Dupilumab Treatment Effects in an Ethnically Diverse Population With Chronic Rhinosinusitis With Nasal Polyposis (CRSwNP)
Conditions: Chronic Rhinosinusitis With Nasal Polyps
Sponsor: Montefiore Medical Center

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Effect of 16-week dupilumab treatment on sinonasal respiratory symptoms and sense of smell 
in ethnically diverse patients with chronic rhinosinusitis and nasal polyposis (CRSwNP)
Study background and Rationale
Chronic rhinosinusitis (CRS) is one of the most common chronic diseases worldwide, with a 
prevalence of approximately 5% to 12% in the adult population.1 Chronic rhinosinusitis with nasal 
polyps (CRSwNP) is an important phenotype of chronic rhinosinusitis.2 Recent additions of biologic 
therapies to improve disease control have been shown to be effective in patients with CRSwNP.3,4 
These treatments are designed to improve objective measures of nasal polyps and patient-reported 
symptoms and their sense of smell among CRSwNP patients. They also prevent a repeated use of 
systemic corticosteroids and decrease the need in recurring sinus surgeries. Dupilumab has been 
shown to be effective in reducing nasal polyp size, radiologically assessed sinus opacification, and 
improving patient-reported symptom scores.3,5 In patients with CRSwNP and comorbid asthma, 
dupilumab improves asthma control.6,7 
While dupilumab efficacy in patients with CRSwNP has been confirmed in multiple studies, a notable 
weakness of these studies is that they have been conducted in a predominantly White populations or 
in populations of unknown ethnicity, making generalizability of the results difficult. If race or ethnicity 
were reported, the inclusion of non-White population was limited to one person in one study.3  Black 
or African-American patients have not been specifically mentioned in the demographics tables of the 
SINUS 24 or SINUS 52 dupilumab trials.  In the SINUS 24 trial, out of the 276 total patients, only 12 
were listed as non-White (“Other”), which comprises only 4.3% of the patients.5 Of note, in Figure S5A 
of this publication, the metric for Nasal Congestion and Nasal Polyp Score in Latino patients, indicated 
that dupilumab did not statistically significantly improved nasal congestion or nasal polyp score in six 
Latino study participants.
Therefore, our knowledge on how dupilumab works in CRSwNP patients from diverse ethnical 
background, is limited. To address this gap, we propose to recruit African American and Latino 
patients with CRSwNP from the Bronx borough of New York City. 
There is no biologic evidence or clinical anecdotal cases to suggest that dupilumab would work 
differently in non-White patients, and our clinical experience in the Bronx thus far has shown us that 
dupilumab is therapeutically very efficacious in our minority patient populations. However, it is 
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important to acknowledge that CRS has several endotypes, which are separated by geography and 
ethnicities.8 African-American patients with CRSwNP and comorbid asthma tend to have a more 
severe disease with increased asthma hospitalizations, compared to White patients.9 The reasons for 
the differences in disease presentation are not well understood. Some biomarkers have different 
levels among White and other populations. For example, non-White patients with asthma tend to have 
higher immunoglobulin E (IgE) levels than White patients.10-12 In addition, African-American patients 
with asthma exhibit greater eosinophilic airway inflammation than White patients with asthma.12 It is 
not well understood what causes these differences, although socio-economic and environmental 
exposures could be at play.13,14 African-American ancestry is associated with higher odds of asthma 
and asthma severity in Latinos.15,16 In addition, African-American and Latino patients with AERD were 
more likely to have worsening of respiratory symptoms and a decline in FEV1 during  aspirin 
treatment than White patients, indicating that their response to treatments may be different.17
Dupilumab treatment for patients with asthma affects both eosinophil counts and IgE levels. Its 
efficacy in asthma control has been shown to be higher in patients who had higher baseline peripheral 
blood eosinophil counts.18 The median eosinophil count of the patients in LIBERTY ASTHMA trial was 
255 cells/L.18  In two nasal polyposis studies on dupilumab efficacy (LIBERTY NP SINUS-24 and 
LIBERTY NP SINUS-52) the mean eosinophil count was 430 cells/L (SD 340).5 In the dupilumab 
asthma study, the median IgE level was 167 IU/mL, the mean IgE level was 432 IU/mL (SD 747), 
while in dupilumab nasal polyp study, mean IgE level was 229 IU/mL (SD 318).5,18 
To highlight the differences between the previously studied cohorts and the cohort of patients with 
CRSwNP from Bronx, NY, the mean is 644 cells/L (SD 550) and the median values of eosinophil 
counts in our cohort is 400 cells/L (IQR 200-900). The mean IgE in our cohort is 821 IU/mL (SD 
1573), and the median is 312 IU/mL (IQR 121-756), nearly a double of what has been observed in 
previously studied populations. These characteristics indicate some of the specific differences in 
CRSwNP presentation between patients from the published cohorts and the patients from our cohort. 
Our established cohort is heavily represented by patients with aspirin-exacerbated respiratory disease 
(AERD), all of whom have CRSwNP and asthma, as well as aspirin-tolerant control patients with 
CRSwNP but without AERD. This cohort is one of the few organized cohorts of well-phenotyped 
AERD patients and the only organized cohort of AERD minority patients available for study in the 
U.S.17,19,20 African-American and Latino patients make up 75% of our ethnically-diverse cohort.
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With this study, we will evaluate some of the potential immune mechanisms that contribute to 
CRSwNP. A goal is to identify pathways by which dupilumab may “normalize” the immune response in 
patients with CRSwNP and prevent nasal polyp recurrence. 
Several immunological features have been identified in CRSwNP that have been suggested as 
relevant drivers of pathology. CRSwNP patients have high systemic levels of pro-inflammatory 
eicosanoids prostaglandin D2 (PGD2) and leukotriene E4 (LTE4) that are especially elevated in patients 
with AERD.21 AERD patients tend to have a greater recurrence rate of the nasal polyps and greater 
need for surgeries.22-24 Published studies show that the change in PGD2 metabolite levels during 
reactions to aspirin in AERD patients mirrors the pattern seen in anaphylactic reactions to an 
allergen.25,26 This suggests that allergy to an environmental antigen or colonizing microbe may be 
involved in the mechanism of AERD.  One candidate for this is Staphylococcus (S.) aureus, which is 
commonly present in nasal polyps, and is a known potential driver of Th2-responses.27-34 We found a 
high frequency of S. aureus-specific serum immunoglobulin E (IgE) among CRSwNP patients. Results 
from studies by us and others show that after surgical removal of the nasal polyps, disease burden in 
most CRSwNP with AERD patients diminishes as reflected in better control of asthma and in reduced 
NSAID sensitivity. 19,35,36 These changes are accompanied by a decrease in urinary PGD2-metabolite 
(PGDM) and uLTE4 levels.19 In patients with undetectable levels of PGD2 in plasma following surgical 
polypectomy (more than one-third of the study population), clinical reactions to aspirin were 
completely eliminated.19,35 These observations point towards an important contribution of PGD2 to 
immune deregulation associated with nasal polyps.
To understand the causes of the immune deregulation in CRSwNP, we have been studying several 
specialized or unconventional subsets of lymphocytes that are known or suspected to be strong 
drivers of allergic inflammation. We have noticed a striking increase in a subset of the unconventional 
T lymphocytes known as iNKT cells, as well as in ILC2 cells and Th2A cells in the nasal polyp tissue, 
suggesting a direct role for them in inciting or amplifying the disease. An in vitro stimulation with 
PGD2, S. aureus or the combination of both, led to an increased expression of CRTH2 receptors on 
peripheral blood iNKT cells, Th2A cells, and augmented IL-4- and IL-13 production by these 
lymphocyte subsets. S. aureus is a frequent colonizer of the nasopharynx,27-30 and is known to 
stimulate Th2 and iNKT cell activation.28,37,38 
Taken together, there are important differences between the previously studied and largely White 
populations, in which dupilumab efficacy has been established, and our diverse Bronx population of 
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patients with CRSwNP with and without comorbid asthma. The proposed study is designed to answer 
the important question of dupilumab efficacy in this ethnically diverse group of patients with CRSwNP 
that is characterized by higher baseline eosinophil counts and higher baseline serum IgE levels.
Hypothesis
The central hypothesis of this proposal is that the addition of dupilumab treatment onto standard-of-
care intranasal corticosteroids will improve patient-reported measures of disease activity and sense of 
smell in a cohort of mostly ethnical and racial minority patients with CRSwNP.
The proposed study will address important research needs in the following ways. First, it will confirm 
the effectiveness of dupilumab the treatment of CRSwNP in ethnic and racial minority patients who 
have traditionally been underrepresented in existing clinical trials of biologics in CRSwNP (Primary 
Objective). Second, this research will establish a biomarker of therapeutic response to dupilumab 
(Secondary Objective) identifying biological effect of dupilumab in CRSwNP patients and its 
association with symptom improvement. We will determine the effect of dupilumab on PGD2 receptor 
and cytokine expression by several lymphocyte subsets by analyzing changes to in vitro stimulation 
with Staphylococcus (S.) aureus and prostaglandin D2 (PGD2) and in patients treated with dupilumab. 
We will compare the effect of dupilumab on cellular function of lymphocyte subsets from CRSwNP 
patients to cellular function of lymphocytes from peripheral blood and sinonasal tissue of control 
patients who undergo endoscopic nasal surgeries for reasons other than CRSwNP (e.g., correction of 
deviated septum). Dupilumab has a strong effect against Th2-associated inflammation. Therefore, our 
hypothesis is that dupilumab will reduce the expression of Th2-proinflammatory markers on 
lymphocytes and lead to a “normalization” of the immune response in CRSwNP patients. Dupilumab-
induced changes will be compared to cellular characteristics of the controls, who do not have 
CRSwNP.
Finally, we will measure the effect of dupilumab on asthma symptoms and lung function in an 
ethnically diverse cohort of patients with CRSwNP and comorbid asthma. In accordance with NIH 
guidelines, ancestral background will be self-identified by the patients.39
Primary Objectives
1.
Measure the effect of 16-week dupilumab treatment on nasal polyp symptoms in a cohort of mostly 
ethnical and racial minority patients. 
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1(a) To determine the effect of dupilumab treatment on Sinonasal Symptom Outcome Test (SNOT-22) 
scores in a diverse patient population with CRSwNP 
2.
Measure the effect of dupilumab on sense of smell in a cohort of mostly ethnical and racial minority 
patients with CRSwNP
2(a) To determine dupilumab treatment effect on University of Pennsylvania Smell Identification Test 
(UPSITTM) and on nasal peak flow (NPF) values in patients with CRSwNP 
Primary Endpoints
In patients with CRSwNP, we will
1(a) Measure SNOT-22 values at baseline, after 2 weeks, and after 16 weeks of dupilumab treatment
2(a) Measure UPSIT scores and NPF values at baseline, after 2 weeks, and after 16 weeks 
dupilumab treatment
Secondary Objectives
1.
Measure the effect of 16-week dupilumab treatment on the biomarkers in a cohort of mostly ethnical 
and racial minority patients with CRSwNP
1(a) To determine dupilumab treatment effect on urinary leukotriene E4 (uLTE4) levels in a cohort of 
mostly ethnical and racial minority patients with CRSwNP.
1(b) To determine dupilumab treatment effect on peripheral blood eosinophil counts and serum 
immunoglobulin E (IgE) levels in a cohort of mostly ethnical and racial minority patients with 
CRSwNP.
2.
Assess the effect of dupilumab on receptor expression and cellular function in several lymphocyte 
subsets from peripheral blood and nasal polyp tissue of patients with CRSwNP and controls to in 
vitro stimulation with Staphylococcus (S.) aureus and prostaglandin D2 (PGD2).
3.
Determine the effect of dupilumab treatment for 16 weeks on the biomarkers in patients with 
CRSwNP
Secondary Endpoints
In patients with CRSwNP, we will
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1(a) Compare changes in uLTE4 levels from baseline, after 2 and after 16 weeks of dupilumab 
treatment
1(b) Compare peripheral blood eosinophil counts and IgE level change from baseline, after 2 and after 
16 weeks of dupilumab treatment
2(a) Determine dupilumab effect in vitro on PGD2 receptor expression (D-type prostanoid receptor 
1 (DP1) and chemoattractant receptor-homologous molecule expressed Th2 cell (CRTH2) 
receptor) on lymphocyte subsets from peripheral blood and sinonasal tissue cells (type 2 innate 
lymphoid cells – ILC2, T-helper 2 allergic cells – Th2A, and invariant Natural Killer T (iNKT) cells) 
at baseline in patients with CRSwNP and compare to controls - patients without CRSwNP who 
undergo elective endoscopic nasal surgeries for reasons other than CRSwNP (e.g., correction of 
deviated septum).
2(b) Assess the effect of dupilumab on cellular function of blood and nasal polyp lymphocyte 
subsets from CRSwNP patients by measuring responses to in vitro stimulation with S. aureus and 
PGD2, and assess changes in expression of GATA-3 (i.e., marker of Th2 differentiation), T-bet (i.e., 
marker of Th1 differentiation), FOXP3 (i.e., marker of T-reg differentiation), and cytokines, IL-4, -5, 
-9, -10, -13, and IFNγ.
3(a) Determine dupilumab effect on changes overtime in DP1 and CRTH2 receptor expression on 
rare lymphocyte subsets from peripheral blood in patients with CRSwNP treated with dupilumab for 
4 weeks, 8 weeks, and 16 weeks
3(b) Determine dupilumab effect on changes overtime in expression of GATA-3, T-bet, FOXP3, IL-
4, -5, -9, -10, -13, and IFNγ by several lymphocyte subsets from peripheral blood in patients with 
CRSwNP treated with dupilumab for 4 weeks, 8 weeks, and 16 weeks
Exploratory Objectives
1.
To determine the effect of dupilumab on asthma symptoms in an ethnically diverse patient population 
with CRSwNP and comorbid asthma
2.
To determine the effect of dupilumab on lung function, as measured by forced expiratory volume in 1 
second (FEV1), in an ethnically diverse patient population with CRSwNP and comorbid asthma
3.
To measure longitudinal changes from baseline in Nasal Fractioned Exhaled Nitric Oxide (N-FeNO) 
levels in a subset of CRSwNP patients with and without AERD
4.
To determine the effect of dupilumab on tissue and peripheral blood lymphocyte subsets both, 
eicosanoid metabolism, T2-inflammatory markers, and sinonasal microbiome changes in patients 
treated with dupilumab and in vitro.
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Exploratory Endpoints
In patients with CRSwNP and comorbid asthma we will:
1. Compare change from baseline in asthma control questionnaire (ACQ) score after 2 and after 16 
weeks of dupilumab treatment
4.
Compare change from baseline in FEV1 after 2 and after 16 weeks of dupilumab treatment
5.
In a subset of CRSwNP patients with and without AERD (10 to 15 patients per group) we will 
determine longitudinal changes in N-FeNO during dupilumab treatment 
6.
In patients with CRSwNP we will collect sinonasal tissue, nasal fluid, and peripheral blood samples 
during dupilumab treatment and assess dupilumab effects on changes in lymphocyte activation, 
eicosanoid metabolism, T2-inflammatory markers, and sinonasal microbiome changes, both in vivo 
and in vitro in a future study.
Study Design
At Montefiore AERD Center and the Combined Chronic Rhino-Sinusitis Clinic, we have a large 
population of patients with CRSwNP. We will offer study participations to the patients on an ongoing 
basis during their scheduled visits at either clinic. The first 60 patients interested in the proposed 
study will be included in it. We anticipate enrolling 20 Latino, 20 African American, non-Latino, and 20 
White, non-Latino patients with CRSwNP. 
We evaluate 5-10 patients with CRSwNP per week. Despite COVID-19 restrictions we continue 
seeing approximately the same number of patients in the last 3 months. Therefore, we conservatively 
anticipate that we would be able to meet recruitment goals within the 18 months. Since this is a “real-
world” observational study, approval-related delays could potentially impact the enrollment. Therefore, 
we suggest a total study duration of 24 months.
The patient sample size of 60 was chosen in part due to feasibility (we estimate 100 patients will 
meet inclusion criteria and expect about half of them to be interested in participation in this study), and 
in part due to sufficiency in sample size as these patients have been chosen to be on the relatively 
severe spectrum of disease (have sought out medical care at a tertiary care CRSwNP Center, and on 
at least one controller medication for asthma if patients have a co-morbid asthma) – this will allow us 
to gather the most robust data regarding therapeutic efficacy and side effects, and will allow us to see 
any window of change in the high level of healthcare utilization for patients who initiate biologics.
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We will also recruit 10 individuals in the control group who have no history of nasal polyps or 
asthma and undergo sinonasal surgery for other reasons, for example deviated septum.
Based on our previous recruitment experience, the estimated drop-out rate should be <10%. Since 
study visits are aligned with the clinical visits, patients are likely to come for follow-ups. 
The study is a prospective, longitudinal 16-weeks study.
This is a single-site study. All participants are patients of Montefiore Medical Center Allergy and 
Immunology and/or Otolaryngology clinics.
Inclusion Criteria
1. Patients with physician-diagnosed CRSwNP, with or without comorbid asthma that meet indication 
criteria for FDA-approved use of Dupixent.
2. Patients aged 18 years and older.
3. Patient willing to provide consent to be a participant in the study.
4. Patients with insurance that allows Dupixent coverage or Dupixent coverage obtained through 
Dupixent MyWay Program
Exclusion Criteria
1.
Age under 18 
2.
Suspected or diagnosed allergic fungal rhinosinusitis.
3.
Suspected or diagnosed cystic fibrosis.
4.
Dupixent coverage denied through insurance or Dupixent MyWay Program
5.
Patients who required a steroid taper in the preceding 30 days. However, patients on chronic 
steroids equal to 20 mg of prednisone daily, are eligible.
6.
Patients who were on a different biologic medication in the preceding 3 months.
7.
Patients with a diagnosis of EGPA/Churg-Strauss Sydnrome
8.
Pregnant patients
9.
Patients with inverted papilloma growth
Visit description for patients with nasal polyps with or without asthma:
1 - screening visit
2 - baseline visit, at which medication will be administered for the first time and patient will be trained 
to self-administer Dupixent
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3 - follow-up visit in 2 weeks from baseline
4 - follow-up visit in 16 weeks from baseline
5 – long term follow-up visits in 36 weeks
6 – long term follow-up visits in 52 weeks
Additional Study Details

The estimated per-participant study duration is 16 weeks, with secondary follow-up visits at 36 and 
52 weeks

Anticipated Study Start/Study Activation: July 2021

Study Completion: 36 months from start date, July 2024

Questionnaires and sample collections will be completed throughout the duration of the study (5 
time points = week 0, 2, and 16) and in a long-term follow up for 36 and 52 weeks
Assessments to be performed

SNOT-22, ACQ, UPSIT

FEV1, NPF, N-FENO, absolute eosinophil count, IgE levels, urine collection for uLTE4 analysis, 
nasal tissue, fluid, and microbiome collection. The nasal inferior turbinate tissue, fluid, and 
microbiome collection will be done at baseline, at 16, 36, and 52 weeks. If sinus surgery is 
clinically indicated and  the patient with nasal polyps undergoes an endoscopic sinus surgery, we 
will collect less than a quarter of the sinonasal tissues such as inferior turbinate, uncinate process, 
nasal polyp, and microbiome swabs during surgery after the remaining has been used for 
diagnostic purposes. 
Randomization Method and Blinding: Not applicable
Study design for the control group:
The control group will include patients without polyps, but having sinonasal surgery for conditions in 
which a small amount of mucosa may be removed incidentally, such as [correction of a deviated 
septum, repair of the facial trauma with sinus fracture, CSF rhinorrhea, or a tumor of the nasal cavity 
or paranasal sinuses], a portion of which is not submitted for pathology diagnosis and could be used 
for research. Sinonasal tissues such as inferior turbinate, uncinate process, nasal polyp, and 
microbiome swabs will be collected during the surgery. We will collect the remnant tissue for research 
after the remaining has been used for diagnostic purposes. The control group will not have any 
subsequent visits associated with the study.
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Materials collected:
The tissue samples and nasal secretions will be collected and stored for future research purposes. 
Nasal polyp tissue and turbinate scrapping collections will be done by the ENT surgeons. The rest will 
be done by the study team. The sinonasal tissues once collected will be analyzed in the 
Porcelli/Jerschow lab,
Nasal scraping:
In order to obtain nasal tissues using the scraping method, plastic disposable nasal curettes (Rhino-
probe, VWR, Radnor, PA, USA) will be used which has been developed specifically to obtain 
cytological samples for research and diagnostic purposes. Nasal scraping can be used for any site in 
the sinonasal cavity. The protocol described below is considered to be reproducible, fast and in 
minimally traumatic40:
1.
Once the patients clear their nose of any excess secretions, the tip of the probe is passed gently 
along the medial surface of the inferior turbinate. This will be performed by direct visualization.
2.
The samples will be obtained by two or three scrapes and will then be spread on microscope 
slides fixed with 95% ethyl alcohol which will be stored for later use. 
3.
These samples may be sent for diagnosis if clinically indicated, but since they are not part of the 
usual diagnostic workup, may be used exclusively for research. 
Nasal mucosal biopsy:
A nasal biopsy will be performed as described below.41 Only nasal polyps will be biopsied. Since 
nasal polyps have no innervation, their biopsy is usually painless.  Topical administration of 
cophenylcaine (5% lidocaine with 0.5% phenylephrine) will be done to achieve local decongestion and 
anesthesia by placing cotton wool pledgets in the nasal cavities for 10 minutes. 
1.
Using an up-cutting 45-degree Blakesley forceps, biopsies will be taken under direct visualization 
from a mucosal fold on the lateral nasal wall anterior to the inferior turbinate.
2.
Gauze will then be placed for 10 minutes in the nasal cavity for hemostasis.  
If practical, the biopsies may be divided and a small portion of one or more sent to pathology for 
diagnosis and correlation with research findings. 
Patient recruitment and retention plan
All patients will be recruited by PI, Dr. Elina Jerschow in the Montefiore Allergy and Asthma clinic. 
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The patients will be provided with informed consent forms and will be assured that they will not lose   
any services, benefits or rights or access to care that they would normally have if you choose not to 
volunteer.
 All study patients will be recruited from this center and while they complete all study visits 
described in this proposal, the PI maintains contact with them during their regular follow-up visits in 
clinics scheduled as part of their medical care. The PI will make it to her priority to personally meet 
with every prospective study participant to answer any questions and ensure that every patient is 
comfortable with the research plans. 
Although patients could voluntarily withdraw from the study at any time, to minimize dropouts during 
the initial recruitment, the following retention plan has been developed: 1) during the initial visit’s 
informed consent discussion, we will discuss study expectations will all participants; 2) we will explain 
in detail the nature of the standard-of-care and aspirin desensitization and treatments that are applied 
during this study, 3) between study visits, the PI will promptly respond to patient questions and 
concerns, 4) the PI and/or the study coordinator remind patients of upcoming study visits; and 5) in 
scheduling study visits, the PI will try to accommodate patient schedules. 
The patient’s information and research records will be kept confidential. The study data file will be de-
identified and will contain the responses to the questionnaires, laboratory, spirometry, and FeNO 
results. The clinical database including consent forms, questionnaires, and study report forms will be 
stored in a locked cabinet in a locked office in a security-protected office space of Montefiore Medical 
Center. The study data will be stored on a password-protected computer. Every effort will be made to 
protect confidential information such as subject identity. The study information will be kept as long as 
they are useful for the research.
The only people who can see the research records are:

Researchers and other individuals who work with the researchers

Organizations and institutions involved in this research, including those that fund the research, if 
applicable

Groups that review research such as central reviewers, Institutional Review Boards, the Office for 
Human Research Protections, the US Food and Drug Administration, data coordinating centers, 
and domestic and foreign agencies that regulate research.
Informed Consent
The informed consent will be obtained by Dr. Elina Jerschow, the principal investigator. The consent 
will be obtained at allergy and combined chronic rhinosinusitis clinics where patients are seen for their 
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condition. No minors will be included in the study as stated by the inclusion criteria. Once the patients 
consent to their participation in the study and are recruited, they will receive $50 for each visit. There 
are no additional costs associated with the study. The routine blood tests (CBC, Chemistry) that are 
usually collected during follow-up visit in patients with CRSwNP on or off dupilumab will be billed to 
their insurance.
Key Personnel: Dr. Elina Jerschow, Dr. Esha Sehanobish, Dr. Mohammad Asad
Statistical analysis
We will evaluate the SNOT-22 and UPSIT at 16 weeks, compute the changes from the baseline for 
each participant, and report the means of changes, and the standard errors. From what is reported by 
SINUS-24 and SINUS-52 at 24 week endpoints, we estimate that the standard deviation of changes is 
about 20 for SNOT-22 and about 9 for UPSIT, which correspond to standard errors at 2.6 and 1.2 
respectively, given the proposed sample size of 60. The standard errors at such level are adequate 
compared to the mean changes from the baseline at 16 weeks as reported by SINUS-24 and SINUS-
52, which is about -25 for SNOT-22 and 10 for UPSIT.
We will report the mean changes from the baseline at 24 and 52 weeks with standard errors. 
Primary Objectives:
Non-inferiority tests will be performed to compare the results from this study to the results reported by 
the Phase 3 clinical trials, with the margin of non-inferiority is set at 75% of reported effect size. We 
will also compare the outcomes between Caucasian and non-Caucasian patients in this study. We 
don’t expect them to be different but will report if significant differences are found. 
Secondary Objectives: Paired T-tests will be used to assess the effect of dupilumab on receptor
expression and cellular function before and after the in vitro stimulation. Paired T-tests will also be 
used to assess the changes of biomarkers in patients between the baseline and 16 weeks after taking 
dupilumab. Log transformation will be applied to the outcome variables when appropriate.
Power Estimation
Primary Objective 1(a):In the Phase 3 trials of nasal polyposis, 6 months of dupilumab induced a 
decline in SNOT-22 score by a LS mean of 30.5 (S.E. =1.54) from the baseline in the treatment group, 
compared to a drop in LS mean score of 9.31 in the placebo group.5 We will compare the mean drop 
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in SNOT-22 score from the baseline of our 60 patients to the reported drop of 30 in the previous 
Phase 3 trials using a t-test. At significance level 0.05, given our sample size, and assume a standard 
deviation at 18.5 as reported by the above mentioned clinical trials, we have 95% power to detect 
non-inferiority with a margin of non-inferiority of 7.5, that is, 75% of reported effect size corresponding 
to a drop in SNOT-22 score by 22.5 from the baseline.  
 
Primary Objective 1(b):In the Phase 3 trials of nasal polyposis, 6 months of dupilumab induced an 
increase in UPSIT score by a LS mean of 11 (S.E.=0.67) from the baseline in the treatment group.5 At 
significance level 0.05, given our sample size, and assumed standard deviation at 8 as reported by 
the above mentioned clinical trials, we have 88% power to detect non-inferiority with a margin of non-
inferiority of 2.75, that is 75% of reported effect size, corresponding to a mean increase of 8.25 from 
the baseline. 
Secondary Objective: Given a sample size of 20 patients with CRSwNP and significance level 0.05, 
we have 80% power to detect a mean change of 0.5, where  is the standard deviation of within 
patient variation.
Statistical analysis of the exploratory objectives will be similar to those of primary and secondary 
objectives.
Data Management
Upon expressing an interest to participate in the study, the patients will be provided with an informed 
consent explaining the details of the study. Each subject will be assigned a study identification 
number at the time of consent and recruitment. RedCap database will be used for capturing of the 
study data.
Data management and analysis will be carried out by Esha Sehanobish, PhD (Postdoctoral Research 
Fellow, Albert Einstein College of Medicine), Elina Jerschow, MD (Attending Allergy/Immunology, 
Montefiore Medical Center).
Data safety and monitoring
All subjects will be from within Montefiore Allergy/Immunology or Otolaryngology clinics. Subjects will 
be provided with the informed consent form when the investigators determined they may be an 
acceptable candidate for the study and that they met the eligibility criteria. The forms, aims of the 
study, data collection, and all potential risks and benefits of the study will be discussed with each 
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subject by qualified study site personnel. No subjects will be enrolled without documentation of 
informed consent, and no waivers of this process will be sought or granted. All data collected will be 
observational and does not alter standard-of-care treatment in these patients.  Risk of data 
confidentiality: data capture system. All users of the REDCap database system will be provided 
access in a secure fashion and can be tracked with user specific audit trails. To provide the best 
protection to research participants, subjects will be assured of complete confidentiality or test results. 
As with all research data, information gathered by the study will be used only for aggregate analysis; it 
will not be released with any information that identifies research participants. The PI for the study will 
monitor the study. The study is not interventional. It is observational and follows standard of care. The 
medication is FDA approved for the indication for which it is used in this study. 
Independent study monitor: Dr. Golda Hudes, MD, PhD, is an Associate Professor in the 
Departments of Medicine (Allergy and Immunology) and Otorhinolaryngology – Head and Neck 
Surgery at Albert Einstein College of Medicine/Montefiore Medical Center. Dr. Hudes has a breadth of 
experience in clinical trials in the field of asthma, nasal polyposis, and eczema. She will serve as an 
independent study monitor. 
Responsibilities: The independent study monitor will review the research protocol and evaluate the 
progress of the clinical study every six months. Dr. Jerschow will provide a study progress summary 
to the independent study monitor every six months. The study monitor will assess data quality, 
timeliness, recruitment, and safety of the study participants. The independent study monitor will 
provide recommendations regarding continuation, modification, and/or termination. All adverse events 
will be compiled every six months and at the conclusion of the study. 
Stopping rules for individual subjects
Any subject enrolled in the study may choose to voluntarily end their participation at any point, without 
affecting their medical care or treatment. For safety reasons, participants may discontinue their 
participation in the study if they develop any study-related serious adverse events (SAEs). At the 
conclusion of the study, subjects will continue on standard therapy based on clinical response and in 
consultation with their physician.
Study termination criteria
The study PI may terminate this study at any time. Reasons for termination may include, but are not 
limited to, the incidence or severity of AEs in this study indicating a potential health hazard. The PI will 
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promptly inform all other participating investigators if the study is suspended or terminated for safety 
reasons and will also inform the IRB and regulatory authorities of the suspension or termination of the 
study and the reason(s) for the action. 
In addition, the study may be terminated for reasons including but not limited to: 
1. Investigator request to withdraw from study participation. 
2. Serious and/or persistent noncompliance by the investigator with the protocol, the clinical research 
agreement, or other local applicable regulatory guidelines in conducting the study. 
3. An IRB/ISM decision to terminate or suspend approval for the investigation or the investigator. 
Reporting adverse events (AE)
An AE is defined as any undesirable event, whether or not related to the investigational protocol, 
which occurs to a subject during the clinical study any time after the subject signs the informed 
consent form, until the last visit, or a premature discontinuation visit. The following precautions are will 
be in place during the recruitment:
Serious adverse events (SAE)
An adverse event is ‘serious’ if it: 
-
Results in death
-
Is life-threatening: when the individual is, in the opinion of the investigator, at immediate risk of death 
from the event as it occurs (this definition does not include an event that hypothetically might have 
caused death if it were more severe)
-
Requires hospitalization or prolongation of existing hospitalization 
-
Results in persistent or significant disability or incapacity (i.e., substantial disruption of a person’s 
ability to conduct normal life functions)
-
Consists of a congenital abnormality or birth defect in the offspring of study participant’s or 
participant’s partner
-
Is a medically important event, which may jeopardize the person and may require medical or surgical 
intervention to prevent one of the outcomes listed above.
Eliciting adverse event Information: The period of observation for AEs/SAEs extends from the time 
the subject signs the informed consent form until their exit from the study. At each study visit and 
telephone contact, subjects will be asked standard questions to elicit medically related changes in 
their well-being. They will also be asked if they have been hospitalized, had any accidents, used any 
new medications, or changed concomitant medication regimens (both prescription and over the-
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counter). In addition to observations by subjects, AEs will be documented from data collected on the 
AE log (e.g., laboratory values, physical examination findings, medical history). 
AE logs/SAE Case Report recording - AEs and SAEs are to be recorded from the time the subject 
signs the informed consent form until their last visit or a premature discontinuation visit. Signs and 
symptoms of each AE were to be described in detail, including onset time/date, offset time/date, 
severity, relationship to dupilumab treatment, and outcome. Action taken are defined as none, 
medication administration, hospitalization, other.
Potential Benefits and knowledge to be gained from the Study
The study will help us identify the effects of 16-week dupilumab treatment on nasal polyp symptoms in 
an ethnically diverse population. It will help us understand the effects of dupilumab on sense of smell 
in the same cohort with CRSwNP. It will also help us understand the effects of the 16-week dupilumab 
treatment on biomarkers such as peripheral blood eosinophil counts, serum IgE and also urinary 
levels of LTE4. We also hope to determine the effects of dupilumab treatment on lung function and on 
the tissue and peripheral blood lymphocytes.
Potential risks
Risk of dupilumab treatment: Dupilumab is used as an add-on maintenance treatment in adult 
patients with inadequately controlled CRSwNP. However, the risks during the dupilumab treatment 
includes hypersensitive reactions such as urticaria, rash, erythema, anaphylaxis, nodosum (skin 
inflammation), and serum sickness. There may be an increase in eosinophilic conditions as evident 
from rashes, worsening pulmonary symptoms and/or neuropathy in cases of reduced oral 
corticosteroid use. There may be cases of new onset or worsening conjunctivitis and keratitis.
Risks of ACT and sinus and nasal symptom score (ACQ, SNOT) questionnaires: Each 
subject will complete these questionnaires at their study visits. Investigators do not interpret the 
questionnaires in any manner. There are no risks associated with administration of these 
questionnaires. 
Risks of blood draws: Risks associated with drawing blood include pain and discomfort that 
usually lasts for several seconds when the needle is inserted. There is a small risk of bruising 
and/or infection at the place where the needle enters the arm. Some people may experience 
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lightheadedness, nausea or fainting. It is possible to develop an infection, but this is rare and can 
be treated. 
Risks of spirometry: Occasionally individuals may develop a slight dizziness and/or temporary 
cough and/or chest discomfort when performing breathing tests. These tests are part of routine 
care for asthma patients and used in clinical settings where asthma care is provided.
Risks of tissue donation during endoscopic sinus surgery: The collection of nasal or sinus 
tissue for research purposes will not affect the surgery or diagnostic pathology, since the latter 
requires only 2 cassettes of tissue (4 grams), which almost always results in left over tissue 
adequate in quantity for research. If the surgeon performing the polypectomy feels that the 
removed tissue may contain a lesion requiring more pathology workup, such as cancer or inverted 
papilloma, it will all be submitted for pathology diagnosis and not collected for this study. 
Risks of sinonasal epithelium collection with Rhino-Pro Currette: We chose  the use of Rhino-
Pro® Currettes as sinonasal epithelium collection tool for several reasons: (i) it is safe; (ii) it causes 
no to minimal discomfort to the patient; (iii) it has been used as a collection tool in previous 
studies.2 The sinonasal epithelium collections will be performed during routine post-surgical care 
The use of the curette may potentially lead to irritation of the nasal mucosa, bleeding, and, rarely, 
an infection that may require antibiotic treatment. Participants may have some soreness around 
the nose or sinuses for 1 or 2 days after the endoscopy. To minimize patient discomfort, we will 
use a local anesthetic (topical lidocaine, 4%), as it is a routine during rhinoscopy. A minimal 
bleeding may occur and will be treated with vasoconstrictor oxymethazoline. 
Adequacy of Protection Against Risks
Recruitment and Informed Consent 
Upon expressing interest to participate, the subject will participate in a full, unpressured explanation of 
the study. Informed consent will be obtained from all study subjects who meet eligibility criteria and 
participate in the study. The investigational nature of the study, its objectives, the procedures 
involved, and their potential risks and benefits will be explained to the participants using simple, direct 
language with full explanation of any medical terms involved (either in Spanish or English). The 
procedures will also be described in the consent form in the same direct language with complete 
description of the procedures entailed. Participants who will consent to the study will sign the informed 
consent form. A notification of study participation will be placed in the medical records. A copy of the 
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signed document will be given to the study participant and another copy will be kept in the locked 
cabinet in the PI’s office to ensure confidentiality. Informed consent will be obtained before any study 
data are captured and before any specimens are collected.
Protection Against Risks 
This study will be conducted in compliance with the protocol, Good Clinical Practice and all applicable 
regulatory requirements. All research personnel have received the required education and training 
needed for conducting clinical research related to the protection of human subjects and personal 
health information according to the Institutional Review Board and Health Insurance Portability and 
Accountability Act of 1996 Public Law 104-191. As per clinical routine, the study visits will take place 
within the confines of the Montefiore Medical Center, with all levels of medical aide and emergency 
care immediately available, for any serious adverse consequences.
Adverse events due to dupilumab treatment: Any adverse reactions during the dupilumab 
treatment such as hypersensitive reactions and conjunctivitis can be easily treated by the use of eye 
drops, and prednisone for eosinophilia with systemic symptoms. If deemed necessary for a patient, 
usage of dupilumab will be discontinued.
Risk to Data Confidentiality: To mitigate potential risk to data confidentiality, two separate data files 
will be maintained. The clinical data file will contain the link between the subject and the study 
identification number. The study data file will be de-identified and will contain the responses to the 
questionnaires, laboratory, and spirometry results. The clinical database including consent forms, 
questionnaires, and study report forms will be stored in a locked cabinet in a locked office in a 
security-protected office space of Montefiore Medical Center. The study data will be stored on a 
password-protected computer. Every effort will be made to protect confidential information such as 
subject identity.
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References
1.
Fokkens W, Desrosiers M, Harvey R, et al. EPOS2020: development strategy and goals 
for the latest European Position Paper on Rhinosinusitis. Rhinology 2019;57:162-8.
2.
Orlandi RR, Kingdom TT, Hwang PH, et al. International Consensus Statement on Allergy 
and Rhinology: Rhinosinusitis. Int Forum Allergy Rhinol 2016;6 Suppl 1:S22-209.
3.
Bachert C, Mannent L, Naclerio RM, et al. Effect of Subcutaneous Dupilumab on Nasal 
Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial. 
JAMA 2016;315:469-79.
4.
Gevaert P, Omachi TA, Corren J, et al. Efficacy and safety of omalizumab in nasal 
polyposis: 2 randomized phase 3 trials. J Allergy Clin Immunol 2020;146:595-605.
5.
Bachert C, Han JK, Desrosiers M, 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;394:1638-50.
6.
Bachert C, Hellings PW, Mullol J, et al. Dupilumab improves patient-reported outcomes 
in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma. J Allergy Clin 
Immunol Pract 2019;7:2447-9 e2.
7.
Maspero JF, Katelaris CH, Busse WW, et al. Dupilumab Efficacy in Uncontrolled, 
Moderate-to-Severe Asthma with Self-Reported Chronic Rhinosinusitis. J Allergy Clin Immunol 
Pract 2020;8:527-39 e9.
8.
Cardell LO, Stjarne P, Jonstam K, Bachert C. Endotypes of chronic rhinosinusitis: Impact 
on management. J Allergy Clin Immunol 2020;145:752-6.
9.
Mahdavinia M, Benhammuda M, Codispoti CD, et al. African American Patients With 
Chronic Rhinosinusitis Have a Distinct Phenotype of Polyposis Associated With Increased 
Asthma Hospitalization. J Allergy Clin Immunol Pract 2016.
10.
Borish L, Chipps B, Deniz Y, et al. Total serum IgE levels in a large cohort of patients with 
severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol 2005;95:247-53.
11.
Vergara C, Murray T, Rafaels N, et al. African ancestry is a risk factor for asthma and high 
total IgE levels in African admixed populations. Genet Epidemiol 2013;37:393-401.
12.
Nyenhuis SM, Krishnan JA, Berry A, et al. Race is associated with differences in airway 
inflammation in patients with asthma. J Allergy Clin Immunol 2017;140:257-65 e11.
13.
Fitzpatrick AM, Gillespie SE, Mauger DT, et al. Racial disparities in asthma-related health 
care use in the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. J 
Allergy Clin Immunol 2019.
14.
Matsui EC, Adamson AS, Peng RD. Time's up to adopt a biopsychosocial model to 
address racial and ethnic disparities in asthma outcomes. J Allergy Clin Immunol 
2019;143:2024-5.
15.
Pino-Yanes M, Thakur N, Gignoux CR, et al. Genetic ancestry influences asthma 
susceptibility and lung function among Latinos. J Allergy Clin Immunol 2015;135:228-35.
16.
Salari K, Burchard EG. Latino populations: a unique opportunity for epidemiological 
research of asthma. Paediatr Perinat Epidemiol 2007;21 Suppl 3:15-22.
IRB NUMBER: 2021-13161
IRB APPROVAL DATE: 09/13/2021

20
17.
Jerschow E, Edin ML, Pelletier T, et al. Plasma 15-Hydroxyeicosatetraenoic Acid Predicts 
Treatment Outcomes in Aspirin-Exacerbated Respiratory Disease. J Allergy Clin Immunol Pract 
2017;5:998-1007 e2.
18.
Castro M, Corren J, Pavord ID, et al. Dupilumab Efficacy and Safety in Moderate-to-
Severe Uncontrolled Asthma. The New England journal of medicine 2018;378:2486-96.
19.
Jerschow E, Edin ML, Chi Y, et al. Sinus Surgery Is Associated with a Decrease in Aspirin-
Induced Reaction Severity in Patients with Aspirin Exacerbated Respiratory Disease. J Allergy 
Clin Immunol Pract 2019;7:1580-8.
20.
Shah SJ, Abuzeid WM, Ponduri A, et al. Endoscopic sinus surgery improves aspirin 
treatment response in aspirin-exacerbated respiratory disease patients. Int Forum Allergy 
Rhinol 2019.
21.
Higashi N, Taniguchi M, Mita H, Yamaguchi H, Ono E, Akiyama K. Aspirin-intolerant 
asthma (AIA) assessment using the urinary biomarkers, leukotriene E4 (LTE4) and prostaglandin 
D2 (PGD2) metabolites. Allergology international : official journal of the Japanese Society of 
Allergology 2012;61:393-403.
22.
Kim JE, Kountakis SE. The prevalence of Samter's triad in patients undergoing functional 
endoscopic sinus surgery. Ear Nose Throat J 2007;86:396-9.
23.
McMains KC, Kountakis SE. Medical and surgical considerations in patients with Samter's 
triad. Am J Rhinol 2006;20:573-6.
24.
Buchheit KM, Hulse KE. Local immunoglobulin production in nasal tissues: A key to 
pathogenesis in chronic rhinosinusitis with nasal polyps and aspirin-exacerbated respiratory 
disease. Ann Allergy Asthma Immunol 2020.
25.
Higashi N, Mita H, Ono E, et al. Profile of eicosanoid generation in aspirin-intolerant 
asthma and anaphylaxis assessed by new biomarkers. J Allergy Clin Immunol 2010;125:1084-91.
26.
Higashi N, Mita H, Yamaguchi H, Fukutomi Y, Akiyama K, Taniguchi M. Urinary tetranor-
PGDM concentrations in aspirin-intolerant asthma and anaphylaxis. J Allergy Clin Immunol 
2012;129:557-9, 9 e1-2.
27.
Hayes SM, Biggs TC, Goldie SP, et al. Staphylococcus aureus internalization in mast cells 
in nasal polyps: Characterization of interactions and potential mechanisms. J Allergy Clin 
Immunol 2019.
28.
Takeda K, Sakakibara S, Yamashita K, et al. Allergic conversion of protective mucosal 
immunity against nasal bacteria in patients with chronic rhinosinusitis with nasal polyposis. J 
Allergy Clin Immunol 2019;143:1163-75 e15.
29.
Corriveau MN, Zhang N, Holtappels G, Van Roy N, Bachert C. Detection of 
Staphylococcus aureus in nasal tissue with peptide nucleic acid-fluorescence in situ 
hybridization. Am J Rhinol Allergy 2009;23:461-5.
30.
Patou J, Gevaert P, Van Zele T, Holtappels G, van Cauwenberge P, Bachert C. 
Staphylococcus aureus enterotoxin B, protein A, and lipoteichoic acid stimulations in nasal 
polyps. J Allergy Clin Immunol 2008;121:110-5.
31.
Perez-Novo CA, Kowalski ML, Kuna P, et al. Aspirin sensitivity and IgE antibodies to 
Staphylococcus aureus enterotoxins in nasal polyposis: studies on the relationship. 
International archives of allergy and immunology 2004;133:255-60.
IRB NUMBER: 2021-13161
IRB APPROVAL DATE: 09/13/2021

21
32.
Suh YJ, Yoon SH, Sampson AP, et al. Specific immunoglobulin E for staphylococcal 
enterotoxins in nasal polyps from patients with aspirin-intolerant asthma. Clin Exp Allergy 
2004;34:1270-5.
33.
Van Zele T, Gevaert P, Watelet JB, et al. Staphylococcus aureus colonization and IgE 
antibody formation to enterotoxins is increased in nasal polyposis. J Allergy Clin Immunol 
2004;114:981-3.
34.
Bachert C, Maurer M, Palomares O, Busse WW. What is the contribution of IgE to nasal 
polyposis? J Allergy Clin Immunol 2021.
35.
Huang GX, Palumbo ML, Singer JI, Cahill KN, Laidlaw TM. Sinus surgery improves lower 
respiratory tract reactivity during aspirin desensitization for AERD. J Allergy Clin Immunol Pract 
2019;7:1647-9.
36.
Bergmark RW, Palumbo M, Rahman S, et al. Aspirin-Exacerbated Respiratory Disease: 
Association Between Patient-Reported Sinus and Asthma Morbidity. J Allergy Clin Immunol 
Pract 2020.
37.
Hayworth JL, Mazzuca DM, Maleki Vareki S, Welch I, McCormick JK, Haeryfar SM. CD1d-
independent activation of mouse and human iNKT cells by bacterial superantigens. Immunol 
Cell Biol 2012;90:699-709.
38.
Ziegler C, Goldmann O, Hobeika E, Geffers R, Peters G, Medina E. The dynamics of T cells 
during persistent Staphylococcus aureus infection: from antigen-reactivity to in vivo anergy. 
EMBO Mol Med 2011;3:652-66.
39.
Racial and Ethnic Categories and Definitions for NIH Diversity Programs and for Other 
Reporting Purposes. 2015. (Accessed 05/18/2021, at 
https://grants.nih.gov/grants/guide/notice-files/not-od-15-089.html.)
40.
Meltzer EO, Orgel HA, Rogenes PR, Field EA. Nasal cytology in patients with allergic 
rhinitis: effects of intranasal fluticasone propionate. J Allergy Clin Immunol 1994;94:708-15.
41.
Thornton MA, Walshe P, Costello RW, McConn-Walsh R, Walsh MA. An alternative 
technique for nasal biopsy. Laryngoscope 2004;114:1060-2.
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