 days, then 10 mg x 4 days and then 
stop
Alterations from the above are allowed at the discretion of the treating physician and will be 
recorded in the study database.
4.6 Preparation/handling/administration/accountability
4.6.1 Preparation and handling
Study drug/placebo will be mailed directly to participants from the study’s central pharmacy 


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(Belmar Pharma Solutions, Lakewood, CO). Batch deliveries will occur at three-month intervals 
and be sent on ice via overnight delivery with temperature monitoring. Injection site and IMP 
preparation will be completed per product insert and SoC. Site investigators or designees must 
confirm appropriate storage conditions for all study treatments. Any discrepancies will be 
reported and resolved prior to treatment administration. Only enrolled participants may receive 
study treatment.
4.6.2 Administration
The IMP will be administered by licensed study staff at randomization (V3, W0) and study visits 
V4-6 (W12, 24, 36). 
Training of subject/caregiver to complete home administration of IMP will be completed after 
randomization (V3, W0). Home administration of IMP will be completed during weeks (2, 4, 6, 8, 
10, 14, 16, 18, 20, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50) to maintain a 2-week treatment 
schedule. Patients will receive a total of 26 doses of IMP. Reminder text messages, as well as 
confirmatory phone calls and used syringe collection will be completed to verify home-
administration. Participants who cannot administer at home can come to the clinic for injections.
4.6.3 Accountability
The Sponsor-Investigator is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).
A study coordinator at each site will verify patient receipt of all study treatments from the central 
pharmacy. Delivery confirmations will be automatically stored in the central study database. 
Additional text reminders, monthly phone calls and collection of IMP will be completed. 
Coordinators will account for all study treatments, and for appropriate destruction or return of 
unused treatments. Certificates of delivery, destruction, and/or return should be signed. 
External study monitoring will be managed by Westat (Rockville, MD). 
Specific monitoring activities include the following:
- On-Site Initiation Visit (2-day visit per site) 
- On-Site Interim Monitoring Visits (3- day visit, twice a year; five visits per site)
- Ad hoc Remote Interim Monitoring Visits
- On-Site Closeout Visit (2-day visit)
4.7 Randomization and blinding 
Randomized participants will be stratified by enrollment site. Randomization will be assigned on 
a 1:1 basis to treatment group (dupilumab 300 mg every 2 weeks) or placebo. The study data team 
will prepare a randomization list based on computer-generated random numbers retrieved using a 
randomization procedure available in statistical packages such as SAS. Block randomization with 
varying block sizes will be employed to ensure that equal numbers of treatment and placebo 
participants occur within strata (site) and are balanced with respect to observed and unmeasured 
baseline factors.
This is a double-blind investigation. Patients, treating physicians and local study personnel will 
not be aware of cohort allocation.


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4.7.1 Unblinding 
The study data team will maintain individual treatment codes for each randomized subject. 
Randomization assignment will only be broken in the setting of a medical emergency, per the 
discretion of the treating physician, where the appropriate management of the subject requires 
knowledge of the treatment cohort. This event will be centrally recorded and monitored.
4.7.2 Treatment compliance
The study treatment provided for this study will be used only as directed in this Protocol. The 
IMP will either be administered at the study site during treatment visits (V3-6) or at home during 
weeks (2, 4, 6, 8, 10, 14, 16, 18, 20, 26, 28, 30, 32, 34, 38, 40, 42, 44, 46, 48, 50) to maintain a 2-
week treatment schedule. Reminder text messages will be sent to all participants the day of a 
home-administration. Home-administration will be confirmed by recording of both confirmatory 
phone calls and used syringe collection.
If a home-administered IMP dose is missed and can be given within 7 days from the planned 
dose date, the IMP should be given. The patient’s original schedule should be resumed. If the 
missed dose is not administered within 7 days, the IMP should not be given. This dose should be 
designated as a missed dose. IMP will then be given at the next date on the original schedule. 
If a treatment visit needs to be rescheduled, the visit must be performed, and the IMP must be 
administered within 7 days of the original visit window. Investigators should make every effort 
to assure that no treatment visits are missed during the course of the study. A subject will be 
discontinued from the study if they miss either two consecutive study visits or IMP doses, or a 
total of three IMP doses throughout the study period. Any change from the dosing schedule will 
be recorded.
Investigators should also assure that participants are compliant and on a stable dose of the 
background INCS spray throughout study period. Any changes to background INCS spray will 
be recorded for subsequent analysis.
4.7.3 Concomitant therapy
All medications, including over the counter and herbal preparations, will be recorded from study 
enrollment until completion. Associated information will be recorded, including: reason for use, 
dosage (amount and frequency) and beginning/ending dates.
4.7.4 Background medication
Patients will be allowed to continue INCS spray prior to surgery. Following surgery all 
participants will undergo standardized postoperative treatment with continued INCS spray. This 
will be completed throughout the EOS visit.
Intranasal corticosteroid compliance will be recorded during study visits and compliance phone 
calls. If a subject cannot tolerate sinonasal irrigations, they should be screen failed prior to 
randomization.


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4.7.5 Rescue therapy 
During study treatment and off treatment follow-up, based on clinical evaluation, in case of 
worsening signs and/or symptoms consistent with an AECRS, the Investigator may consider 
rescue treatment. This typically involves corticosteroids or antibiotics delivered orally or 
topically to the sinonasal mucosa. Rescue therapies are not prescribed in this Protocol but will be 
recorded in the study database. 
Patients receiving rescue treatment other than surgery during the study should continue on study 
drug unless the Investigator decides to withdraw the study treatment. 
4.7.6 Treatment following study conclusion
Following the EOS visit, participants should resume standardized therapies [4] at the discretion 
of their healthcare team and local practice.
4.8 Pharmacy
Belmar Pharma Solutions (Lakewood, CO) will maintain and dispense study drug. Samantha 
Lebsock, PharmD will be the lead pharmacist for this study. Once participants are randomized 
the pharmacy will be notified via REDCap. Study drug will be mailed directly to the subject in 
three-month intervals (Visits 3-6) during the course of the study and be sent on ice via overnight 
delivery with continuous temperature monitoring. The patient will bring their first dose with 
them to the clinic during Visit 3.
5. Procedures Involved
5.1 Nasal endoscopy
All study participants will undergo diagnostic nasal endoscopies at each study visit, per SoC, to 
monitor treatment outcomes[1]. Unique to this Protocol, a digital recording of the nasal 
endoscopy will be collected and stored centrally on a study approved repository. This will be 
completed in accordance with appropriate care for the management of CRSwNP.
5.2 Study Measures
The study design and endpoints will answer important clinical questions about the efficacy of 
dupilumab on mucosal inflammation and symptoms and effect on the number of rescue 
medications per subject after sinus surgery. Examining the effect of dupilumab after 
comprehensive sinus surgery for AFRS with clinically relevant endpoints addresses a clinical 
treatment pathway that has yet to be formally explored.
5.2.1 Objective measures of disease
Modified Lund-Kennedy Endoscopic Score: 
Modified Lund-Kennedy score (mLK) is a validated measure of sinonasal inflammation, as 
evaluated by means of nasal endoscopy. The composite score ranges from 0 to 12, with 
increasing score representing worsening inflammation among three separate findings (Nasal 
polyps, Discharge, Edema). Each finding is rated from 0 (absent) to 2 (severe). A ≥ 2-point 
increase from baseline total postoperative score represents clinically significant worsening of 
sinonasal inflammation[5]. The treating physician will complete the nasal endoscopy per SoC, 


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with automated recording on local storage drives . Following completion of the patient 
encounter, study personnel will transfer this recording to the study database for central review 
and scoring. A blinded reader will review all nasal endoscopies to determine the mLK score.
Lund-MacKay Radiologic Score:
The change in radiographic opacification between baseline and EOT will be analyzed by the 
Lund- MacKay radiologic score (LM) [6]. The LM Radiologic scoring system assigns a value of 
0, 1, or 2 to each of the following sinuses: maxillary, anterior ethmoid, posterior ethmoid, 
frontal, and sphenoid. Score assignments are 0 if the sinus is totally patent, 1 if the sinus is 
partially opacified, and 2 if the sinus is completely opacified. The osteomeatal complex is scored 
either 0 if not occluded or 2 if occluded. The maximum score for each side is thus 12, with a total 
score determined out of 24. Baseline LM scores will be assessed from baseline preoperative CT 
scan. Preoperative and EOT CT scans will be transferred to the study database by trained 
personnel, where the blinded reader may determine the associated LM score.
Endoscopic Nasal Polyp Score:
Endoscopic nasal polyp score is determined by the treating Investigator. Unlike prior study of 
dupilumab in nasal polyps, [7] we will separately record the Nasal Polyp Score for each side, 
with a maximum unilateral score of 4. This is appropriate for monitoring efficacy in AFRS, as a 
subgroup of participants may present with unilateral disease. This will be considered in statistical 
analysis and reporting of results (see Section 14.6- Primary Analysis).
Table 5: Endoscopic Nasal Polyp Score
Polyp Score
Polyp Size
0
No polyps
1
Small polyps in the middle meatus not reaching below the inferior border of 
the middle turbinate
2
Polyps reaching below the lower border of the middle turbinate
3
Large polyps reaching the lower border of the inferior turbinate or large 
polyps of score 2 with additional large polyps medial to the middle turbinate
4
Large polyps causing complete or near-complete obstruction of the inferior 
nasal cavity i.e. touching the floor of the nose
Spirometry:
Pulmonary function testing is performed according to the standardized methods of the lung 
function tests of the American Thoracic Society and European Respiratory Society. (Miller et al. 
2005). The following parameters are measured or calculated: percent predicted vital capacity 
(%VC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), percent 
predicted FEV1 (%FEV1) and FEV1/FVC ratio.
5.3 Patient Reported Outcome Measures
22-item Sino-nasal Outcome Test (SNOT-22): 
The SNOT-22 score is a validated disease-specific questionnaire quantifying quality-of-life 
among participants with chronic rhinosinusitis. The individual question scores range from 0 (no 
problem) to 4 (as bad as can be) among 22 individual questions. The threshold value for minimal 
clinically significant change is ≥ 8.90 [8]. 


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Asthma Control Questionnaire (ACQ)  (only for participants with asthma):
The Asthma Control Questionnaire (ACQ) is a validated, self-administered survey used to assess 
a participants’ perception of disease control over the preceding week using Likert scale 
responses (range: 0 - 6) [9]. The ACQ consists of 7 items surveying the frequency of asthma 
related symptoms, the need for rescue medications, and perceived control of disease. The items 
are equally weighted and the ACQ score is the mean of the 7 items and therefore between 0 (well 
controlled) and 6 (extremely poorly controlled)[9]. Score change of 0.5 on the 7-point scale has 
previously been defined as the Minimal Important Difference (MID).  
6. Data Specimen Collection and Banking
There is no routine laboratory monitoring planned. If laboratory monitoring is needed to provide 
standard of care for participants, this will be performed and monitored. Whole blood will be 
collected for research purposes for metabolomic profiling and for preparation of serum and 
plasma samples for analysis of proteins and inflammatory markers. Nasal secretions will be 
collected for analysis of inflammatory markers at specified study visits. Blood samples and nasal 
secretions will be collected prior to IMP dosage (V1,3-5,7-8). Additionally, nasal polyps will be 
collected from all participants, concurrent with their sinus surgery and per SoC. Samples will be 
processed, frozen, and shipped to the central study repository (Mike Koval Laboratory; Emory 
University, 615 Michael St., Suite 235, Atlanta GA 30322).
The subject’s consent to the collection and storage of biologic samples is optional. Samples will 
be collected for future, exploratory analysis to query the effect of dupilumab on biomarkers of 
upper and lower airway inflammation, NP recurrence and predictors of therapeutic response.
7. Inclusion and Exclusion Criteria
Each subject must meet all inclusion and none of the exclusion criteria for the study in order to 
be consented into the study; ie. enrolled. Further, each subject must continue to meet all 
inclusion and none of the exclusion criteria for the study post SoC surgery in order to be 
randomized to a study intervention. Participants who do not meet I/E requirements prior to 
randomization are screen failures (see section 9.3- Screen failures)
In this protocol, “enrolled” participants are defined as those signing informed consent. 
“Randomized” participants are defined as those undergoing randomization and receiving IMP.
7.1 Inclusion Criteria
Patients are eligible for study participation if all inclusion and no exclusion criteria are met. Non-
English-speaking people will be included if they fulfill the criteria.
7.1.1 Informed consent
1. Patients must be capable of giving signed informed consent as listed in the informed 
consent form (ICF) and this protocol. 
2. ICF must be signed and dated prior to study specific procedures. Informed consent 
process is described in Appendix A3. 
7.1.2 Age
3. Patients must be aged >18 years at the time of signing the ICF.


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7.1.3 Types of subject and disease characteristics
4. Patients with nasal polyps in the setting of suspected AFRS and electing to undergo 
comprehensive sinus surgery per established criteria. [1, 4] 
•
Diagnosis of nasal polyps by consensus criteria.
•
Failure of appropriate medical therapy, including topical intranasal corticosteroid 
(spray or irrigation) > 8 weeks duration, systemic corticosteroid trial of 1-3 
weeks duration and nasal saline irrigation of > 4 weeks duration.
•
A minimum SNOT-22 score of 20 at time of enrollment.
•
A minimum CT Lund-MacKay score of > 1 at time of enrollment.
5. Suspected AFRS based on Bent and Kuhn criteria [10]
•
Patients must meet 3/5 criteria at time of enrollment
- Environmental atopy by skin or serum testing
- Nasal polyposis
- Characteristic CT findings
- Eosinophilic mucous
- Fungal identification on histopathology
•
Patients must meet 5/5 criteria at time of randomization
Enrolled participants are expected to undergo SoC allergy testing and sinus surgery prior to 
randomization. This will complete evaluation for suspected AFRS, thus enabling further study 
participation. 
7.1.4 Sinus Surgery
6. All study participants will have met criteria for sinus surgery and undergo a 
comprehensive surgery prior to randomization. The surgery will not be assigned and 
will be completed per SoC for the management of nasal polyps in suspected AFRS. 
[4]
7.1.5 Reproduction
7. Negative urine pregnancy test will be required at enrollment and study visits 3-8 
throughout treatment period for female participants of childbearing potential (i.e., 
post-pubescent, premenopausal females). 
8. Women of childbearing potential must use an effective form of birth control 
(confirmed by the Investigator) e.g., total sexual abstinence, vasectomized sexual 
partner, tubal occlusion, intrauterine device or levonorgestrel Intrauterine system, 
Depo-Provera injections, oral contraceptive, Evra Patch, or Nuvaring. Women of 
childbearing potential must agree to use a highly effective method of birth control, as 
defined above, from enrollment, throughout the study duration and for 12 weeks after 
the last dose of IMP.
9. To protect against possible side effects, men should not get a sexual partner pregnant 
while taking the study drug and for 13 weeks after the last dose.  Men should agree 
on a method of birth control to use throughout the study. 


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7.2 Exclusion criteria
7.2.1 Medical conditions
1. Patients who have undergone nasal or sinus surgery within 3 months prior to 
enrollment. 
2. Patients with conditions or comorbid disease findings that exclude nasal endoscopy 
for evaluation of primary outcome, such as:
•
Current rhinitis medicamentosa
•
Nasal cavity tumors
•
Occlusive septal deviation following surgery
3. Clinically important comorbidities that may confound interpretation of clinical 
efficacy, including:
•
Aspirin-exacerbated respiratory disease
•
Cystic fibrosis
•
Primary ciliary dyskinesia
•
Hereditary Hemorrhagic Telangiectasia
•
Antrochoanal polyposis
•
Non-asthma eosinophilic disease, such as bronchopulmonary aspergillosis, 
eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome
•
Granulomatosis with polyangiitis
•
Any corticosteroid dependent condition
4. A comorbid health disorder that is not medically controlled in the opinion of the 
Investigator, and has the potential to:
•
Affect the safety of the subject throughout the study
•
Impede the subject’s ability to complete the duration of the study
•
Influence the primary or secondary outcomes of the study
5. Patient experiencing a symptomatic asthma exacerbation requiring systemic 
corticosteroids or hospitalization (>24 hours) within 4 weeks of randomization.
6. Infection requiring systemic antibiotics within 4 weeks of randomization.
•
Parenteral and/or oral antibiotics associated with surgery are allowed (see Section 
4.5.3-Postoperative care)
7. Medical contraindication to receiving dupilumab:
•
Know hypersensitivity to dupilumab or any of its excipients
•
Live vaccine administration within 30 days of randomization or during study 
period
•
Known helminth infection
8. Unable to tolerate sinonasal irrigations.
9. Pregnancy, current lactation, or lack of effective contraception plan, as determined 
by the site investigator.
7.2.2 Prior/concomitant therapy
10. Initiation of allergen immunotherapy within 3 months prior to randomization or a 
plan to begin therapy or change its dose during the study period.
11. Immunosuppressive medication within 3 months prior to randomization and during 
the study period from randomization through EOS.
12. Receipt of any marketed or investigational biologic products (monoclonal or 


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polyclonal antibody) within 6 months or 5 half-lives, whichever is longer, prior to 
randomization during the study period.
13. Previous use of dupilumab.
14. Receipt of immunoglobulin or blood products within 30 days prior to randomization.
15. Receipt of any investigational drug within 30 days or 5 half-lives, whichever is 
longer prior to randomization.
16. Scheduled systemic corticosteroid treatment during the study period:
•
Standardized corticosteroid taper associated with planned surgery is allowed (see Section 
4.5.3-Postoperative care.)
17. Receipt of leukotriene antagonists or modifiers for participants who were not on a 
stable dose for > 30 days prior to randomization.
7.2.3 Prior/concurrent clinical study experience
18. Concurrent enrollment in another investigational drug trial during the study period.
7.2.4 Other exclusions
19. Patient involvement in the planning or conduct of the study.
20. Investigator assessment that the subject is unlikely to comply with study procedures.
21. Prior randomization in the present study.
22. Unable to undergo sinus surgery due to comorbid medical condition.
7.3 Screen Failures
Defined as participants appearing to qualify for study participation, sign the ICF, but ultimately 
do not meet randomization criteria. Reporting of screen failure information is required to ensure 
transparent reporting. Minimal information includes subject demographics, screen failure details 
and eligibility criteria.
Re-screening is allowed once for each subject.
Re-screening is allowed prior to surgery for transient reasons (including operating room 
availability or unforeseen personal events) that result in delayed randomization.
For participants who require oral corticosteroids and/or antibiotics for an asthma exacerbation or 
an acute exacerbation of CRS during the run-in period (prior to surgery), the run-in period may 
be extended for up to 6 weeks beyond the initially planned 6 weeks, provided the treatment 
duration with corticosteroids and/or antibiotics is ≤ 14 days. If the duration of treatment is >14 
days, participants should be screen failed but can be considered for re- screening. 
Re-screened participants should re-sign ICF. All procedures from the screening period should be 
repeated. Re-screening should be documented so that its effect on study results may be assessed.
8. Local Number of Participants 
The study will be completed at 3 North American sites. A total of 132 participants will be 
randomized. While we intend to enroll equal numbers of participants from each site (44 
participants at each), variability in available participants may require an unequal distribution of 
participants to support target enrollment within the study period.


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9. Recruitment Methods
All three sites taking place in this research study will recruit participants who are undergoing 
elective endoscopic sinus surgery for the treatment of AFRS. The participants will be identified 
from the clinics of the site Investigators and their colleagues during the subject’s pre-operative 
consultation.
10. Withdrawal of Participants
10.1 Discontinuation of study treatment
Participants may be discontinued from study treatment under the following circumstances:
•
Subject decision. Participants may discontinue treatment at any time
•
AE that, in the opinion of the Investigator, contraindicates continuation.
•
Pregnancy
•
IMP unblinding
•
Development of any study specific criteria for discontinuation:
-
Anaphylactic reaction to the IMP requiring epinephrine
-
Helminth parasitic infestations requiring hospitalization
-
If 2 consecutive study visits or 2 doses of IMP are missed during the course of the 
study
All participants who discontinue treatment should remain enrolled and complete their 
discontinuation visit within 8 weeks of last IMP. At that visit, although no longer receiving IMP, 
participants should be encouraged to complete all subsequent study visits and procedures. Data 
collection should continue according to the study protocol.
10.2 Lost to follow-up
A subject is considered lost to follow-up if they fail to return for scheduled study visits and are 
unable to be reached by study staff. This includes 3 attempts of either phone calls or emails; 
having sent 1 certified letter; or 1 unsuccessful effort to check the vital status of the subject using 
publicly available sources.
10.3 Study Withdrawal
Patients may withdraw study consent at any time without prejudice to further treatment. They 
may request destruction of collected samples, which will be completed and documented in study 
records.
11. Risk to Participants
Dupilumab is an add-on maintenance treatment in adult participants with uncontrolled CRSwNP. 
The most common adverse reactions that took place in 2 randomized, placebo-controlled, 
multicenter trials were injection site reactions, eosinophilia, insomnia, toothache, gastritis, 
arthralgia, and conjunctivitis.
12. Potential Benefits to Participants
There are no direct benefits for participating in this study. 
13. Compensation to Participants


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Participants will be reimbursed a subject stipend for participating in the research study to help 
with the cost of expenses/travel for the research visit and to compensate for their time and effort. 
Participants will receive a stipend of $50 after completing the following visits: V1, V3, V4, V5, 
V6, V7, and V8. They will also receive $25 for each visit of dupilumab/placebo injection. If they 
complete all study visits, they will get a total of $1000. The payment will be processed when 
participants come in person and will include that clinic visit' payment and injections payments 
since the last clinic visit.  Each site will decide how participant stipends will be given to the 
subject. 
14. Data Management and Confidentiality
The site-Investigator will ensure that all data are recorded appropriately and consistent with good 
clinical and research practice.
14.1 Sample Size and Power analysis
A sample size of 66 participants per group achieves 90% power to detect a mean difference of 2 
points on the modified Lund-Kennedy Endoscopic score at 52 weeks with a standard deviation of 
3.5 and significance level of 0.05 using a two-tailed test. The clinically meaningful mean 
difference of 2 points and the standard deviation are based on previous study of mLK in a 
heterogeneous population with nasal polyps [5].
14.2 Database Set-up and Management 
The REDCap (Research Electronic Data Capture, Nashville, TN) system will be used as a central 
resource for data processing and management. REDCap is an open-source software program 
supported through a consortium led by Vanderbilt University. REDCap is a metadata driven 
electronic data capture system available for investigators to use for form-based data collection. 
The system is supported by Emory Library and Information Technologies Services (LITS) and 
hosted on a LITS virtual machine (VM) environment with nightly backup and full redundancy 
for high application availability and reliability.
REDCap is a web-based system with the Apache/PHP web server located in the DMZ and the 
MySQL database backend hosted in a HIPAA- and FDA 21 CFR Part 11-compliant secure data 
zone. Access to the system requires an Emory University or Emory Healthcare user account with 
external users (e.g. University of Texas Health Science Center at Houston and NIH) supported 
using Emory University sponsored accounts. REDCap provides an intuitive interface for data 
entry with data validation, audit trails for tracking data manipulation and export procedures, 
automated export procedures for seamless data downloads to common statistical packages, 
including SAS, and procedures for importing data from external sources. A dedicated database 
developer will create a study-specific application for data collection.
All data management standards will reflect the goal of reproducible research. To reduce data 
entry errors and omissions, we will take advantage of REDCap’s built-in quality control 
functions such as branching logic, range and data-type limits, pop-up messages, and prompted 
data entry. Data integrity is aided by the system’s automated logging of all input and edits. 
Datasets will be clearly identified according to a pre-specified naming system that includes 
download date. SAS or other programs will be well-commented and be checked for errors by a 
second programmer or statistician. For quality control and assurance, we will periodically 


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complete reports on data stored in REDCap. This entails export to our local secure drive, imports 
as SAS datasets, and production of multiple types of output for data management and reporting. 
Reports, overall and site-specific, will be provided for data management (e.g., flagging of 
questionable or missing data and missing forms, variable description, flagging of overdue visits) 
and for investigators (e.g., screening and enrollment, follow-up tracking, exits).
Microsoft OneDrive will be used as a central repository to store all nasal endoscopy and CT files 
collected during the course of the study. This HIPPA compliant database will provide access for 
our central reader while maintaining a backup of study files should additional review be 
required. All data will be stored with study identification numbers.
14.3 Clinic site data management
Trained study staff will enter data directly to the REDCap application. We will enable auto-
validation (via range and data checks) and use skip logic to facilitate data entry and ensure 
adequate quality.
Data entry personnel will receive standardized training. The study’s statistician will examine the 
distribution of the data for purposes of maintaining integrity of the data. Quality control metrics 
such as timeliness and completeness of data entry will be reported.
14.4 Randomization
After eligibility is established and consent is obtained, the participants will be randomized on a 
1:1 basis to treatment (dupilumab 300 mg every 2 weeks) or placebo. The study biostatistician 
will prepare a randomization list based on computer-generated random numbers retrieved using a 
randomization procedure available in statistical packages such as SAS. Block randomization 
with varying block sizes will be employed to ensure that equal numbers of treatment and placebo 
participants occur within strata (site) and are balanced with respect to observed and unmeasured 
baseline factors.
14.5 Statistical Approach
All data will first be assessed by the data management staff, under direction of the lead 
biostatistician, for missing data and out-of-range values with basic statistical procedures such as 
univariate statistics (means, standard deviations, ranges, frequencies, proportions, percentiles) 
and graphs such as histograms, box and whisker plots, scatter plots and Q-Q plots. In addition, 
plots may be produced of individual and average trajectories of all repeated measures over time 
according to assigned treatment. All questions of data quality and integrity will be investigated 
before any statistical modeling, as complete and accurate data are essential for unbiased 
estimates and confidence intervals.
Baseline and demographic characteristics will be summarized overall for all participants and 
when applicable, by treatment group. Univariate summary statistics will be provided for 
continuous variables and frequencies for categorical variables. Graphical methods mentioned 
above will be used to examine distributions and identify potential influential points. Data 
transformations for variables may be considered. The balance of baseline measures across the 
two treatment groups will be compared using appropriate 2-sample tests, including Wilcoxon 
rank-sum and t-tests, and Fisher's exact and Pearson Chi-square tests. All analyses will be 


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conducted using SAS version 9.1 for Windows (SAS Institute, Inc., Cary, NC). All analyses will 
be two-tailed with significance level of 0.05 and conducted using the intention-to-treat principle.
14.6 Primary Analysis
To examine changes in the co-primary outcomes, the modified Lund-Kennedy score and the 
incidence of oral corticosteroid utilization per participant, a mixed effects longitudinal model 
will be fit that includes group (dupilumab, placebo) as a between participants factor and time 
(randomization through post-treatment period) as a categorical within participants factor plus 
their interaction term. Time is treated as categorical so that we can use the group-time 
interactions with the time main effect to estimate and test intent-to-treat (ITT) group differences 
at each time point, with 52 weeks as our primary ITT test. As randomization is stratified by site, 
site will also be included in the model. This mixed effects model allows incorporation of a 
random intercept term for each subject, different numbers of measurements (in case a visit is 
skipped), and the choice of appropriate variance-covariance structure. The mixed model will also 
permit identification of any significant changes in the post-treatment period from 52 to 64 weeks. 
This primary mixed model will incorporate all subject’s randomized. 
The primary objective will be assessed by testing this null hypothesis: treatment with Dupilumab 
post-surgery is equivalent to treatment with placebo post-surgery at 52-week end of treatment. 
The additional time point at 64 weeks is included in the model to ensure efficient evaluation of 
both co-primary outcomes at the EOT and 12 weeks after EOT. Significant changes between 
weeks 52 and 64 will be examined by linear contrast. We will test the following null hypotheses 
against two-sided alternatives: 
-
H01: there is a lack of difference between the changes in mLK from baseline to 52 
weeks and from baseline to 64 weeks for the untreated.
-
H02: there is a lack of difference between the changes in mLK from baseline to 52 
weeks and from baseline to 64 weeks for the treated.
-
H03: the treatment effect dissipates between 52 and 64 weeks.
The primary estimand for the primary endpoint is the composite/treatment policy strategy.
The intercurrent events will be handled as follows:
•
Undergoing sinus surgery for AFRS: data after surgery will be assigned the worst 
possible score (composite strategy)
•
Taking SCS or other rescue medications: data collected after use will be used in the 
analysis (treatment policy strategy)
•
Discontinuing treatment: all data collected after discontinuation will be used in the 
analysis (treatment policy strategy)
We will examine the treatment effect in the subgroup of patients with unilateral disease by 
recording patients’ time until next sinus surgery. We will investigate differences in this subgroup 
by examining the Kaplan-Meier curves and utilizing the log rank test of the difference between 
treated and non-treated. If there is a difference between survival times, we will use the Cox 
proportional hazard model to account for other relevant covariates such as disease severity.  
The Bonferroni correction will be used to account for multiple testing and ensure Type-I error 
rate remains nominal.


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14.7 Secondary and Exploratory analyses
In a secondary analysis, a similar mixed model as described above will be fit that includes the 
subset of participants who are receiving treatment (dupilumab or placebo) for both nostrils. This 
model will incorporate nesting factors to identify repeated measures by subject and by nostril.
In an exploratory analysis, we will also compare the proportion of participants whose modified 
Lund- Kennedy score improved by greater than or equal to 2 units. For participants who undergo 
sinus surgery for AFRS prior to Week 52, non-responder imputation will be used. We will utilize 
a Chi-square or Fisher’s exact test to examine if this proportion is significantly different by 
treatment group (dupilumab or placebo) at 52 weeks.
For the continuous secondary outcomes (e.g. SNOT-22 score, NPS, FEV1), a mixed effects 
longitudinal model will be fit that includes group (dupilumab, placebo), time (randomization 
through post-treatment period), and their interaction term in a similar fashioned as described for 
the primary outcome modified Lund-Kennedy score. For the secondary outcomes that compare 
the number of participants requiring rescue treatment and the number of adverse events (safety) 
over 52 weeks, similar mixed effects models will be fit but with consideration of a Poisson 
distribution (as opposed to normal distribution). The mixed effects models for both primary and 
secondary outcomes will permit the inclusion of any significant potential confounders.
14.8 Missing data handling
Analyses will be conducted using a multiple imputation (MI) procedure. The imputed items are 
obtained from combining two components, a random component based on a normal distribution 
using the mean and standard deviation from the non-missing items from the variable being 
imputed, and a predicted component based on a multivariable regression model consisting of a 
set of variables with no missing data and the non-missing items from the variable being imputed. 
Multiple imputation does not attempt to estimate each missing value through simulated values 
but rather to represent a random sample of the missing values. This process results in valid 
statistical inferences that properly reflect the uncertainty due to missing values.
14.9 Interim analyses
No interim analysis is planned for this study.
14.10 Expected Results 
We expect to detect a significant protective effect of dupilumab on the postoperative control of 
sinonasal inflammation among participants with AFRS. This will be detected as a significant 
worsening of postoperative endoscopic mLK score and more frequent occurrences of needed 
rescue medications among the placebo group. We also anticipate a more conspicuous response to 
IL-4/13 blockade parallel with decreasing levels of Type 2 cytokines and eosinophil activation 
markers. While this study is not designed to detect a significant difference in secondary outcome 
measures, the collected data will nonetheless complement our exploratory studies seeking to 
define predictive biomarkers and mechanisms of treatment response.
14.11 Safety evaluation plan


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Safety outcomes will include the occurrence of any adverse events of special interest (AESI) as 
described in section 15.3.3. Cumulative incidence of AESIs will be used to evaluate safety.  We 
will compare treatment groups using the risk difference and a 95% confidence interval for that 
difference at each of the five follow up time points in the study.
15. Provisions to Monitor the Data to Ensure the Safety of Participants
15.1 Obligations of Sponsor-Investigator
A sponsor-investigator assumes all sponsor responsibilities required by the FDA of the sponsor 
and the investigator, including those related to record keeping and prompt reporting of safety 
reports to the FDA. The responsibilities include:
•
Selection of research staff qualified by training and experience
•
Commitment to personally conduct or supervise the investigation according to the 
research plan
•
Selection of study monitor(s) qualified to monitor the progress of the project
•
Maintenance of accurate, complete, and current records, including correspondence with 
the FDA, monitor and IRB, records on shipment and disposition of drug and records of 
participants’ case histories and exposure to the device
•
Completion of regulatory filings, including amendments (supplemental applications)
•
Timely submission of Final Report within 30 days of completion of investigation
15.2 Definitions 
15.2.1 Adverse Event
An AE is any untoward medical occurrence in a subject administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. An AE also includes any worsening (ie, any clinically significant change in frequency 
and/or intensity) of a pre-existing condition that is temporally associated with the use of the 
study drug. Routine laboratory monitoring is not a component of this study. If laboratory 
abnormalities are noted on laboratory testing obtained for other reasons or for work-up of an AE, 
these should be reported.
15.2.2 Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:
•
Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (e.g., a car accident in which a subject is a passenger).
•
Is life-threatening – in the view of the investigator, the subject is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a more 
severe form, might have caused death.
•
Requires in-patient hospitalization or prolongation of existing hospitalization. In-patient 
hospitalization is defined as admission to a hospital or an emergency room for longer 
than 24 hours. Prolongation of existing hospitalization is defined as a hospital stay that is 
longer than was originally anticipated for the event or is prolonged due to the 
development of a new AE as determined by the investigator or treating physician.
•
Results in persistent or significant disability/incapacity (substantial disruption of one’s 
ability to conduct normal life functions).
•
Is a congenital anomaly/birth defect


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•
Is an important medical event - Important medical events may not be immediately life- 
threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the other serious outcomes listed above (e.g., 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse).
15.3 Recording and Reporting Adverse Events
See Section 10.1- Discontinuation of study treatment for safety criteria resulting in study 
discontinuation.
Recording and reporting will be performed from the time the informed consent is signed until the 
EOS. The Participants or their legally authorized representative will report adverse events to the 
investigator or trained members of the study team. 
The investigator is responsible for detecting, evaluating, recording, and evaluating all events that 
meet the definition of AEs and SAEs, by following the following steps:
-
Review all documentation related to the event, including symptoms, clinic 
progress notes, laboratory reports, and diagnostic reports,
-
Attempt to establish a diagnosis of the event and document as the AE /SAE
-
Record the AE/SAE on the CRF
-
Report to the sponsor
The investigator will also be reporting and following up with the events related to the study 
intervention or that caused the participant to discontinue the intervention.
The follow-up consists of further tests and examinations (laboratory, histopathological, 
consultation with other healthcare professionals) to demonstrate the nature and/or causality of the 
AE/SAE.
15.3.1 Adverse events
The site-Investigator (or designee) will transcribe the information in the CRF and enter in 
REDCap. The source documents will be kept with patients' records and be available for further 
review upon request.
15.3.2 Serious Adverse Events
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
Sponsor-Investigator within 24 hours. The S-I will be notified electronically through REDCap 
and/or email.
Information not available at the time of the initial report must be documented in a follow-up 
report. Substantiating data such as relevant hospital or medical records and diagnostic test reports 
may also be requested.
15.3.3 Other Events that Require Accelerated Reporting
The following events are considered Adverse Event of Special Interest (AESI) and require 
reporting to the sponsor (or designee) within 24 hours of learning of the event:


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•
Anaphylactic reactions
•
Systemic hypersensitivity reactions
•
Helminthic infections
•
Any severe type of conjunctivitis or blepharitis 
•
Keratitis
•
Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms)
•
Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in the study with IMP;
-
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial will be qualified as an SAE 
only if it fulfills one of the seriousness criteria.
-
In the event of pregnancy in a female participant, IMP should be discontinued.
-
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined.
-
Abnormal pregnancy outcomes (e.g., 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 or other medication (NIMP)
-
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the intended dose during an interval of less than 7 days. The circumstances (ie, 
accidental or intentional) should be clearly specified in the verbatim and symptoms, if 
any, entered on the AE forms.
-
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the maximum prescribed daily dose, within the intended therapeutic interval. The 
circumstances (ie, accidental or intentional) should be clearly specified.
Per FDA regulation 312.32, written IND safety reports will be submitted to the FDA by the IND 
sponsor, for serious, unexpected suspected adverse reactions within 15 calendar days of the 
sponsor determining that the event qualifies for reporting. If the event is fatal or is deemed to be 
life threatening, the report will be made within 7 calendar days of receipt of such information.  
The IND sponsor will also make an assessment of whether the event constitutes an unanticipated 
problem posing risks to participants or others (UP). This assessment will be provided to the 
Emory University IRB, which, in turn will make a final determination. If the Emory IRB 
determines an event is a UP it will notify the appropriate regulatory agencies and institutional 
officials.
15.4 Evaluation of Severity and Causality
15.4.1 Evaluation of Severity 
The severity of AEs will be graded according to the Common Terminology Criteria for Adverse 
Events version 5.0 (CTCAE). Available: 


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nce_5x7.pdf
For adverse events not included in the standardized toxicity grading scale, the following scale 
will be used:
•
Mild: Awareness of sign or symptom but is tolerated. Does not interfere in a significant 
manner with the subject’s normal functioning level. It may be an annoyance.  
Prescription drugs are not ordinarily needed for relief of symptoms but may be given 
because of personality of the subject.
•
Moderate: Discomfort that causes interference with normal activities. Produces some 
impairment of functioning but is not hazardous to health. It is uncomfortable or an 
embarrassment. Treatment for symptom may be needed.
•
Severe: Incapacitating, with inability to perform normal activities. Produces significant 
impairment of functioning and is a definite hazard to the subject’s health. Treatment for 
symptom may be given and/or subject hospitalized.
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
An event is “serious” if it meets one of the definitions described in section 15.2.2 (SAE), NOT 
when assessed as severe.
15.4.2 Injection Site Reactions
The severity of injection site reactions will be graded according to the following scale (semi-
colon indicates “or” within description of grade:
•
Mild: Pain that does not interfere with activity; mild discomfort to touch; <5 cm of 
erythema or induration that does not interfere with activity
•
Moderate: Pain that requires repeated use of non-narcotic pain reliever >24 hours or 
interferes with activity; discomfort with movement; 5.1 cm to 10 cm erythema or 
induration or induration that interferes with activity
•
Severe: Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; 
requires ER visit or hospitalization; necrosis or exfoliative dermatitis.
15.4.3 Evaluation of Causality
Relationship of Adverse Events to Study Drug:
The relationship of AEs/SAEs to study drug will be assessed by the masked investigator and will 
be a clinical decision based on all available information. The following question will be 
addressed:
Is there a reasonable possibility that the AE/SAE may have been caused by the study drug? The 
possible answers are:
•
Not Related: There is no reasonable possibility that the event may have been caused by 
the study drug


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•
Related: There is a reasonable possibility that the event may have been caused by the 
study drug
A list of factors to consider when assessing the relationship of AEs to study drug is provided in 
Appendix B. The investigator should consult the Investigational Brochure, which lists the 
possible adverse events.
The investigator should justify the causality assessment of each SAE.
15.5 Safety Monitoring 
The site investigator will monitor the safety of study subject at his/her site(s) as per the 
requirements of this protocol and consistent with current Good Clinical Practice (GCP). The 
sponsor-investigator will monitor the safety data from across all study sites. Safety monitoring 
will be performed on an ongoing basis (e.g., individual review of SAEs) and on a biannual 
cumulative aggregate basis by the DSMB.
15.6 External Study Monitor
Westat (Rockville, MD) will serve as the independent study monitor. All on-site monitoring 
visits are expected to require a maximum of 3 days and will be conducted according to Westat’s 
standard operating procedures (SOPs). The site monitor will perform 100 percent informed 
consent review, 100 percent review of eligibility and SAE documentation, 30 percent overall 
source data verification, and 100 percent source data verification for queries. 


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15.7 Monitoring Table 2
DSMP Requirement
How this Requirement is Met 
Frequency
Responsible 
Party(ies)
Site Monitoring at pre-
determined intervals: The 
Principal Investigator has 
a responsibility to ensure 
that the study is 
following all aspects of 
the protocol. 
There should be a standard 
operating procedure to review 
data (whether a sample or 
100%) at pre-determined 
intervals to ensure that there is 
adequate documentation of 
critical elements such as 
eligibility criteria. Monitoring is 
required at the following 
timepoints (but may be done 
more frequently):

study initiation  

at least every six months 
while participants are 
receiving intervention 
and 

annually while 
participants are in 
follow-up
At a minimum, a 
review is required 
annually when no 
one has been 
enrolled or the 
study is in long 
term follow up. 
Additional interim 
monitoring at least 
once every 12-24 
weeks based on the 
site activity, and 
more as needed, to 
include the 
possibility of 
remote monitoring. 
Delegate a responsible 
party for each 
requirement below*. 
Self-assessment is 
NOT acceptable. An 
experienced, 
knowledgeable person 
who is independent of 
the study team should 
serve as monitor. A 
Contract Research 
Organization (CRO) 
may be used. Consult 
the IRB Office 
regarding acceptable 
qualifications for the 
independent monitor, 
if not using an outside 
expert such as a CRO.
Real-time review of 
participant data during 
initial data collection.
Follow the Quality management 
Plan and the Manual of 
Operating Procedures 
Expectation is that 
this happens every 
time you obtain 
information.
Everyone on the study 
team responsible for 
primary data 
collection.
100% review of 
regulatory files
Based on the site monitoring 
plan developed by Westat
Reviewed at a 
minimum of first 
and close-out visits
Westat 
100% review of consent 
forms
Based on the site monitoring 
plan developed by Westat
Biannually
Westat
Review of credentials, 
training records, the 
delegation of 
responsibility logs (if 
applicable)
Included in the regulatory 
startup package from Westat
Biannually
Westat
Comparison of case 
report forms (CRF) to 
source documentation for 
accuracy and completion
Included in the Manual of 
Operating Procedures
Biannually
Westat
Review of documentation 
of all adverse events
Monitoring plan and startup 
package
Biannually
Westat
Monitoring of critical 
Monitoring plan
Biannually
Westat


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data points (eligibility, 
study endpoints, etc.)
Laboratory review of 
processing and storage of 
specimens
Monitoring plan
Reviewed at first 
and close-out visits 
and at least 
biannually
Westat
Assessment of laboratory 
specimens stored locally
Monitoring plan and startup 
package
Biannually
Westat
Test article accountability 
review
Monitoring plan and startup 
package
Reviewed at first 
and close-out visits 
and at least 
biannually
Westat
Accountability logs, 
dispensing records, and 
other participant records 
Monitoring plan and startup 
package
At least biannually
Westat
For FDA regulated 
studies, the following 
requirements apply:
How this Requirement is Met
Timing, 
frequency, and 
intensity of 
monitoring
Responsible 
Party(ies)
Monitoring methods 
(may include centralized, 
on-site, and self-
monitoring)
Self-monitoring
Annually
Sponsor-Investigator
*For international studies, you are required to engage a CRO that is working in the site country and/or to 
consult with Emory’s legal counsel regarding compliance with the country’s clinical research regulations.
                                                                                                                       


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16. Provisions to Protect the Privacy Interest of Participants
Each subject will be assigned a unique identifier. Any subject records or data sets transferred to 
the coordinating study center will contain only the identifier. Patient names or any information 
which would make the subject identifiable will not be transferred. The subject must be informed 
that his/her personal study-related data will be used by the study team in accordance with local 
data protection law. The level of disclosure must also be explained to the subject.
The subject will be informed that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by study Investigators, appropriate 
IRB/IEC members, and by inspectors from RAs.
17. Informed Consent 
The Investigator or his/her representative will explain the nature of the study to the subject in a 
private setting and answer all questions regarding the study. Patients must be informed that their 
participation is voluntary. Patients will be required to sign a statement of informed consent and 
authorization that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements and the IRB/IEC or study site.
The research record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. Patients must be re-
consented to the most current version of the ICF(s) during their participation in the study as 
deemed appropriate by the overseeing IRB.
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. Patients who are re-screened are required to sign a new ICF.
The ICF will contain a separate section addressing the use of subject samples for future 
exploratory research. The Investigator or authorized designee will explain to each subject the 
objectives of the future exploratory research. If a subject withdraws consent to the use of donated 
biological samples, the samples will be disposed of/destroyed, and the action documented. If 
samples already have been analyzed at the time of the request, the Investigator will not be 
obliged to destroy the results of this research.
18. Setting
Research procedures will take place in the clinic of the principal investigators. Patients will be 
identified from the schedules of the investigators and collaborators. 


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19. Appendix
Appendix A: Regulatory, ethical and study oversight considerations
A1.
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 Council for International Organizations of Medical 
Sciences International Ethical Guidelines;
•
Applicable International Conference on Harmonization (ICH)/Good Clinical 
Practice (GCP) Guidelines;
•
Applicable laws and regulations.
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, and 
other relevant documents (e.g. advertisements) must be submitted to an Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) by the Investigator and reviewed and approved 
by the IRB/IEC before the study is initiated at that site.
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:
•
Notifying the IRB/IEC of serious adverse events 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, and all other applicable 
local regulations.
A2.
Financial disclosure
Investigators and Sub-Investigators will provide accurate financial information as requested to 
allow for complete and accurate financial certification or disclosure statements to the appropriate 
Regulatory Authorities. Investigators will provide information on financial interests during the 
course of the study and for 1 year after completion of the study.
A3.
Informed Consent
The Investigator or his/her representative will explain the nature of the study to the subject and 
answer all questions regarding the study.
Patients must be informed that their participation is voluntary. Patients will be required to sign a 
statement of informed consent and authorization that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements 
and the IRB/IEC or study site.
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.
Patients who are re-screened are required to sign a new ICF.
The ICF will contain a separate section addressing the use of subject samples for future 
exploratory research. The Investigator or authorized designee will explain to each subject the 
objectives of the future exploratory research. If a subject withdraws consent to the use of donated 


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biological samples, the samples will be disposed of/destroyed, and the action documented. If 
samples already have been analyzed at the time of the request, the Investigator will not be 
obliged to destroy the results of this research.
A4.
Data Protection
Each subject will be assigned a unique identifier. Any subject records or data sets transferred to 
the coordinating study center will contain only the identifier. Patient names or any information 
which would make the subject identifiable will not be transferred. The subject must be informed 
that his/her personal study-related data will be used by the study team in accordance with local 
data protection law. The level of disclosure must also be explained to the subject.
The subject will be informed that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by study Investigators, appropriate 
IRB/IEC members, and by inspectors from FDA.
A5.
Dissemination of Study Data
A description of this clinical trial and summary of results (when available) will be available on 
http://www.clinicaltrials.gov.
A6.
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Sponsor-Investigator agrees to submit all manuscripts or abstracts to Sanofi before 
submission. This allows Sanofi to protect proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
 


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Appendix B: Factors in Assessing the Relationship of Adverse Events to Study Drug 
Is there a reasonable possibility that the event may have been caused by the study drug?
No:
•
Due to external causes such as environmental factors, ESIs or other treatment(s) 
being administered
•
Due to the subject’s disease state or clinical condition
•
Do not follow a reasonable temporal sequence following the time of 
administration of the dose of study drug or injection procedure, study procedure, 
or background treatment, etc.
•
Do not reappear or worsen when dosing with study drug or injection procedure, 
study procedure, or background treatment, etc. is resumed are not a suspected 
response to the study drug or injection procedure, study procedure, or 
background treatment, etc. based upon preclinical data or prior clinical data 
Yes:
•
Could not be explained by environmental factors or other treatment(s) being administered
•
Could not be explained by the subject’s disease state or clinical condition follow a 
reasonable temporal sequence following the time of administration of the dose of study 
drug, etc.
•
resolve or improve after discontinuation of study drug, etc.
•
reappear or worsen when dosing with study drug is resumed
•
are known or suspected to be a response to the study drug based upon preclinical data or 
prior clinical data detailed in the package insert. 
NOTE: This list is not exhaustive.


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Appendix C: Data and Safety Monitoring Board Charter
Data and Safety Monitoring Board (DSMB) Charter
Protocol: 
S-I: A randomized, 52-week treatment double-blind, placebo-controlled efficacy and safety study 
of dupilumab 300 mg every other week after endoscopic sinus surgery in patients with allergic 
fungal rhinosinusitis (AFRS) on a background therapy with intranasal corticosteroid spray
Short: 
Add-on Dupilumab for AFRS as Postoperative Therapy (ADAPT)
Sponsor-Investigator: 
Office of the Clinical Director
Emory Principal investigator:
Assistant Professor, Rhinology and Skull Base Surgery Division
Department of Otolaryngology – Head & Neck Surgery 
Emory University School of Medicine 


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TABLE OF CONTENTS
INTRODUCTION .....................................................................................................................3
DSMB RESPONSIBILITIES............................................................................................................3
DSMB MEMBERSHIP..........................................................................................................4
DSMB CHAIRPERSON........................................................................................................................4
DSMB SAFETY OFFICER....................................................................................................................4
DSMB EXECUTIVE SECRETARY...........................................................................................................4
CONFLICT OF INTEREST.............................................................................................................5
CONFIDENTIALITY.........................................................................................................................5
BOARD PROCESSES .....................................................................................................................5
MEETING FORMAT ...........................................................................................................................6
MEETING MATERIALS ......................................................................................................................7
MEETING RECOMMENDATIONS...........................................................................................................7
MEETING MINUTES..........................................................................................................................7
ADDITIONAL REPORTING ...................................................................................................................8
Status Reports (during active enrollment)........................................................................................8
Unanticipated Problems................................................................................................................8
Serious Adverse Events...................................................................................................................8
Discrepancies with Assessments Concerning Unanticipated Problems....................................................8
Protocol Deviation/Violations........................................................................................................9
Protocol Amendments....................................................................................................................9
Communication with the DSMB ....................................................................................................9
RELEASE OF STUDY DATA .................................................................................................................9
APPENDICES.......................................................................................................................10
DSMB MEMBERSHIP ..................................................................................................................10
TEMPLATE FOR DSMB RECOMMENDATIONS..............................................................................11


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INTRODUCTION
The Data and Safety Monitoring Board (DSMB) acts in an advisory capacity to the Sponsor-
Investigator to review participant safety and study progress for “A randomized, 52-week 
treatment double-blind, placebo-controlled efficacy and safety study of dupilumab 300 mg 
every other week after endoscopic sinus surgery in patients with allergic fungal rhinosinusitis 
(AFRS) on a background therapy with intranasal corticosteroid spray”. This study is funded by 
Sanofi (Paris, FR). The purpose of this document is to outline the charge to the DSMB 
regarding its responsibilities, composition, and processes for the above-mentioned study. The 
NIH mandate requires safety oversight and monitoring for all interventional studies to be 
commensurate with risks, nature, size, and complexity of the study. This Charter is intended 
to be a living document to be modified at any time. 
DSMB RESPONSIBILITIES
Responsibilities of the DSMB are to:
a) Review the research protocol, Data and Safety Monitoring Plan (DSMP), and informed consent 
documents, including all proposed revisions. 
b) Evaluate the progress of the study on an ongoing basis, as needed, including periodic assessments 
of data quality, participant recruitment, accrual and retention, participant risk versus benefit, 
performance of study sites, and other factors that can affect the outcome.
c) Consider the impact of factors external to the study when new information, such as scientific or 
therapeutic developments, becomes available and may affect safety of participants, their willingness 
to participate in the study or the ethics and conduct thereof.
d) Review unanticipated problems, serious and non-serious adverse event reports and 
documentation and make recommendations to the Sponsor-Investigator regarding 
protection of the study participants.
e) Assist the Sponsor-Investigator by commenting on any problems with study conduct or performance.
f)
Ensure that the plan for maintaining the confidentiality of the study data and the results by the 
investigative team is appropriate.
g) Review and evaluate requests for protocol modifications.
h) Review accumulating data at the specified intervals, and as appropriate, and make a 
recommendation to continue, terminate or modify the study based on observed benefit or 
harm.
The Sponsor-Investigator may discharge one or all of the DSMB members from their duties when:
a) “A randomized, 52-week treatment double-blind, placebo-controlled efficacy and safety study of 
dupilumab 300 mg every other week after endoscopic sinus surgery in patients with allergic fungal 
rhinosinusitis (AFRS) on a background therapy with intranasal corticosteroid spray” is complete;
b) a member is not able to fulfill the DSMB responsibilities as outlined in the Charter;
c) the Sponsor-Investigator no longer has oversight responsibilities of the study and/or;
d) a member is found to have a Conflict of Interest (COI).


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Additionally, a DSMB member may resign at any point during the study when:
e) a member is not able to fulfill the responsibilities, as outlined in the Charter;
f) a member believes a Conflict of Interest (COI) exists.
DSMB MEMBERSHIP
The DSMB consists of four members who have been appointed by the Sponsor-Investigator. Three
members will constitute a quorum for voting. Membership consists of persons independent of the 
study who have no financial, scientific, or other conflicts of interest with the Principal Investigator 
(PI) or any Co-Investigators.
The DSMB includes experts in or representatives from the fields of Otolaryngology, 
Allergy/Immunology and Biostatistics.
Individuals with additional expertise may be invited to participate as non-voting members in the DSMB 
meeting in certain situations. Non-voting members must also be independent of the study and have no 
financial, scientific, or other conflicts of interest with the PI or any Co-Investigators.
DSMB Chairperson
The DSMB Chairperson is appointed by the Sponsor-Investigator and confirmed by DSMB vote at the 
first meeting. The DSMB members must provide a full consensus vote when electing the DSMB 
Chairperson. The Chairperson is responsible for overseeing the meetings, working with the Sponsor-
Investigator and/or the Executive Secretary (ES) to develop the agenda, and summarizes all DSMB 
recommendations. The Chairperson is the primary contact person for the DSMB.
Dr. Mihir Patel has been appointed as the DSMB Chairperson.
DSMB Safety Officer 
The DSMB Safety Officer (SO) is appointed by the DSMB Chairperson and confirmed by DSMB vote at 
the first DSMB Meeting. The DSMB must provide a full consensus vote when electing the DSMB Safety 
Officer. The Safety Officer is the DSMB contact person for expedited reports (e.g., SAEs, protocol 
violations, and unanticipated problems). Expedited reports must be reported to the DSMB Safety Officer 
and Executive Secretary within 48 hours of the study personnel receiving notification of the event. The 
Safety Officer provides an assessment of the action taken by the investigative team and makes a 
recommendation as to whether further action should be taken (e.g. collection of follow up information or a 
full DSMB discussion).
While the FDA requires expedited reporting of Serious Adverse Events (SAEs) through the Executive 
Secretary, the Safety Officer does not provide real time assessment of SAEs. It is the responsibility of the 
Sponsor-Investigator to provide real time assessment and take the necessary, immediate action with regard 
to participant safety.
Dr. Edward McCoul has been appointed as the DSMB Safety Officer.


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DSMB Executive Secretary
The Executive Secretary (ES) drafts meeting agendas in consultation with the Sponsor-Investigator, 
DSMB Chairperson, and program staff. The agenda is sent to the full DSMB and the Sponsor-
Investigator for input. The ES coordinates the DSMB meetings and conference calls and provides 
logistics support and meeting summaries. The ES will transcribe the meeting recommendations and 
minutes and will distribute them to the Sponsor-Investigator, DSMB Chairperson and members. The ES 
is the primary contact point for DSMB communication with the Sponsor-Investigator.
Dr. Mark Arnold has been appointed as the DSMB Executive Secretary.
CONFLICT OF INTEREST
Individuals invited to serve on the DSMB as must disclose any potential conflicts of interest, whether 
real or perceived, to the Sponsor-Investigator. Conflicts of interest can include, but are not limited to, 
professional, proprietary, and miscellaneous interests. Any real or potential conflicts that develop 
during a member’s tenure on a DSMB must be disclosed for the Sponsor-Investigator consideration at 
the time the potential conflict is realized. In addition, written documentation attesting to an absence 
of conflict of interest is required annually.
Confidentiality
Each member of the DSMB must sign a statement of confidentiality annually. All materials, discussions, 
and proceedings of the DSMB are completely confidential. Members and other participants in DSMB 
meetings are expected to maintain confidentiality.
BOARD PROCESSES
Prior to commencement of recruitment, the study team drafts or revises study materials (protocol, DSMP 
and report templates, and any other materials required for the DSMB’s review). The study team delivers 
relevant materials to the ES, who facilitates the review process with the DSMB.
a) Upon completion of the initial review, the DSMB members are to send the ES their comments for 
consideration. Accepted comments and recommendations are sent to the Sponsor-Investigator for 
review.
b) ES concurrently schedules an introductory teleconference between the Sponsor-Investigator 
and DSMB. All discussions are confidential.
The first meeting is held either by teleconference or in-person before initiation of the study to discuss 
the materials and whether the study is ready to commence, establish guidelines for monitoring and 
determine the format for future meetings. The Sponsor-Investigator and ES prepare the agenda to 1) 
review the study materials, 2) appoint the DSMB Chairperson and Safety Officer, 3) discuss the plan and 
timing for safety monitoring 4) make recommendations to initiate the study and/or modify the study 
materials and 5) review the charter. During the initial DSMB meeting, a representative provides a training 
session outlining the board process and DSMB procedures for all meeting participants (DSMB members, 
study staff and coordinator).
Reports for both the open and closed sessions should be established at the initial DSMB meeting, 


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although changes throughout the study may be requested by the DSMB. In addition, the DSMB 
members will vote to recommend commencement of the study.
Routine meetings of the DSMB are held two times a year via video conference call. Attendance at all 
meetings is highly critical for all DSMB members. Each DSMB member is specifically selected for 
his/her expertise and thus the member’s consistent participation ensures rigorous monitoring 
throughout the course of the study. The DSMB coordinator also attends all DSMB meetings and 
meeting sessions to provide logistical support and transcribe meeting summaries. Meetings are to be 
closed to the public because of participant confidentiality considerations.
All DSMB discussions are confidential. An ad hoc meeting of the DSMB may be called at any time by 
the Chairperson should ethical or patient safety issues arise. The suggestion to convene an ad-hoc 
meeting should be transmitted to the ES, who will notify the Sponsor-Investigator and DSMB 
coordinator. Depending on the situation, this meeting may include the Chairperson alone, a quorum of 
the DSMB, or the full DSMB.
Meeting Format
DSMB meetings consist of open and closed sessions. Discussion held in all sessions is confidential. All 
invited meeting participants, including the investigators, institution staff and the ES, may attend open 
sessions. All sessions are normally attended by a minimum of three voting DSMB members. The 
Sponsor-Investigator and the study statistician must be present. The number of coordinating staff 
attending DSMB meetings should be minimized and only include experienced and trained staff. Other 
staff may be invited to attend only when appropriate. Open session discussion focuses on the conduct and 
progress of the study, including patient accrual, protocol compliance, and problems encountered. 
Unmasked data are not presented in the open session.
The closed session is normally attended by the DSMB members, the ES, and the unmasked study 
statistician or unmasked study team designee. If necessary, all unmasked safety data and efficacy data 
by treatment group may be presented during the closed session. The DSMB determines in advance, in 
what format it wishes to see the data during the closed session. The discussion during the closed session 
is completely confidential, and thus attendance is limited to the members listed in this section, based on 
their safety monitoring and oversight roles and responsibilities. The DSMB remains unmasked at 
all times during the closed session.
If necessary, an open session may be called following the closed session to clarify any questions that arise 
from the DSMB. A second closed session may also be held, if needed.
Ad-hoc meetings may be held at any time should ethical or safety issues arise. The suggestion to 
convene an ad-hoc meeting should be transmitted to the ES, who will notify the Chairperson.
Each meeting, whether routine or ad-hoc, must include a recommendation made by a formal DSMB 
majority to initiate, continue, place on hold or to terminate the study. The decision is ultimately made 
by the Sponsor-Investigator and sponsoring institution IRB, taking into consideration the 
recommendation of the DSMB. The vote may be postponed until further information is acquired. 
Should the DSMB decide to issue a termination recommendation, the full DSMB must vote. In the event 
of a mixed vote, majority vote will rule and a minority report will be appended. 


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Specific recommendations will be transmitted in writing to the Sponsor-Investigator within 7 days of 
meeting completion.
Meeting Materials
DSMB report templates are prepared by the study staff, typically the statistician and/or the data 
coordinating center in consultation with the Sponsor-Investigator, to be reviewed by the DSMB members 
at the first meeting. Additions and modifications to the reports can be requested at any time throughout the 
study. The reports list and summarize safety data, as relevant, and describe the status of the study. All 
meeting materials must be sent to the ES at least two weeks prior to the meeting for distribution to the 
DSMB. The ES distributes study materials via the HIPPA compliant, central study data repository 
(Microsoft OneDrive, Redmond WA). Access will be limited to DSMB members and trained staff. 
Hard copies of the materials may be sent via express mail to DSMB members at their request. Materials 
are divided into two parts if requested: Part 1 contains open session materials, which may be shared with 
the study staff and meeting participants and referenced during any session of the meeting; and Part 2 
contains closed session materials, which may contain sensitive or unmasked data and should be discussed 
in closed sessions only.
Part 1 – Open session materials include administrative reports by study site that describe patients 
screened, enrolled, completed, and discontinued, as well as baseline characteristics of the study 
population. Listings and summaries of adverse events and serious adverse events, along with any other 
information requested by the DSMB may also be in the open session report, but none of the data should be 
presented in an unmasked manner.
Part 2 – Closed session materials may contain safety data in aggregate, by masked treatment group (A/B 
presentation), by unmasked treatment group, or in other formats as requested by the DSMB. The closed 
session reports are confidential. Printed copies of the closed reports should be destroyed immediately 
following the meeting. 
It is important that access to outcome data, when necessary, be limited to the study statistician and/or 
unmasked study team designee and the DSMB to protect the study from bias in patient entry and/or 
evaluation. Any unmasked study personnel should be pre-designated.
Meeting Recommendations
Meeting recommendations are drafted by the ES and are distributed for review by the DSMB 
Chairperson within two working days after the meeting. Once the recommendations are accepted by the 
Chairperson, the ES sends the recommendations to the full DSMB. Comments from DSMB members are 
obtained within two working days. Once finalized, the recommendations are circulated to the DSMB and 
the Sponsor-Investigator for their review. The Sponsor-Investigator has 14 calendar days to submit a 
formal, written response to the recommendations. If the DSMB has any further questions or concerns, 
the ES will notify the Sponsor-Investigator for further clarification via email. It is the responsibility of 
the Sponsor-Investigator to distribute this report to all co-investigators and to assure copies are submitted 
to all the IRBs associated with the study. The response will also be discussed at the following DSMB 
meeting.


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Meeting Minutes
The full meeting minutes are drafted by the ES and distributed for review and approval by the 
Chairperson within 5 business days after the meeting. Any recommendations are inserted at the end of the 
minutes. Once approved by the Chairperson, the ES sends the minutes to the full DSMB. Comments from 
DSMB members are generally obtained within 5 working days after the meeting and meeting minutes 
finalized no later than 30 calendar days after the meeting. Each report concludes with a recommendation 
to continue, place on hold or to terminate the study. A formal vote to approve the minutes is held at the 
next DSMB meeting.
Additional Reporting
Status Reports (during active enrollment)
All clinical trials must provide semi-annual enrollment reports once the first participant is enrolled into the 
study. These reports will contain an Actual versus Expected graph and a CONSORT diagram and should 
be submitted to the Sponsor-Investigator through the ES. The reports will be shared with the DSMB for 
their reference.
Unanticipated Problems
Unanticipated problems are 1) unexpected events that are 2) related or possibly related to participation 
in the research that 3) place participants or others at greater risk of harm than was previously known or 
recognized. All three criteria above must be met to qualify the event as an unanticipated problem. The 
Office for Human Research Protections (OHRP), the Department of Health and Human Services (HHS), 
provides a complete definition and the following guidance for reporting unanticipated problems to 
the IRBs: Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Participants 
or Others and Adverse Events. (http://www.hhs.gov/ohrp/policy/advevntguid.html). Unanticipated 
problems must be reported within 48 hours of the PI receiving notification of the event.
The DSMB Chairperson reviews the unanticipated problems to determine if further action is required.
Serious Adverse Events
All Serious Adverse Events (SAEs) (regardless of expectedness, relatedness, or if they meet the definition 
for unanticipated problems) must be reported to the DSMB Chairperson within 48 hours of the Sponsor-
Investigator receiving notification of the event. The report will include a description of the event, as well as 
the Investigator’s assessment of expectedness, relatedness, and other information, as relevant. Any action 
taken by the investigative team should be provided in the report. The DSMB Chairperson will be provided 
with this information but will provide an independent assessment on attribution and expectedness, as well 
as whether further action is recommended (e.g. collection of follow up information).
Discrepancies with Assessments Concerning Unanticipated Problems
On occasion, there may be disagreements between the Sponsor-Investigator and the DSMB regarding the 
assessment and/ or management of an event that qualifies as an unanticipated problem. The following 
excerpt gives guidance for cases where there is a difference of opinion among the DSMB (referred to as the 
“monitoring entity” in the excerpt below) and the investigator 
http://www.hhs.gov/ohrp/policy/advevntguid.html.
If the investigator determines that an adverse event is not an unanticipated problem, but the 
monitoring entity subsequently determines that the adverse event does in fact represent an 
unanticipated problem (for example, due to an unexpectedly higher frequency of the event), the 


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monitoring entity should report this determination to the investigator, and such reports must be 
promptly submitted by the investigator to the IRB (45 CFR 46.103(b)(5)).
Please note: The DSMB and the Sponsor-Investigator may have iterative discussions regarding the 
assessment and may later come to agreement regarding the assessment and/or management of an AE. In 
cases where the DSMB and Investigator come to an agreement after discussions and the event is 
determined not to be an unanticipated problem, the Investigator is not required to report the event as an 
unanticipated problem to the IRB. Such discussions should take place promptly so as not to delay 
appropriate reporting to the IRB.
Please also note that additional reporting requirements [e.g., to the Food and Drug Administration 
(FDA) and the IRB] are the responsibility of the Sponsor-Investigator.
Protocol Deviation/Violations
Protocol deviations/violations that impact participant safety should be reported to the DSMB 
Chairperson (through the ES) within 48 hours of the Sponsor-Investigator becoming aware of the 
event. Protocol deviations/violations that occur but do not affect participant safety are submitted with 
the routine DSMB meeting report. The Investigator must also adhere to the Institution's policy on 
reporting protocol deviations/violations to the IRB.
Additional reporting may be required if the violation meets the definition of an unanticipated problem 
as described in the OHRP, HHS guidance (http://www.hhs.gov/ohrp/policy/advevntguid.html).
Protocol Amendments
Requests for protocol amendment approvals must be submitted by the Sponsor-Investigator for review 
by the DSMB between regularly scheduled meetings. Approvals may be conducted via email 
correspondence, deferred until the next regularly scheduled meeting, or a call may be scheduled if 
immediate discussion is warranted. The Sponsor-Investigator is notified by the ES of the approved 
changes. IRB review of protocol amendments are separate from this process and are the Sponsor-
Investigator’s / site-investigator’s responsibility.
Communication with the DSMB
To maintain the independent nature of the DSMB, the Sponsor-Investigator and study staff should only 
communicate DSMB-related requests, questions, or concerns through the ES. The DSMB members should 
only communicate with the Sponsor-Investigator through the ES.
Release of Study Data
Publications and abstracts containing primary study results are the responsibility of the investigator(s), 
and prior review or approval by the DSMB is not required. However, the perspective of the DSMB can 
add value to such publications/abstracts, and their comments may be useful to the investigator(s). 
Therefore, the PI is encouraged to provide the DSMB with a copy of all abstracts or manuscripts 
reporting primary study results well in advance of submission to a journal or scientific meeting. 


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APPENDICES
DSMB Membership 
Role
Name
Affiliation
Contact
Chairperson
Mihir Patel, MD
Emory University
Mihir.r.patel@emory.edu
Safety 
Officer
Edward McCoul, 
MD, MPH
Ochsner Clinic
Edward.mccoul@ochsner.org
Study 
Statistician
Christina Mehta, 
PhD, MSPH
Emory University
Christina.Mehta@emory.edu
Executive 
Secretary
Mark Arnold, MD
SUNY Upstate
arnoldm@upstate.edu


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Template for DSMB Recommendations 
Protocol: A randomized, 52-week treatment double-blind, placebo-controlled efficacy 
and safety study of dupilumab 300 mg every other week after endoscopic sinus surgery in 
patients with allergic fungal rhinosinusitis (AFRS) on a background therapy with 
intranasal corticosteroid spray
The Data and Safety Monitoring Board (DSMB) met on: MMDDYYYY for a Data 
Review Meeting that included: review of current study status and review and 
discussion of the Safety Report.
Materials provided for review:
•
Agenda:  
•
Charter:  
•
Contact List:  
•
Informed Consent:  
•
Manuscript:  
•
Presentation:  
•
Protocol:  
•
Safety Report:  
Recommendations from the DSMB:
•
No safety concerns were identified; the study may continue as planned.
Add: 
Signatures and Dates of DSMB Chair and any other required approvals


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Appendix D: List of Study Personnel
Coordinating Sponsor Investigator:
Office of the Clinical Director
Emory University School of 
Medicine
Co-Investigators:
Assistant Professor
Department of Otolaryngology – Head & Neck Surgery
Professor of Medicine and Cell Biology
Division of Pulmonary, Allergy, Critical Care and 
Sleep Medicine
Collaborators:
Department of Otolaryngology – Head & Neck Surgery
 
Professor 
Department of Otolaryngology – Head & Neck Surgery 
Department of Otolaryngology – Head & Neck Surgery
Research Coordinators:
Department of Otolaryngology – Head & Neck Surgery 
Department of Otolaryngology – Head & Neck Surgery 
McGovern Medical School at 
the University of Texas Health
Science Center at Houston
Site Principal Investigator:
Associate Professor of Otolaryngology
Department of Otolaryngology – Head & Neck Surgery 


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Collaborators:
Professor & Chair of Otolaryngology
Department of Otolaryngology – Head & Neck Surgery 
Assistant Professor of Otolaryngology
Department of Otolaryngology – Head & Neck Surgery 
Research Coordinators:
Department of Otolaryngology – Head & Neck Surgery 


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Appendix E: List of Study Vendors
Vendor
Role
Contact
Email
Address
Belmar 
Pharma 
Solutions
Investigationa
l Pharmacy
Sam 
Lebsock
sam@belmarpharmacy.com
231 Violet Street, 
Ste 140
Golden, CO 
80401
Clear 
Analytics
Database 
construction 
and data 
management
Jesse 
Chittams
clearanalyticsllc@gmail.co
m
17121 Aspen Leaf 
Drive
Bowie, MD 20716
Daniel 
Spielman, 
MD
Central reader
Daniel 
Spielman, 
MD
dbspielman@gmail.com
3800 Reservoir 
Road NW
Gorman Building, 
1st Floor
Washington, DC 
20007
Westat
External study 
monitoring
Michele 
Snyder
MicheleSnyder@Westat.co
m
1600 Research 
Boulevard
Rockville, 
Maryland 20850-
3129


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20. Resources Available
AFRS participants are seen in clinic at all three sites participating in this study. We do not 
anticipate recruitment barriers in identifying and enrolling participants. 
21. Multi-Site Research monitoring
There will be a total of 132 participants across the three sites participating. Each site will enroll 
44 participants. The sponsor-investigator will communicate regularly among sites to ensure each 
site has the current version of the protocol, consent documentation, and HIPAA authorization. 
Site visits to the other participating sites may be done to review progress of the study. In 
addition, Principal Investigators will meet regularly to discuss any issues that may arise during 
the study. 


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22. References
1.
Orlandi, R.R., et al., International consensus statement on allergy and rhinology: 
rhinosinusitis 2021. International Forum of Allergy & Rhinology, 2021. 11(3): p. 213-739.
2.
Tyler, M.A., et al., Large-scale gene expression profiling reveals distinct type 2 
inflammatory patterns in chronic rhinosinusitis subtypes. J Allergy Clin Immunol, 2017. 
139(3): p. 1061-1064 e4.
3.
Tyler, M.A., et al., Distinguishing Molecular Features of Allergic Fungal Rhinosinusitis. 
Otolaryngol Head Neck Surg, 2018. 159(1): p. 185-193.
4.
Rudmik, L., et al., Defining appropriateness criteria for endoscopic sinus surgery during 
management of uncomplicated adult chronic rhinosinusitis: a RAND/UCLA 
appropriateness study. Rhinology, 2016. 54(2): p. 117-28.
5.
Psaltis, A.J., et al., Modification of the lund-kennedy endoscopic scoring system improves 
its reliability and correlation with patient-reported outcome measures. The 
Laryngoscope, 2014. 124(10): p. 2216-2223.
6.
Lund, V.J. and I.S. Mackay, Staging in rhinosinusitus. Rhinology, 1993. 31: p. 183 184.
7.
Bachert, C., et al., Efficacy and safety of dupilumab in patients with severe chronic 
rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results 
from two multicentre, randomised, double-blind, placebo-controlled, parallel-group 
phase 3 trials. Lancet, 2019. 394(10209): p. 1638-1650.
8.
Hopkins, C., et al., Psychometric validity of the 22-item Sinonasal Outcome Test. Clin 
Otolaryngol, 2009. 34(5): p. 447-54.
9.
Juniper, E.F., et al., Development and validation of a questionnaire to measure asthma 
control. Eur Respir J, 1999. 14(4): p. 902-7.
10.
Bent, J.P. and F.A. Kuhn, Diagnosis of Allergic Fungal Sinusitis. Otolaryngology–Head and 
Neck Surgery, 1994. 111(5): p. 580-588.


 
 
 
 
 
 
 
 
A Randomized, 52-week Treatment Double-blind, Placebo-controlled 
Efficacy and Safety Study of Dupilumab 300 mg Every Other Week 
After Endoscopic Sinus Surgery in Patients With Allergic Fungal 
Rhinosinusitis (AFRS) on a Background Therapy With Intranasal 
Corticosteroid Spray   
 
NCT05545072 
 
Date: April 02, 2024 
STUDY00000090