A Randomized, Double-blind, 52-week, Placebo Controlled Efficacy and Safety Study of Dupilumab, in Patients With Bilateral Nasal Polyposis on a Background Therapy With Intranasal Corticosteroids
Phase: PHASE3
Conditions: Chronic Rhinosinusitis Phenotype With Nasal Polyps (CRSwNP)
Sponsor: Sanofi

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According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
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COMPOUND: DUPILUMAB/SAR231893  
A randomized, double-blind, 52-week, placebo controlled efficacy and safety study 
of dupilumab, in patients with bilateral nasal polyposis on a background therapy 
with intranasal corticosteroids 
STUDY NUMBER: EFC14280 
STUDY NAME: SINUS-52 
VERSION DATE / STATUS: Approval date (17-May-2017) / Approved 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 17-May-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 3.0) 
Date : 18-Jul-2016 
Version Number: 
1  
EudraCT and/or IND 
Number(s) 
2015/001314-10/105379 
Date: 
17-May-2017  
Total number of pages: 
142 
(electronic 1.0)
NCT Number:NCT02898454

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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
COMPOUND: SAR231893 
(Dupilumab) 
STUDY No: EFC14280  
  
TITLE 
A randomized, double-blind, 52-week, placebo controlled efficacy and safety 
study of dupilumab, in patients with bilateral nasal polyposis on a background 
therapy with intranasal corticosteroids 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVES 
Primary objective 
• 
To evaluate the efficacy of dupilumab 300 mg every 2 weeks (q2w) 
compared to placebo on a background of mometasone furoate nasal 
spray (MFNS) in reducing nasal congestion/obstruction (NC) severity 
and endoscopic nasal polyposis score (NPS) in patients with bilateral 
nasal polyposis (NP). In addition for Japan, reduction in computed 
tomography (CT) scan opacification of the sinuses will be also a co-
primary objective. 
Secondary objectives  
• 
To evaluate the efficacy of dupilumab in improving total symptoms 
score (TSS). 
• 
To evaluate the efficacy of dupilumab in improving sense of smell.  
• 
To evaluate the efficacy of dupilumab in reducing CT scan 
opacification of the sinuses (for Japan, this is part of the primary 
objective).  
• 
To evaluate the ability of dupilumab in reducing the proportion of 
patients who require treatment with systemic corticosteroids (SCS) or 
surgery for NP. 
• 
To evaluate the effect of dupilumab on patient reported outcomes 
(PROs) and health related quality of life (HRQoL). 
• 
To evaluate the efficacy of dupilumab 300 mg q2w up to Week 52. 
• 
To evaluate the efficacy of dupilumab 300 mg q2w up to Week 24 
followed by 300 mg every 4 weeks (q4w) up to Week 52. 
• 
To evaluate the effect of dupilumab in the subgroups of patients with 
prior surgery and co-morbid asthma [including non-steroid anti-
inflammatory drug (NSAID) exacerbated respiratory disease (NERD)]. 
• 
To evaluate the safety of dupilumab in patients with bilateral NP.  
• 
To evaluate functional dupilumab concentrations (systemic exposure) 
and incidence of treatment-emergent anti-drug antibodies (ADA). 
Exploratory objectives  
• 
To explore the effects of dupilumab on biomarkers of type 2/TH2 
inflammation in blood, 
. 
• 
To evaluate the effect of dupilumab on healthcare resource utilization. 
• 
To evaluate the effect of dupilumab on SNOT-22 items: “decreased 
sense of smell/taste”, “difficulty falling asleep”, “'wake up at night”, 
“lack of a good night's sleep”, “wake up tired”, “fatigue”, and “reduced 
productivity”. 
• 
To assess the effect of dupilumab in improving sense of taste. 
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STUDY DESIGN 
General design 
Multinational, multicenter, randomized, double-blind, placebo-controlled, parallel 
group study comparing the efficacy of dupilumab compared to placebo, in 
patients with bilateral NP treated with intranasal corticosteroids (INCS). 
Study periods 
The clinical trial consists of 3 periods: 
Run-in period (4 weeks +/-3 days): 
All patients will enter a run-in period of 4 weeks receiving MFNS of 2 actuations 
(50 µg/actuation) in each nostril twice daily (BID), total daily dose of 400 µg, 
starting at Visit 1 (V1), unless the patients are unable to tolerate or there is a 
specific regulatory requirement preventing use of this dose in which case, they 
can stay on a lower dose regimen (200 µg once daily) of MFNS. 
Randomized treatment period (up to 52 weeks +/-3 days): 
Patients will be randomized to one of the following treatments: 
• 
Arm A: dupilumab 300 mg subcutaneous (SC) q2w until Week 52. 
• 
Arm B: dupilumab 300 mg SC q2w until Week 24, then 300 mg q4w 
until Week 52. 
• 
Arm C: placebo matching dupilumab SC q2w administration until 
Week 52. 
All patients will continue on the stable dose of MFNS used during the run-in 
period except if dose is changed due to adverse event (AE). 
Rescue:  
During the study treatment period and off treatment follow-up, based on clinical 
evaluation, in case of worsening of signs and/or symptoms requiring medical 
intervention, the Investigator may consider rescue treatment with: 
• 
Nasal lavage with saline and/or systemic antibiotics (up to 2 weeks in 
case of acute infection) 
• 
Short course oral corticosteroids (OCS) (prednisone or prednisolone) 
• 
Sino-nasal surgery for nasal polyps (based on previous observations, 
8 weeks of IMP treatment is recommended prior to surgery to allow 
onset of treatment effect). 
Patients receiving rescue treatment other than surgery during the study should 
continue on study drug unless the Investigator decides to withdraw the study 
treatment (see Section 8.2.2). Before starting treatment with SCS patients 
should come to the study site for the clinical assessments including endoscopy 
and PROs. 
For patients who undergo or are planned for surgery for NP the Investigator may 
decide to continue IMP up to the time of surgery or end of treatment whichever 
date comes first (see Section 9.2.1.5 for details). At the time of surgery patients 
will be permanently discontinued from study treatment and assessed as soon as 
possible using the procedures described in Section 10.3.1. 
Post treatment period (12 weeks +/- 3 days): 
After completing 52 weeks of treatment with the investigational medicinal 
product (IMP) (or following early discontinuation of IMP or discontinuation from 
the study), patients will be instructed to: 
Return to the study site for such evaluations as pharmacokinetic (PK) and ADA, 
physical examination, nasal peak inspiratory flow (NPIF), University of 
Pennsylvania Smell Identification Test (UPSIT), NPS, PROs (SNOT-22, VAS), 
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and safety (for details see Section 10.3.1). 
• 
Continue to complete the e-diary for symptom evaluation. 
• 
Continue on MFNS stable dose during the post treatment period 
except if dose is changed due to AE. 
• 
Contact the Investigator during the post treatment period up to the 
EOS visit if the symptoms worsen requiring medical attention. 
• 
Report any adverse event (AE). 
For procedure to be followed for early discontinuation of IMP refer to  
Section 10.3.1. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria  
Patients with bilateral sino-nasal polyposis that despite prior treatment with SCS 
anytime within the past 2 years; and/or have a medical 
contraindication/intolerance to SCS;  and/or had prior surgery for NP at the 
screening visit, have: 
• 
An endoscopic bilateral NPS at V1 of at least 5 out of a maximum 
score of  
8 (with a minimum score of 2 in each nasal cavity).  
• 
Ongoing symptoms (for at least 8 weeks before V1) of: 
- 
Nasal congestion/blockage/obstruction with moderate or severe 
symptom severity (score 2 or 3) at V1 and a weekly average 
severity of greater than 1 at time of randomization (V2) and,  
- 
Another symptom such as loss of smell, rhinorrhea 
(anterior/posterior).  
• 
Signed written informed consent. 
Exclusion criteria 
(See Section 7.2 for the complete list of exclusion criteria) 
• 
Patients <18 years of age. 
• 
Patient who has been previously treated in dupilumab studies. 
• 
Patient who has taken: 
- 
Biologic therapy/systemic immunosuppressant to treat 
inflammatory disease or autoimmune disease (eg, rheumatoid 
arthritis, inflammatory bowel disease, primary biliary cirrhosis, 
systemic lupus erythematosus, multiple sclerosis, etc.) within 
2 months before V1 or 5 half-lives, whichever is longer,  
- 
Any experimental monoclonal antibody (mAB) within 5 half-lives 
or within 6 months before V1 if the half-life is unknown. 
- 
Anti-immunoglobulin E (IgE) therapy (omalizumab) within 
130 days prior to V1, 
- 
Patients who are receiving Leukotriene antagonists/modifiers at 
V1 unless they are on a continuous treatment for at least 30 days 
prior to V1. 
• 
Initiation of allergen immunotherapy within 3 months prior to V1 or a 
plan to begin therapy or change its dose during the run-in period or the 
randomized treatment period. 
• 
Patients who have undergone any intranasal and/or sinus surgery 
(including polypectomy) within 6 months before V1. 
• 
Patients who have had a sino-nasal or sinus surgery changing the 
lateral wall structure of the nose making impossible the evaluation of 
NPS. 
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• 
Patients with conditions/concomitant diseases making them 
nonevaluable at V1 or for the primary efficacy endpoint such as: 
- 
Antrochoanal polyps, 
- 
Nasal septal deviation that would occlude at least one nostril, 
- 
Acute sinusitis, nasal infection or upper respiratory infection, 
- 
Ongoing rhinitis medicamentosa, 
- 
Allergic granulomatous angiitis (Churg-Strauss syndrome), 
granulomatosis with polyangiitis (Wegener’s granulomatosis), 
Young’s syndrome, Kartagener’s syndrome or other dyskinetic 
ciliary syndromes, concomitant cystic fibrosis, 
- 
Radiologic suspicion, or confirmed invasive or expansive fungal 
rhinosinusitis. 
• 
Patients with nasal cavity malignant tumor and benign tumors (eg, 
papilloma, blood boil etc.) 
• 
Patients with forced expiratory volume (FEV1) 50% or less (of 
predicted normal). 
Total expected number of patients: 
 
 
 
 
 
 
 
 
Expected number of sites: 
A total of approximately 360 patients with bilateral NP will be randomized to 3 
treatment arms (120 patients/Arm). 
The randomization will be stratified based on asthma status, prior surgery, and 
country. 
In order to have adequate number of patients for the subgroup analysis of 
patients with asthma/NERD and prior surgery, enrollment of the following 
categories of patients will be limited as follows (see rationale Section 4.2):  
• 
Patients without asthma and/or NERD history will be limited to  
180 patients (out of the total 360 randomized patients). 
• 
Patients without prior surgery will be limited to 180 patients (out of the 
total 360 randomized patients). 
Patients may fall in more than one category without limitation in numbers. 
Approximately 130 sites. 
STUDY TREATMENT(s) 
Dupilumab (SAR231893/REGN668) or matching placebo. 
Investigational medicinal product 
Formulation 
Dupilumab: 150 mg/mL in pre-filled syringe to deliver 300 mg in 2 mL. 
Placebo: Pre-filled syringe to deliver 2 mL. 
Route of administration 
Subcutaneous (SC) injection. 
Dose regimen 
Randomized 1:1:1 to the following regimens until Week 52: 
• 
Arm A: dupilumab 300 mg SC q2w until Week 52. 
• 
Arm B: dupilumab 300 mg SC q2w until Week 24 then 300 mg q4w 
until Week 52. 
• 
Arm C: placebo matching dupilumab SC q2w administration until 
Week 52. 
Noninvestigational medicinal 
product 
Formulation 
• 
Mometasone furoate (NASONEX®) 50 µg/actuation nasal spray, 
suspension. 
Nasal spray is provided in a bottle that contains 18 g (140 actuations) of product 
formulation. 
Route of administration 
Mometasone furoate (NASONEX): Nasal spray. 
Dose regimen 
 
Mometasone furoate nasal spray 2 actuations (50 µg/actuation) in each nostril 
BID (total daily dose of 400 µg) or once daily (total daily dose of 200 µg) if the 
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patients are unable to tolerate BID or there is a specific regulatory requirement 
preventing use of this dose in which case, they can stay on a lower dose 
regimen (200 µg) of MFNS. 
ENDPOINT(S) 
 
Co-primary endpoints: 
Change from baseline at Week 24: 
• 
Nasal congestion/obstruction (NC) symptom severity score based on 
the patient daily morning (AM) assessment. 
• 
Nasal polyp score, as assessed by central video recordings of nasal 
endoscopy. 
For Japan, in addition to the 2 co-primary endpoints above, the following will 
also be a co-primary endpoint: 
• 
Change from baseline in sinus opacifications assessed by CT scans 
using the Lund Mackay Score (LMK) at Week 24.  
Secondary endpoint(s): 
Efficacy key secondary 
• 
Change from baseline in TSS at Week 24: composite severity score 
consisting of the patient daily AM assessed nasal 
congestion/obstruction, decreased/loss of sense of smell, 
anterior/posterior rhinorrhea. 
• 
Change from baseline in UPSIT smell test at Week 24.  
• 
Change from baseline in the severity of decreased/loss of smell daily 
assessed by the patient at Week 24.  
• 
Change from baseline in sinus opacification assessed by CT scans 
using the LMK score at Week 24. This endpoint will not be assessed 
as a secondary endpoint for Japan as it is already a co-primary 
endpoint. 
• 
Change from baseline in SNOT-22 at Week 24.  
• 
Proportion of patients during study treatment receiving SCS for NP 
and/or planned to undergo surgery for nasal polyps. 
• 
Change from baseline in NC for q2w (Arm A) versus placebo (Arm C) 
at Week 52. 
• 
Change from baseline in NPS for q2w (Arm A) versus placebo (Arm 
C) at Week 52. 
• 
Change from baseline in NC for q2w/q4w (Arm B) versus placebo 
(Arm C) at Week 52. 
• 
Change from baseline in NPS for q2w/q4w (Arm B) versus placebo 
(Arm C) at Week 52. 
Other secondary 
• 
Change from baseline and time course profiles in NC, NPS, TSS, 
UPSIT, daily assessed loss of smell, SNOT-22 and LMK at Week 52. 
• 
Change from baseline at Week 24 and Week 52 in: 
• 
VAS for overall rhinosinusitis. 
• 
NPIF. 
• 
Rhinorrhea (anterior/posterior nasal discharge) daily symptom score 
assessed by the patient. 
• 
Efficacy endpoints for the sub-groups of patients with prior surgery, 
co-morbid asthma (including NERD history). 
• 
Safety (incidence of treatment-emergent adverse events treatment 
(TEAE), of treatment-emergent serious adverse events (TESAEs), 
and TEAEs leading to treatment discontinuation), laboratory values, 
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vital signs. 
• 
Total SCS rescue dose prescribed (in mg) during the treatment period. 
• 
Total SCS rescue intake in days during the treatment period. 
• 
Patient reported outcomes including HRQoL scale (EQ-5D-5L VAS 
score, self-rated health). 
• 
Dupilumab concentration in serum and ADA. 
Details in the statistical analysis for other secondary endpoints in the intent-to-
treat (ITT) and pre-defined sub-groups will be provided with the final SAP. 
Additional analyses in the ITT and subgroup exploratory analyses are 
discussed in Section 9 and Section 11.4.2. 
Exploratory endpoint(s): 
• 
Healthcare resource utilization. 
• 
Proportion and time-to-event of patients with SCS rescue for nasal 
polyps. 
• 
Proportion and time-to-event of patients who have or are planned for 
surgery of nasal polyps. 
• 
Change from baseline in decreased/loss of sense of taste symptom 
severity. 
• 
SNOT-22 items: “decreased sense of smell/taste”, “difficulty falling 
asleep”, ”wake up at night”, “lack of a good night's sleep”, “wake up 
tried”, ”fatigue”, and “reduced productivity”. 
• 
Pharmacodynamic biomarkers in blood and urine. 
• 
 
• 
 
• 
FEV1, forced vital capacity (FVC) and forced expiratory flow 25-75% 
(FEF 25-75) in patients with asthma. 
• 
Efficacy endpoints for the sub-group of patients with SCS use in the 
year prior to study Visit 1. 
• 
Patient reported outcomes including HRQoL scale (EQ5D-5L, Index 
Score) 
ASSESSMENT SCHEDULE 
Run-in period: 4 weeks +/- 3 days. 
Randomized treatment period: 52 weeks +/- 3 days. 
Post treatment period: 12 weeks +/- 3 days. 
For detailed assessment schedule across the study randomized treatment 
period refer to the study flow chart (Section 1.2). 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The sample size is chosen to enable an adequate characterization of the 
efficacy between dupilumab 300 mg q2w (pooled A and B arms) and placebo 
with regard to the 2 co-primary endpoints, changes from baseline in NC and 
NPS at Week 24. 
The observed mean NC reduction of the dupilumab group with weekly dosing 
(qw) in ACT12340 is 0.95 and the observed mean NC reduction of the placebo 
group is 0.26. To calculate power, a conservative estimate is used that assumes 
the placebo-adjusted NC reduction of the dupilumab 300 mg q2w group is 80% 
of the dupilumab 300 mg qw group, the mean NC reduction of the dupilumab 
300 mg q2w group is then assumed to be 0.81 = 0.8 * (0.95 - 0.26) + 0.26. 
Assuming normal distribution of the change in NC, a common standard 
deviation (SD) of 1.03, which has incorporated a 20% inflation from the 
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observed SD in ACT12340, and a 25% dropout rate, with 240 patients for the 
q2w pool and 120 patients in placebo, the study will have 99% power to detect 
an effect size of 0.534 using a two-sided test with alpha = 0.05 for the change in 
NC at Week 24 in the dupilumab 300 mg q2w group.  
The observed mean NPS reduction of the dupilumab group with qw dosing in 
ACT12340 is 1.85 and the observed mean NPS reduction of the placebo group 
is 0.30. Using same conservative approach that assumes the placebo-adjusted 
NPS reduction of the dupilumab 300 mg q2w group is 80% of the dupilumab 
300 mg qw, the mean NPS reduction of the dupilumab 300 mg q2w group is 
then assumed to be 1.54 = 0.8*(1.85-0.30)+0.30. Assuming normal distribution 
of the change in NPS, a common standard deviation (SD) of 2.11, which has 
incorporated a 20% inflation from the observed SD in ACT12340, and a 25% 
dropout rate, with 240 patients for the q2w pool and 120 patients in placebo, the 
study will have 99% power to detect an effect size of 0.588 using a two-sided 
test with alpha = 0.05 for the change in NPS at Week 24 in the dupilumab  
300 mg q2w group.  
Therefore, with a sample size of 240 patients for the q2w pool (Arm A and B) at 
Week 24, the combined power of the 2 co-primary efficacy endpoints is at least 
98% for dupilumab 300 mg q2w group with alpha = 0.05 assuming no negative 
correlation between the 2 endpoints. 
The observed mean LMK reduction of the dupilumab group with qw dosing in 
ACT12340 is 9.07 and the observed mean LMK reduction of the placebo group 
is 0.23. Using same conservative approach that assumes the placebo-adjusted 
LMK reduction of the dupilumab 300 mg q2w group is 80% of the dupilumab 
300 mg qw, the mean LMK reduction of the dupilumab 300 mg q2w group is 
then assumed to be 7.30 = 0.8*(9.07-0.23)+0.23. Assuming normal distribution 
of the change in LMK, a common standard deviation (SD) of 5.50, which has 
incorporated a 20% inflation from the observed SD in ACT12340, and a 25% 
dropout rate, with 240 patients for the q2w pool and 120 patients in placebo, the 
study will have 99% power to detect an effect size of 1.285 using a two-sided 
test with alpha = 0.05 for the change in LMK at Week 24 in the dupilumab  
300 mg q2w group. 
With a same sample size of 240 patients for the q2w pool (Arm A and B) at 
Week 24, the combined power of the 3 co-primary efficacy endpoints for Japan 
is at least 97% for dupilumab 300 mg q2w group with alpha = 0.05 assuming no 
negative correlation between the 3 endpoints. 
Assuming the proportion of patients receiving SCS and/or who undergo or are 
planned for surgery for NP is 15% in the placebo group, and is 5% in the 
dupilumab group, with 240 patients for the q2w pool and 120 patients in 
placebo, the study will have 87% power to detect a hazard ratio of 0.316 
between the treatment groups using a two-sided log rank test with alpha = 0.05. 
The sample size calculations were performed using nQuery Advisor 7. 
Randomization: 
Patients will be randomized using a 1:1:1 randomization ratio to dupilumab 
300 mg q2w, dupilumab 300 mg q2w/q4w, or placebo. The randomization will be 
stratified based on asthma status, prior surgery, and country. 
Analysis population 
The primary analysis population for the efficacy endpoints will be the 
randomized ITT population which includes all patients who have been allocated 
to a randomized treatment regardless of whether the treatment kit was used or 
not. The efficacy analyses will be conducted according to the treatment to which 
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they were randomized. 
The analysis population for safety endpoints is defined as all patients exposed 
to study medication, regardless of the amount of treatment administered. The 
safety analyses will be conducted according to the treatment patients actually 
received. 
The treatment emergent period is defined as the time from the first 
administration of study medication to Week 12 of post treatment period. 
Co-primary efficacy variables 
The co-primary efficacy variables are: change from baseline in NC and in NPS 
at Week 24 assessed for dupilumab 300 mg q2w (pooled A and B arms) versus 
placebo, respectively. 
The following null hypothesis and alternative will be tested for pooled dupilumab 
arms against placebo:  
• 
H0: No treatment difference between the dupilumab dose regimen and 
placebo. 
• 
H1: There is a treatment difference between the dupilumab dose 
regimen and placebo. 
 
Analysis of the co-primary efficacy variables 
Each of the 2 co-primary efficacy endpoints (3 co-primary efficacy endpoints for 
Japan) will be analyzed using a hybrid method of the worst-observation carried 
forward (WOCF) and the multiple imputation. With this approach, for patients 
who undergo surgery for NP or receive SCS for any reason, data collected  
postsurgery or post SCS will be set to missing, and the worst postbaseline value 
on or before the time of surgery or SCS will be used to impute missing Week 24 
value (for patients whose postbaseline values are all missing, the baseline will 
be used to impute). For patients who discontinue the treatment without being 
rescued by surgery or receiving SCS, a multiple imputation approach will be 
used to impute missing Week 24 value, and this multiple imputation will use all 
patients who have not been rescued by surgery or receiving SCS at Week 24 
and data collected after treatment discontinuation will be included in the 
analysis. Each of the imputed complete data will be analyzed by fitting an 
ANCOVA model with the baseline covariate and factors for treatment, asthma 
status, prior surgery history, and regions. Statistical inference obtained from all 
imputed data will be combined using Rubin’s rule. Descriptive statistics including 
number of subjects mean, standard error, and least squares (LS) means will be 
provided. In addition, difference in LS means and the corresponding 95% 
confidence intervals (CI) will be provided along with the p-values. 
Analyses of key secondary efficacy endpoints 
Analysis of the change from baseline in TSS, UPSIT score, the daily loss of 
smell assessment, the LMK, and SNOT-22 scores at Week 24 for dupilumab 
300 mg q2w versus placebo 
The change from baseline in TSS, SNOT-22, UPSIT, daily loss of smell and 
LMK score at Week 24 will be assessed for dupilumab 300 mg q2w (pooled A 
and B arms) versus placebo and will be analyzed using the hybrid method of the 
WOCF and the MI in the same fashion as for the co-primary endpoints.  
Analysis of proportion of patients receiving SCS and/or planned to undergo 
surgery for nasal polyps during the treatment period for dupilumab  
300 mg q2w versus placebo 
Proportion of patients with first SCS rescue or surgery (actual or planned) for NP 
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during the treatment period will be derived and analyzed using the Cox 
proportional hazards model and log rank test stratified by asthma status, prior 
surgery history, and regions, by considering the first SCS rescue use or surgery 
(actual or planned) for NP as the event. The entire treatment period in Arms A 
and the treatment period of 300 mg q2w in Arm B (that is, the first 24 weeks) will 
be pooled and used as the treatment period by dupilumab 300 mg q2w, and the 
entire treatment period in Arm C will be used as the treatment period by 
placebo. For this analysis of proportion of patients with SCS rescue or surgery 
(actual or planned) for NP for dupilumab 300 mg q2w and placebo, patients in 
Arm B will be considered as censored at the end of 300mg q2w treatment. 
Descriptive statistics including number of patients with rescue or surgery and 
number of patients without rescue or surgery (censored) and the corresponding 
rates will be provided by treatment group. The estimates of the hazard ratio and 
corresponding 95% CI will be provided for dupilumab 300 mg q2w versus the 
placebo. 
Analysis of the change from baseline in NC and in NPS at Week 52  
The change from baseline in NC and in NPS at Week 52 will be assessed 
separately for dupilumab 300 mg q2w (Arm A) and dupilumab 300 mg q2w/q4w 
(Arm B) versus placebo and will be analyzed using the hybrid method of the 
WOCF and the MI in the same fashion as for the co-primary endpoints.  
Analyses of other secondary efficacy endpoints 
Analyses of efficacy endpoints for Arm A and Arm B versus placebo at Week 52 
The change from baseline in TSS, SNOT-22, UPSIT, daily loss of smell and 
LMK score at Week 52 will be assessed separately for dupilumab 300 mg q2w 
(Arm A) and dupilumab 300 mg q2w/q4w (Arm B) versus placebo and will be 
analyzed using the hybrid method of the WOCF and the MI in the same fashion 
as for the key secondary endpoints of change from baseline in NC and in NPS 
at Week 52. 
Proportion of patients with first SCS rescue or surgery (actual or planned) for NP 
during the treatment period up to Week 52 will be assessed separately for 
dupilumab 300 mg q2w (Arm A) and dupilumab 300 mg q2w/q4w (Arm B) 
versus placebo and will be analyzed using the same approach as those for the 
key secondary endpoint of the proportion of patients with SCS rescue or surgery 
(actual or planned) for NP during the treatment period for dupilumab 300 mg 
q2w versus placebo. With this approach, proportion of patients with first SCS 
rescue or surgery (actual or planned) for NP during the treatment period will be 
derived and analyzed using the Cox proportional hazards model and log rank 
test stratified by asthma status, prior surgery history, and regions, by 
considering the first SCS rescue use or surgery (actual or planned) for NP as 
the event. The entire treatment period in Arms A, B, and C will be used in the 
analysis, and comparisons will be made between Arms A and C, and between 
Arms B and C, separately. Descriptive statistics including number of patients 
with rescue or surgery and number of patients without rescue or surgery 
(censored) and the corresponding rates will be provided by treatment group. 
The estimates of the hazard ratio and corresponding 95% CI will be provided for 
Arms A versus C and Arms B versus C, respectively. 
Analysis for Arms A versus B at week 52 
Comparisons between dupilumab 300mg q2w and dupilumab 300 mg q2w/q4w 
will be made at Week 52. For such comparisons, descriptive statistics will be 
provided, and no statistical testing will be conducted. In more details, for 
changes from baseline in continuous endpoints, descriptive statistics including 
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number of subjects, mean, standard error, min, and max will be provided by 
treatment group; for proportions of responders, number and proportion of 
responders/non-responders will be provided by treatment group; for proportion 
of patients with SCS rescue or surgery (actual or planned) for NP, descriptive 
statistics including number of patients with rescue or surgery and number of 
patients without rescue or surgery (censored) and the corresponding rates will 
be provided by treatment group. In addition, corresponding 95% confidence 
intervals between Arms A and B will be provided. 
Time course profile of the different efficacy endpoints over 52 weeks will be 
provided to estimate magnitude of effect loss after w24 potentially resulting from 
the switch to a lower dosing/regimen (q4w) in the arm B of EFC14280 study. 
Analysis of sub-groups with comorbid asthma/NERD and prior surgery  
For each subgroup factor, interaction tests will be carried out to investigate 
consistency of the dupilumab effect across different subgroups identified by that 
factor.  
In addition, for these subgroups, comparisons at Week 24 will be analyzed 
between dupilumab 300mg q2w (pooled A and B arms) versus placebo, and 
comparisons at Week 52 will be analyzed separately between dupilumab 300mg 
q2w (Arm A) versus placebo, and between dupilumab 300mg q2w/q4w (Arm B) 
versus placebo. Details of these analyses will be provided in the statistical 
analysis plan. 
In addition to the analysis in the current study, statistical analysis for these 
subgroups with comorbid asthma/NERD and prior surgery will be further 
conducted using the pooled data of EFC14280 and EFC14146, and the details 
will be provided in the statistical analysis plan (SAP) for the Integrated Summary 
of Efficacy (ISE).  
Analysis of responder type endpoints 
For any responder type endpoints, the Cochran-Mantel-Haenszel test stratified 
by asthma status, prior surgery history, and region will be used. Comparisons of 
the proportions of responders between dupilumab 300mg q2w and placebo and 
between dupilumab 300 mg q2w/q4w and placebo will be derived. Patients who 
undergo surgery for NP or receive SCS for any reason will be considered as 
non-responders for time points after using SCS or surgery. For patients who 
discontinue treatment without using SCS or surgery, data collected during the 
off- treatment period will be used to determine the responder/non- responder 
status. Missing data will be considered as non-responders. 
Analysis of the proportion and time-to-event of patients with SCS rescue for any 
airway exacerbated disease 
Proportion and time-to-event of patients with SCS rescue for any airway 
exacerbated disease will be analyzed using a similar approach as the key 
secondary endpoint of the proportion of patients with SCS rescue or surgery 
(actual or planned) for NP. 
The safety variables, including AEs, laboratory parameters, vital signs, 
electrocardiogram (ECG) and physical examinations will be summarized using 
descriptive statistics. 
Missing data handling: 
For all continuous efficacy endpoints, in the primary approach for missing data 
handling, for patients who undergo surgery for NP or receive SCS for any 
reason, data collected postsurgery or post SCS will be set to missing, and the 
worst postbaseline value on or before the time of surgery or SCS will be used to 
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impute missing value at the certain analyzed visit (for patients whose 
postbaseline values are all missing, the baseline will be used to impute), and for 
patients who discontinue the treatment without being rescued by surgery or 
receiving SCS on or before the analyzed visit, a multiple imputation approach 
will be used to impute missing value at the certain analyzed visit, and this 
multiple imputation will use all patients who have not been rescued by surgery 
or receiving SCS at that analyzed visit and data collected after treatment 
discontinuation will be included in the analysis. 
For responder type endpoints, patients who undergo surgery for NP or receive 
SCS for any reason will be considered as non-responders for time points after 
using SCS or surgery; for patients who discontinue treatment without using SCS 
or surgery, data collected during the off- treatment period will be used to 
determine the responder/non-responder status, and missing data will be 
considered as non-responders. 
In addition, the reason and pattern of missing data will be carefully examined 
and tipping point analyses and other sensitivity analyses will also be performed. 
Multiplicity considerations: 
The multiplicity procedure is proposed to control the overall type-I error rate for 
testing the co-primary and selected secondary endpoints. The overall alpha is 
0.05. The comparisons with placebo will be tested based on the hierarchical 
order below at 2-sided α = 0.05: 
 
1) Co-primary efficacy endpoints: 
In countries other than Japan: 
• 
Change from baseline in NC and in NPS at Week 24 for 300mg q2w 
versus placebo. 
In Japan: 
• 
Change from baseline in NC, in NPS, and in CT LMK at Week 24 for 
300mg q2w versus placebo. 
2) Secondary efficacy endpoints:  
• 
Change from baseline in TSS at Week 24 for 300mg q2w versus 
placebo. 
• 
Change from baseline in UPSIT at Week 24 for 300mg q2w versus 
placebo. 
• 
Change from baseline in loss of smell daily symptoms at Week 24 for 
300mg q2w versus placebo. 
• 
Change from baseline in SNOT-22 at Week 24 for 300mg q2w versus 
placebo. 
• 
Change from baseline in CT LMK score at Week 24 for 300mg q2w 
versus placebo (this will not be a secondary endpoint for Japan as it is 
already a co-primary endpoint). 
• 
Proportion of patients with SCS rescue or surgery (actual or planned) 
for NP during the treatment period. 
• 
Change from baseline in NPS at Week 52 for q2w (Arm A) versus 
placebo (Arm C). 
• 
Change from baseline in NC at Week 52 for q2w (Arm A) versus 
placebo (Arm C). 
• 
Change from baseline in NPS at Week 52 for q2w/q4w (Arm B) versus 
placebo (Arm C). 
• 
Change from baseline in NC at Week 52 for q2w/q4w (Arm B) versus 
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placebo (Arm C). 
In countries other than Japan, the study is considered positive when both  
co-primary endpoints, the change from baseline in NC and in NPS at Week 24, 
achieve statistical significance. 
In Japan, the study is considered positive when all co-primary endpoints, the 
change from baseline in NC, in NPS, and in CT LMK at Week 24, achieve 
statistical significance. 
First step analysis:  
A first step analysis may be performed when all patients complete the Week 24 
visit, including early dropouts. The co-primary endpoints and other 24-week 
endpoints and proportion of patients with SCS rescue or surgery for NP (actual 
or planned) will be analyzed at this first step analysis as the final analysis for 
these endpoints, and 52-week endpoints will not be analyzed at this first step 
analysis. No decision on the conduct of the study will be made based on the first 
step analysis (in particular, no decision to prematurely stop the study). Specific 
steps will be taken to maintain the blind of the study to all individuals involved in 
the conduct of the study and/or analysis. 
DURATION OF STUDY PERIOD (per 
patient)  
The total duration of the study (per patient) is expected to be approximately 
68 weeks: 
• 
Run-in period (4 weeks +/- 3 days).  
• 
Randomized treatment period (52 weeks +/- 3 days). 
• 
Post treatment period (12 weeks +/- 3 days).  
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
 
 
R*= Randomization; EOT: end of treatment; EOS: end of study; V: Visit; D: Day; q2w: every 2 weeks; q4w: every 4 weeks; 
IMP: Regardless of the treatment group, all randomized patients will receive q2w subcutaneous administrations of dupilumab or placebo. For Arm B, after week 24 dupilumab administration will be alterned by placebo 
matched injection every other week up to week 50 (last IMP administration). Every other week investigational product administrations must be separated by at least 11 days. At V2 the Investigator or delegate will 
perform the injection. After V2, every other week administration of IMP will be performed at the investigational site up to at least Week 8 (V6). Patients will be monitored at the study site for at least 30 minutes or 
minimum time required by your local regulator after injections. From Week 10, every other week home administration of IMP (patient, caregiver, or health care professional) is possible if the patient (or the caregiver) 
has been trained. If the patient (or caregiver) is unable or unwilling to administer IMP, arrangements must be made for qualified site personnel and/or healthcare professionals to administer IMP for the doses not 
scheduled to be given at the study site.  
Non-investigational medicinal product: mometasone furoate nasal spray (MFNS) will be self-administered by the patient twice daily or once daily (if they cannot tolerate twice daily). At each visit the Investigator 
must ensure that the patient has the necessary doses up to the next visit, knowing that one MFNS device (1 bottle) contains sufficient doses for: either 2 weeks of BID treatment/regimen or 4 weeks of QD 
treatment/regimen. 
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1.2 
STUDY FLOW CHART 
 
Run-
ina 
Randomized treatment period 
EOTc 
EOS 
VISIT 
1 
2 
3 
4 
5 
6 
 
7 
 
8 
 
9 
 
10 
11 
Week 
 DAY +/-3 days 
W-4  
D-28 
W0 
 D1 
2 
D15 
4 
D29 
 
6 
D43 
8 
D57  
10,12,14b 
 
16 
D113 
18,20,22b 
24 
D169 
26,28,30,32,34,36,38b 
 
40 
D281 
42,44,46,48,50b 
52 
D365 
64 
D449 
Informed Consentsd  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical/Medication Historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Spirometrye 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Chest X-rayf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMPg: Dupilumab/placebo injection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Review IMP and/or NIMP compliance 
 
I------------------------------------------------------------------------------------------- X ------------------------------------------------------------------------------------I 
 
 
Call IVRS (IWRS) at scheduled and 
unscheduled visits as needed 
X 
I------------------------------------------------------------------------------------------- X ------------------------------------------------------------------------------------I 
X 
X 
Dispense or download electronic diary for 
symptomsh 
I-------------------------------------------------------------------------------------------------------X----------------------------------------------------------------------------------------------------------------I 
NIMP 
I-------------------------------------------------------------------------------------------------------X----------------------------------------------------------------------------------------------------------------I 
Record concomitant medication 
I------------------------------------------------------------------------------------------------------ X----------------------------------------------------------------------------------------------------------------I 
Record planned surgery for NP, SCS use, 
and other rescue medication use i 
I-------------------------------------------------------------------------------------------------------X----------------------------------------------------------------------------------------------------------------I 
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Nasal endoscopyj 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
CT scank 
Xk 
 
 
 
 
 
 
 
 
X 
 
 
 
Xk 
 
Smell test (UPSIT) 
 
X 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
NPIF 
X 
I-------------------------------------daily AM up to Week 24----------------------------------I 
X 
(W28, W32, W 36) 
X 
X 
(W44, W48) 
X 
 
Patient reported outcomes/HRQoLl 
I-------------------------------------------------------------------------------------------------X----------------------------------------------------------------------------------------------------------------I 
22-item sino-nasal outcome test (SNOT-
22) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Visual analogue scale (VAS) for 
rhinosinusitis and symptom severity (0-3) 
for reduced sense of taste 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Quality of life (EQ-5D)  
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
ACQ-6 in patients with asthmal 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Health care resource utilisationm  
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE /SAE recording (if any) 
I-----------------------------------------------------------------------------------------X-----------------------------------------------------------------------------------------------------------------I 
Vital signsn 
X 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
ECG (local reading) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testingo 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Hepatitis B viral loadp 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
Pregnancy test (for WOCBP)q  
X 
X 
 
X 
 
X 
X  
(W12) 
X 
X  
(W20) 
X 
X 
(W28, W32, W 36) 
X 
X 
(W44, W48) 
X 
X 
Sampling for serum dupilumab 
concentrationr 
 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Anti-drug antibody samplingr 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
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Blood biomarkers (TARC, eotaxin-3, 
periostin, serum total IgE)  
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Spot urine for biomarker sampling  
(LTE4 and PGDM and creatinine)  
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
a The run-in period is 28 days in duration to run in any patient on MFNS, and to collect baseline data. Patients receiving rescue medication with SCS or and surgery during this period will not be randomized. V2 will take 
place 28 days+/-3 days window after V1. Window for subsequent visits is also +/-3 days. Assessments/procedures at a site visit are performed in the following order if applicable: Patient-reported outcomes and 
other questionnaires; Procedures; Safety and laboratory assessments; IMP administration. 
b Optional interim visits may be scheduled at site for IMP/NIMP supply or IMP administration. 
c Patients who discontinue treatment early will be assessed as soon as possible using the procedures normally planned for the EOT Visit and will be instructed to return to the study site as described in  
Section 10.3.1. 
d Past medical history including allergic comorbidities (asthma, aspirin sensitivity, allergic rhinitis etc.). Surgeries for NP will be assessed including number, type and dates of sino-nasal surgeries, polypectomies in 
the past. Systemic corticosteroids (SCS) use (number of courses, doses, way of administration and duration) in the past 2 years before V1 and/or contraindication/intolerance to SCS, as well as long term 
antibiotics use (>2weeks) in the previous year will be entered in the e-CRF. NERD: NSAID (non-steroid anti-inflammatory drug) Exacerbated Respiratory Disease will be assessed through a specific questionnaire 
Appendix F.  
e Spirometry (FEV1, FVC and FEF 25-75): should be performed anytime during run-in period (between V1 and V2) before a first administration of IMP for all patients, locally after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours. FEV1, FVC and FEF 25-75 will be determined at the designated treatment visits. All patients should have the result of FEV1 (% of predicted 
normal) recorded in e-CRF: anytime during run-in period (before V2). Patients with forced expiratory volume (FEV1) 50% or less (of predicted normal) will not be randomized. For the other scheduled visits during 
the randomized treatment period, spirometry will be performed only in patients with asthma and the result of FEV1, FVC and FEF 25-75 will be recorded in e-CRF at the study scheduled visits. 
f 
Chest X-ray if no chest imaging (X-ray, CT, MRI) is available within the previous year of V1. In countries for which a specific approval procedure for the x-ray or CT scan is required by a different committee than 
the local EC/IRB, a chest MRI between V1 and V2 can be performed. Note for Japan: According to the request from the health authority, chest X-ray should be performed at V1 if there is no chest imaging (Chest 
X-ray, CT, MRI) available within 3 months prior to V1 to exclude patients with suspected active or untreated latent tuberculosis.  
g Refer to Section 1 and Section 6 Study Design for details on treatment arms. IMP will be administered after completion of all scheduled clinical assessments and sample collections at the visit or at home. 
h Electronic diary/NPIF meter is used for daily recording of MFNS use, morning NPIF (daily up to Week 24 and monthly from Week 24 onward) and daily symptoms severity from V1 to end of study): 1) nasal 
congestion/obstruction 2) anterior rhinorrhea (runny nose), 3) posterior rhinorrhea (post nasal drip), and 4) loss of sense of smell, scored using a 0-3 categorical scale where 0 = no symptoms, 1 = mild symptoms, 
2 = moderate symptoms and 3 = severe symptoms); This device is dispensed at V1 and information is downloaded from this device on the other indicated days. For nasal congestion, a severity ≥2 on V1 and a 
weekly average severity greater than 1 at time of randomization (V2) is required and will be made available to the site to determine patient eligibility. If there are 4 or more measurements collected within 7 days 
prior to randomization, the baseline will be the average of these measurements; if less than 4 measurements are collected, the baseline will be the average of the most recent 4 prior to randomization. 
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i 
At baseline (V1 and V2) eligibility to surgery based on Investigator opinion will be assessed. During the study treatment and follow up if rescue medication with SCS is required, oral prednisone or prednisolone will 
be dispensed by the site to the patient through a scheduled or unscheduled in-clinic visit. Use of oral steroids for rescue treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date and dosing information (daily dose, duration, INN) will be informed. Details on actual or planned date for surgery for NP, type 
and outcome (whenever possible) of surgery will be recorded in a specific e-CRF page. If surgery is performed during the study treatment period or follow-up an AE or SAE page will be completed. Patients will be 
discontinued from study treatment and assessed as soon as possible using the procedures normally planned for the EOT Visit and will be instructed to return to the study site as described in  
Section 10.3.1. If surgery is scheduled after the planned end of study, EOS visit will not be delayed. A follow up contact(s) should be performed around the time of planned surgery to document the surgery date 
and outcome. Surgery data will be collected until e-CRF closure of the trial. 
j 
Nasal endoscopy: endoscopy (including use of decongestants before the procedure) will be performed after all other efficacy assessments have been completed for each visit; Standard video sequences will be 
downloaded by the Investigator to the central reader’s secured internet site. For eligibility, central reading of V1 will be used. At V2, Investigator will review V1 results from central reader to confirm entry criteria and 
reconfirm eligibility based on review of Inclusion/Exclusion Criteria and the V2 endoscopy local reading. To confirm eligibility at V2, only the V1 central reading will be made available to the site. In addition at V2 the 
investigator will perform the NE to confirm eligibility score and enter the result in the e-CRF. Thus the patient is considered eligible based on a V1 central reading followed by a V2 local reading NPS score of 5 or 
more and at least 2 each side. The final results of central reading from V2 onward will be made available to the site after the study. 
k A CT scan should be performed anytime during the run-in period before the first administration of IMP and at V8 (Week 24). Central reading will be used for comparison baseline (BL) to Week 24 for the primary 
analysis and at EOT. A Week 52 CT scan may be performed if approved by local ethics committees. A Week 52 CT scan may be performed if approved by local ethics committees. Whenever possible a cone 
beam CT scan should can be utilized. In countries where local EC do not approve a CT scan or for which a specific approval procedure for the CT scan is required by a different committee than the local EC/IRB, 
patients may be enrolled using a CT available in the previous year or perform an MRI of the sinuses between V1 and V2. These countries will be exempted from all the planned study CT scans until approval from 
these committees is received. The MRI will be used only for confirmation of exclusion criteria. 
l 
During the study the PROs should be completed by the patient in the e-diary, in the following order: daily symptoms of NC, loss of smell and anterior and posterior rhinorrhea; SNOT-22; VAS rhinosinusitis; EQ-5D; 
ACQ-6 (in patients with asthma). 
m Health care resource utilization to be collected through the eCRF.  
n Vital signs, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per minute), body temperature (degrees Celsius) and body weight (kg) will be measured at the screening and 
randomization visits (V1 and V2) and subsequent visit pre-specified in the flow-chart. Height (cm) will be measured at screening (V1) only. Vital signs will be measured prior to receiving IMP at the clinic visits in the 
sitting position using preferably the same arm at each visit. 
o Hematology: hemoglobin, hematocrit, platelet count, total white blood cell (WBC) count with five-part differential count, and total red blood cell count. Serum chemistry: creatinine, blood urea nitrogen, glucose, uric 
acid, total cholesterol, total protein, albumin, total bilirubin (in case of values above the normal range, differentiation in conjugated and nonconjugated bilirubin), alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, lactate dehydrogenase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. Clinical laboratory testing at V1 includes hepatitis screen 
covering hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb) including HBcAb IgM and total, hepatitis C virus antibodies (HCVAb), Human 
Immunodeficiency Virus (HIV) screen (anti-HIV-1 and HIV-2 antibodies) and antinuclear antibody (ANA). In case of results showing HBsAg (negative), and HBcAb total or HBcAb IgM (positive), an HBV DNA 
testing may be performed prior to randomization to rule out a false positivity if the Investigator believes the patient is a false positive, or to clarify the serological status if the Investigator finds it unclear to interpret in 
absence of known HBV infection. In case of results showing HCV Ab (positive), an HCV RNA testing may be performed to rule out a false positivity, if the Investigator believes the patient is a false positive. Note: 
Anti-ds DNA antibody will be tested if ANA is positive (≥1:160 titer). Tuberculosis local testing at baseline would be performed on a country by country basis according to local guidelines if required by regulatory 
authorities or ethic committees.  
p This is only applicable for patients in countries/regions where there is local regulatory requirement who are HBs Ag negative and HBs Ab positive at the run-in period visit.  
q Serum pregnancy test at V1 and urine pregnancy tests every 4 weeks thereafter. A negative result must be obtained between V1 and V2 prior to randomization visits. Urinary test could be performed at home as 
part of visit with or without the assistance of a home care provider. In case of positive urinary test the study treatment will be withhold and a serum pregnancy test to confirm the pregnancy should be performed as 
soon as possible. Pregnancy will lead to definitive treatment discontinuation in all cases. 
r 
Serum dupilumab concentration, immune response assessment (ADA) samples will be collected and archived prior to administration of investigational product and during the randomized treatment period. Blood 
samples for PK and ADA assessment will be collected at any time in case an SAE occurs. In response to AE’s of special interest like anaphylaxis or hypersensitivity additional ADA samples closer to the event 
may be analyzed, based on the judgment of the medical Investigator and/or medical monitor. Patients who are ADA positive at their last study visit (early termination or end of study), will be considered for 
follow-up based on the overall clinical presentation at that time. Patients who are considered for follow-up may be asked to return to the clinic to have additional samples collected for analysis 
 
 
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Abbreviations: ACQ-6: asthma control questionnaire-6; ADA: antidrug antibodies; AE: adverse event; CT: computerized tomography; D: day; EC: ethics committee; ECG: electrocardiogram; e-CRF: electronic case 
report form; EOS: end of study; EOT: end of treatment; FEF 25-75: forced expiratory flow to 25% to 75% of pulmonary volume; FEV1: forced expiratory volume in one second; FVC: forced volume capacity; FU: 
follow up; HRQoL: health-related quality of life; IgE: immunoglobulin E; IMP: investigational medicinal product; IRB: institutional review board; IVRS: interactive voice response system; IWRS: interactive web 
response system; LTE4: leukotriene E4; MFNS: mometasone furoate nasal spray; MRI: magnetic resonance imaging; NC: nasal congestion; NERD: NSAID exacerbated respiratory disease; NIMP: 
noninvestigational medicinal product; SCS: systemic corticosteroid use; NP: nasal polyposis; NPIF: nasal peak inspiratory flow; PGDM: tetranor metabolite of prostaglandin D2; PK: pharmacokinetic; SAE: serious 
adverse event; SNOT-22: sino-nasal outcome test; UPSIT: University of Pennsylvania smell identification test; VAS: visual analog scale; W: week; WBC: white blood cell; WOCBP: women of child bearing potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
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2 
TABLE OF CONTENTS 
1 
FLOW CHARTS.............................................................................................................................15 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................15 
1.2 
STUDY FLOW CHART ..................................................................................................................16 
2 
TABLE OF CONTENTS ................................................................................................................21 
2.1 
LIST OF TABLES...........................................................................................................................27 
3 
LIST OF ABBREVIATIONS ..........................................................................................................28 
4 
INTRODUCTION AND RATIONALE.............................................................................................31 
4.1 
INTRODUCTION............................................................................................................................31 
4.2 
STUDY RATIONALE......................................................................................................................33 
4.3 
POPULATION................................................................................................................................33 
4.4 
STUDY DESIGN ............................................................................................................................34 
4.4.1 
Endpoints rationale and description...............................................................................................34 
4.4.2 
Dupilumab dose and regimen rationale .........................................................................................36 
4.5 
OVERALL BENEFITS AND RISKS ASSESSMENT......................................................................37 
5 
STUDY OBJECTIVES ...................................................................................................................39 
5.1 
PRIMARY.......................................................................................................................................39 
5.2 
SECONDARY OBJECTIVES.........................................................................................................39 
5.3 
EXPLORATORY OBJECTIVES.....................................................................................................39 
6 
STUDY DESIGN ............................................................................................................................40 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................40 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................41 
6.2.1 
Duration of study participation for each patient .............................................................................41 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................41 
6.3 
FIRST STEP ANALYSIS................................................................................................................41 
6.4 
STUDY COMMITTEES..................................................................................................................42 
6.4.1 
Data monitoring committee ............................................................................................................42 
6.4.2 
Clinical advisory committee ...........................................................................................................42 
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7 
SELECTION OF PATIENTS..........................................................................................................43 
7.1 
INCLUSION CRITERIA..................................................................................................................43 
7.2 
EXCLUSION CRITERIA ................................................................................................................43 
7.2.1 
Exclusion criteria related to study methodology ............................................................................43 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......44 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi compound......................................45 
7.2.4 
Additional exclusion criteria during or at the end of the run-in period............................................47 
8 
STUDY TREATMENTS .................................................................................................................48 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................48 
8.1.1 
Dupilumab......................................................................................................................................48 
8.1.2 
Placebo for dupilumab ...................................................................................................................48 
8.1.3 
Preparation of investigational medicinal product ...........................................................................48 
8.1.4 
Dosing schedule.............................................................................................................................48 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................49 
8.2.1 
Intranasal corticosteroid background therapy................................................................................49 
8.2.1.1 
Run-in period..................................................................................................................................49 
8.2.1.2 
Randomized treatment period........................................................................................................50 
8.2.1.3 
Post treatment period.....................................................................................................................50 
8.2.2 
Rescue treatment...........................................................................................................................50 
8.3 
BLINDING PROCEDURES............................................................................................................51 
8.3.1 
Methods of blinding........................................................................................................................51 
8.3.2 
Randomization code breaking during the study.............................................................................51 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................51 
8.5 
PACKAGING AND LABELING ......................................................................................................52 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................53 
8.7 
RESPONSIBILITIES ......................................................................................................................53 
8.7.1 
Treatment accountability and compliance......................................................................................54 
8.7.2 
Return and/or destruction of treatments ........................................................................................54 
8.8 
CONCOMITANT MEDICATION.....................................................................................................54 
8.8.1 
Prohibited concomitant medication................................................................................................54 
8.8.2 
Permitted concomitant medication.................................................................................................55 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................57 
9.1 
CO-PRIMARY ENDPOINTS ..........................................................................................................57 
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9.2 
SECONDARY ENDPOINTS ..........................................................................................................59 
9.2.1 
Key secondary efficacy endpoints .................................................................................................59 
9.2.1.1 
Disease specific daily symptom assessment and total symptom score (TSS)..............................59 
9.2.1.2 
Smell test: University of Pennsylvania Smell Identification Test (UPSIT) .....................................59 
9.2.1.3 
Decreased/loss of sense of smell ..................................................................................................60 
9.2.1.4 
Lund-Mackay score........................................................................................................................60 
9.2.1.5 
Proportion of patients during the treatment period who receive SCS rescue or are planned 
to undergo surgery for NP..............................................................................................................60 
9.2.1.6 
22-Item sino-nasal outcome test (SNOT-22).................................................................................61 
9.2.2 
Other secondary endpoints............................................................................................................61 
9.2.2.1 
SCS dose and number of courses.................................................................................................61 
9.2.2.2 
Visual analogue scale ....................................................................................................................62 
9.2.2.3 
Nasal peak inspiratory flow............................................................................................................62 
9.2.2.4 
Asthma Control Questionnaire, 6-question version (ACQ-6) in those patients comorbid with 
asthma ...........................................................................................................................................63 
9.2.2.5 
Health related quality of life (HRQoL) ............................................................................................63 
9.3 
EXPLORATORY ENDPOINTS:.....................................................................................................64 
9.3.1 
Spirometry......................................................................................................................................64 
9.4 
SAFETY ENDPOINTS ...................................................................................................................64 
9.4.1 
Adverse events ..............................................................................................................................64 
9.4.2 
Laboratory safety variables............................................................................................................65 
9.4.3 
Hepatitis screening.........................................................................................................................65 
9.4.4 
Pregnancy test ...............................................................................................................................65 
9.4.5 
Vital signs.......................................................................................................................................65 
9.4.5.1 
Physical examination .....................................................................................................................66 
9.4.6 
Electrocardiogram variables ..........................................................................................................66 
9.5 
OTHER ENDPOINTS.....................................................................................................................66 
9.5.1 
Functional dupilumab concentration and anti-drug antibodies in serum .......................................66 
9.5.1.1 
Sampling time ................................................................................................................................66 
9.5.1.2 
Handling procedures......................................................................................................................66 
9.5.1.3 
Bioanalytical methods ....................................................................................................................67 
9.5.1.4 
Functional dupilumab concentration and anti-drug antibody measurement and samples ............67 
9.5.2 
Pharmacodynamics........................................................................................................................68 
9.5.2.1 
Serum biomarkers..........................................................................................................................68 
9.5.2.2 
Plasma biomarkers ........................................................................................................................68 
9.5.2.3 
Urine biomarkers............................................................................................................................68 
9.5.2.4 
.............................................68 
9.5.3 
........................................................................................................................69 
9.5.3.1 
......................................................................69 
9.6 
FUTURE USE OF SAMPLES ........................................................................................................70 
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9.7 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................70 
10 
STUDY PROCEDURES ................................................................................................................71 
10.1 
VISIT SCHEDULE..........................................................................................................................71 
10.1.1 
Visit 1 (Week -4/Day -28 ±3 days): Run-in period .........................................................................73 
10.1.2 
Visit 2 (Week 0): Randomization....................................................................................................74 
10.1.3 
Visit 3 (Week 2)..............................................................................................................................77 
10.1.4 
Visit 4 (Week 4)..............................................................................................................................77 
10.1.5 
Visit 5 (Week 6)..............................................................................................................................78 
10.1.6 
Visit 6 (Week 8)..............................................................................................................................79 
10.1.7 
Optional visits (Week 10, 12, 14)...................................................................................................80 
10.1.8 
Visit 7 (Week 16)............................................................................................................................81 
10.1.9 
Optional visits (Week 18, 20, 22)...................................................................................................82 
10.1.10 Visit 8 (Week 24)............................................................................................................................83 
10.1.11 Optional visits (Week 26, 28, 30, 32, 34, 36, 38)...........................................................................84 
10.1.12 Visit 9 (Week 40)............................................................................................................................85 
10.1.13 Optional visits (Week 42, 44, 46, 48, and 50)................................................................................86 
10.1.14 Visit 10 (Week 52): End of treatment.............................................................................................86 
10.1.15 Visit 11 (Week 64): End of study....................................................................................................88 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................89 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................89 
10.3.1 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................89 
10.3.2 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................90 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................91 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................91 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................92 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................92 
10.4.1 
Definitions of adverse events.........................................................................................................92 
10.4.1.1 Adverse event ................................................................................................................................92 
10.4.1.2 Serious adverse event ...................................................................................................................93 
10.4.1.3 Adverse event of special interest...................................................................................................94 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................95 
10.4.3 
General guidelines for reporting adverse events ...........................................................................95 
10.4.4 
Instructions for reporting serious adverse events ..........................................................................95 
10.4.5 
Guidelines for reporting adverse events of special interest...........................................................96 
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10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................96 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................97 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................98 
10.6.1 
Hypersensitivity..............................................................................................................................98 
10.6.2 
Severe injection site reactions .......................................................................................................98 
10.6.3 
Infections, including opportunistic and parasitic infections ............................................................98 
10.6.4 
Elevated liver function tests ...........................................................................................................99 
10.7 
ADVERSE EVENTS MONITORING............................................................................................100 
11 
STATISTICAL CONSIDERATIONS............................................................................................101 
11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................101 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................102 
11.3 
ANALYSIS POPULATIONS.........................................................................................................102 
11.3.1 
Efficacy populations .....................................................................................................................102 
11.3.1.1 Intent-to-treat population..............................................................................................................102 
11.3.2 
Safety population .........................................................................................................................103 
11.3.3 
Systemic drug concentration population......................................................................................103 
11.3.4 
Anti-drug antibody population ......................................................................................................103 
11.3.5 
Nasal biomarker substudy population..........................................................................................103 
11.4 
STATISTICAL METHODS ...........................................................................................................103 
11.4.1 
Extent of study treatment exposure and compliance...................................................................103 
11.4.1.1 Extent of investigational medicinal product exposure..................................................................103 
11.4.1.2 Compliance ..................................................................................................................................104 
11.4.2 
Analyses of efficacy endpoints.....................................................................................................104 
11.4.2.1 Analysis of co-primary efficacy endpoint(s) .................................................................................104 
11.4.2.2 Analyses of key secondary efficacy endpoints ............................................................................105 
11.4.2.3 Multiplicity considerations ............................................................................................................106 
11.4.2.4 Analyses of other secondary efficacy endpoints..........................................................................107 
11.4.2.5 Analyses of exploratory efficacy endpoints..................................................................................109 
11.4.2.6 Missing data handling ..................................................................................................................110 
11.4.3 
Analyses of safety data................................................................................................................110 
11.4.3.1 Adverse events ............................................................................................................................110 
11.4.4 
Analyses of pharmacokinetic, anti-drug antibodies and pharmacodynamic variables ................112 
11.4.4.1 Functional dupilumab concentration analysis ..............................................................................112 
11.4.4.2 Anti-drug antibodies analysis .......................................................................................................112 
11.4.4.3 Pharmacodynamics......................................................................................................................113 
11.4.5 
Analyses of patient reported outcomes (Health-related Quality of Life/health economics 
variables)......................................................................................................................................113 
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11.5 
FIRST STEP ANALYSIS..............................................................................................................113 
12 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................................114 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................114 
12.2 
INFORMED CONSENT ...............................................................................................................114 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC).................................................................................................115 
13 
STUDY MONITORING.................................................................................................................116 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................116 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................116 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................117 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST....................................................................................................................................117 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................117 
14 
ADDITIONAL REQUIREMENTS.................................................................................................118 
14.1 
CURRICULUM VITAE..................................................................................................................118 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................118 
14.3 
CONFIDENTIALITY .....................................................................................................................118 
14.4 
PROPERTY RIGHTS...................................................................................................................119 
14.5 
DATA PROTECTION...................................................................................................................119 
14.6 
INSURANCE COMPENSATION..................................................................................................120 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................120 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................120 
14.8.1 
By the Sponsor.............................................................................................................................120 
14.8.2 
By the Investigator .......................................................................................................................121 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................121 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................121 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................122 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................123 
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APPENDICES..............................................................................................................................126 
APPENDIX A 
LIST OF PROHIBITED LIVE ATTENUATED VACCINES.................................................126 
APPENDIX B 
SNOT-22............................................................................................................................127 
APPENDIX C EQ-5D-5L...........................................................................................................................128 
APPENDIX D VAS....................................................................................................................................131 
APPENDIX E 
ACQ-6................................................................................................................................132 
APPENDIX F QUESTIONS FOR PATIENTS WITH CRSWNP TO ASSIST DETERMINATION OF 
NERD DIAGNOSIS......................................................................................................................135 
APPENDIX G 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................136 
APPENDIX H DEFINITION OF ANAPHYLAXIS ......................................................................................141 
APPENDIX I 
LIST OF OPPORTUNISTIC INFECTIONS.........................................................................142 
 
2.1 
LIST OF TABLES 
Table 1 - Endoscopic nasal polyp score........................................................................................................58 
Table 2 - Summary of handling procedures for SAR231893 (dupilumab) ....................................................67 
Table 3 - Summary of bioanalytical methods for dupilumab and anti-dupilumab antibody...........................67 
Table 4 - Summary of adverse event reporting instructions..........................................................................97 
 
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3 
LIST OF ABBREVIATIONS 
 
ACQ-6: 
asthma control questionnaire-6 
AD: 
atopic dermatitis 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
AM: 
ante meridiem 
ANA: 
anti-nuclear antibody 
BID: 
twice daily 
CI: 
confidence interval 
CPK: 
creatine phosphokinase 
CRSwNP: 
chronic rhinosinusitis with nasal polyposis 
CSR: 
clinical study report 
CT: 
computed tomography 
CYP: 
cytochrome P 
DMC: 
data monitoring committee 
DNA: 
deoxyribonucleic acid 
DRF: 
discrepancy resolution form 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
e-diary: 
electronic diary 
EOS: 
end of study 
EOT: 
end of treatment 
EQ-5D: 
European quality of life-5D scale 
FEF 25-75: 
forced expiratory flow at 25% to 75% of forced vital capacity 
FEV1: 
forced expiratory volume in 1 second 
FVC: 
forced vital capacity 
GCP: 
good clinical practice 
GSO: 
Global Safety Officer 
HBcAb: 
hepatitis B core antibody  
HBsAb: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen  
HBV: 
hepatitis B virus 
HCVAb: 
hepatitis C virus antibody 
HIV: 
human immunodeficiency virus 
HLGT: 
high level group term 
HLT: 
high level term 
HRQoL: 
health related quality of life 
ICH: 
International Council for Harmonisation 
IDMC: 
independent data monitoring committee 
IEC: 
independent ethic committee 
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IgE: 
immunoglobulin E 
IL: 
interleukin 
IL-4Rα: 
interleukin-4 receptor alpha 
IM: 
intramuscular 
IMP: 
investigational medicinal product 
INCS: 
intranasal corticosteroid spray 
INN: 
international nonproprietary name 
IRB: 
institutional review board 
ITT: 
intent-to-treat 
IV: 
intravenous 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
K-M: 
Kaplan-Meier 
LFT: 
liver function test 
LMK: 
Lund Mackay 
LS: 
least squares 
mAB: 
monoclonal antibody 
MCID: 
minimal clinically important difference 
MFNS: 
mometasone furoate nasal spray 
MI: 
multiple imputation 
MID: 
minimal important difference 
NC: 
nasal congestion 
NERD: 
non-steroid anti-inflammatory drug exacerbated respiratory disease 
NIMP: 
non-investigational medicinal product 
NP: 
nasal polyposis 
NPIF: 
nasal peak inspiratory flow 
NPS: 
nasal polyp score 
NSAID: 
non-steroid anti-inflammatory drug 
OC: 
osteomeatal complex 
OCS: 
oral corticosteroid 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
PGDM: 
metabolite of prostaglandin D2 
PK: 
pharmacokinetics 
POC: 
proof of concept 
PRO: 
patient reported outcome 
PT: 
preferred term 
q2w: 
every 2 weeks 
q4w: 
every 4 weeks 
QD: 
once daily administration 
QoL: 
quality of life 
qw: 
once weekly 
RNA: 
ribonucleic acid 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
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SCS: 
systemic corticosteroid 
SD: 
standard deviation 
SEM: 
standard error of the mean 
SNOT-22: 
22-item sino-nasal outcome test 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse event 
TARC: 
thymus and activation regulated chemokine 
TEAE: 
treatment emergent adverse event 
Th2: 
T-helper cell-2 
TSS: 
total symptoms score 
ULN: 
upper limit of normal 
UPSIT: 
University of Pennsylvania smell identification test 
US: 
United States 
V: 
Visit 
VAS: 
visual analogue scale 
WOCBP: 
women of childbearing potential 
WOCF: 
worst observation carried forward 
β-hCG: 
beta human chorionic gonadotrophin 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a clinical condition characterized by the 
presence of multiple polyps in the upper nasal cavity, originating from the osteomeatal complex 
(OC) and the spheno-ethmoid recess and characterized by mucosal inflammation of the nasal 
cavity and paranasal sinuses with symptoms lasting more than 12 weeks. Clinically, CRSwNP is 
defined by long-term symptoms of nasal obstruction and congestion, reduction in or loss of sense 
of smell, and anterior and posterior rhinorrhea. These symptoms can impact greatly upon a 
patient’s quality of life (QoL). The presence or absence of polyps is confirmed by performing 
endoscopy. Coronal computed tomography (CT) scans can confirm the presence and extent of 
sinus and polyp involvement. With an estimated prevalence of 2% to 4% (in Europe and the 
United States [US]), CRSwNP has a high burden of symptoms and a high relapse rate after 
treatment. Despite the high prevalence and significant morbidity associated with CRSwNP, 
treatment option range from local or systemic corticosteroids (SCS) to functional endoscopic 
sinus surgery. Patients with CRSwNP and comorbid asthma (30% of patients) have a 
characteristically poor therapeutic response and a high recurrence rate, and their disease tends to 
be more resistant (1, 2). 
The pathogenesis of nasal polyps is unknown. Nasal polyps are most commonly thought to be 
caused by allergy, although a significant number are associated with non-allergic adult asthma or 
no respiratory or allergic trigger that can be demonstrated. Risk factors include genetic 
susceptibility, anatomic abnormalities, infection, local immunologic imbalance and eicosanoid 
dysmetabolism (manifested as aspirin intolerance), some or most of which may play a role in its 
pathogenesis (3, 4, 5). 
Pathophysiologically, CRSwNP is an inflammatory and remodeling process affecting the mucosa 
of the nose and paranasal sinuses often associated with mucocilliary impairment, bacterial 
infection, allergic disease, and/or anatomical abnormalities (6, 7, 8). CRSwNP is a T-helper cell-2 
(Th2) driven inflammatory process in which eosinophils are the predominant inflammatory cell 
found in the sinuses and nasal polyps, and is frequently associated with asthma and aspirin 
sensitivity (9). In European and US populations, more than 80% of patients with CRSwNP have 
eosinophilic upper airway inflammation. The extent of sinomucosal involvement, the size of the 
polyps, and the severity of nasal disease correlate with the extent of eosinophilic inflammation 
(10). The chronic inflammation associated with eosinophilic polyps exhibits elevated levels of 
interleukin-5 (IL-5) (promoter of eosinophil survival, differentiation and taxis), eosinophil 
cationic protein (eosinophil activation product), eotaxins (eosinophil chemoattractants), and 
immunoglobulin E (IgE) in the nasal polyps and local secretions (11).  
The therapeutic armamentarium of clinically proven medical interventions for CRSwNP is 
limited. First-line treatment is topical corticosteroids. Intranasal corticosteroid sprays (INCS) 
improve the symptoms of nasal obstruction (12), secretion, and sneezing to some extent. 
However, their effect in reducing polyp size and on improving the sense of smell (13), a cardinal 
symptom of nasal polyposis (NP) (14) is limited. Overall, due to the relatively modest effects on 
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the symptoms of NP, in many instances, INCSs do not address the main QoL issues for patients. 
Short courses of oral steroids are also prescribed as adjunctive therapy to INCS or in cases of 
severe disease (15); however, the long-term use of systemic steroids for the treatment of nasal 
polyps is not recommended as the risk of prolonged systemic steroids use is not outweighed by 
the benefit (12). 
The current US practice guidelines indicate that the duration of clinical benefit of oral 
corticosteroids (OCS) is variable and may decrease with repeated courses of treatment (16). 
The only alternative for most patients that respond inadequately to medical treatment is surgery of 
the sinuses. However, even after surgical treatment, continued use of at least INCS is needed and 
disease recurrence requiring repeated surgeries is high. 
Recent therapeutic approaches have been focused on trying to control the Th2 response and 
clinical improvement in CRSwNP and associated symptoms were observed in other studies of 
biological therapies, including the anti-IgE monoclonal antibody (mAB) omalizumab (17) or the 
anti-IL-5 mAB mepolizumab (18).  
Dupilumab is a systemic targeted immunomodulatory agent, inhibiting the Th2 pathway. It is a 
fully human mAB directed against the interleukin-4 receptor alpha (IL-4Rα) subunit, a component 
of IL-4 receptors Type I and Type II, which mediate signaling by IL-4 (both receptors) and by 
IL-13 (Type II receptor). Dupilumab binds to IL-4Rα, preventing IL-4 and IL-13 activation of 
their respective receptors. 
For further information regarding the preclinical and clinical evaluation of dupilumab to date, 
refer to the current version of the Investigator Brochure.  
Dupilumab is in clinical development for the treatment of CRSwNP worldwide. However in the 
US, based on FDA feed-back, this clinical development program will support the indication of 
nasal polyposis. 
Preliminary clinical evidence, based on the proof of concept (POC) data and the mechanism of 
action, suggests that dupilumab provides an effective treatment and substantial improvement over 
INCS for patients suffering from CRSwNP. In a POC study (ACT12340), 60 patients with 
bilateral NP and chronic symptoms of sinusitis refractory to nasal corticosteroids were 
randomized to dupilumab 300 mg once weekly (qw) SC administration for 16 weeks or placebo, 
with background mometasone furoate nasal spray (MFNS) (NASONEX). In this study, dupilumab 
demonstrated a significant improvement in endoscopic, radiographic and clinical measures of NP 
and sinusitis, as well as improvements in lung function and disease control in patients with 
comorbid asthma (19). 
Dupilumab, therefore, offers promise of significant benefit above and beyond current standard of 
care in this patient population and may provide an alternative for those patients who are respond 
inadequately to INCS and may obviate the need for repeated surgeries. 
 
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4.2 
STUDY RATIONALE 
This is a phase 3, randomized, placebo-controlled efficacy and safety study of dupilumab in 
patients with moderate to severe signs and symptoms of NP who are not controlled on standard of 
care. 
This study will primarily investigate the efficacy and safety of dupilumab 300 mg every 2 weeks 
(q2w) (Arms A and B) as compared to placebo (Arm C) on top of the current standard of care 
background therapy (daily use of intranasal MFNS [NASONEX]), utilizing multiple objective and 
subjective outcome measures in patients with NP. By allowing Investigators, at their discretion, to 
use SCS or surgery as a rescue therapy for worsening of NP, the study will also assess the effect 
of dupilumab on the need for surgery and SCS use over the randomized treatment period. 
In addition, the study is designed to inform on the long-term efficacy of an initial treatment with 
dupilumab 300 q2w for 24 weeks followed by a less frequent dosing regimen (300 mg every 
4 weeks [q4w]) up to Week 52.  
4.3 
POPULATION 
The population of the EFC14280 study is composed of patients with bilateral NP (endoscopic 
bilateral nasal polyp score [NPS] has to be ≥5 out of a maximum score of 8) who present with 
chronic symptoms of nasal congestion (NC) (moderate/severe) and another symptom such as loss 
of smell or rhinorrhea despite background treatment with INCS and maximum therapy with 
standard of care including SCS (in the previous 2 years) and/or surgery in the past (see Section 
7.1).  
The proposed patient selection criteria will reflect standard of care in this severe uncontrolled 
patient setting by allowing enrollment of patients that received INCS, SCS prior to the run-in 
period and/or patients with previous surgeries.  
Approximately 26-50% of NP patients suffer from comorbid asthma and it is estimated that 
asthma is underdiagnosed in up to 25% of these patients (20, 21).NP has also been observed to be 
associated with chronic bronchitis and, in those with asthma, lower airway obstruction (6, 20).  
NP patients also more frequently present with non-steroid anti-inflammatory drug (NSAID) 
intolerance (22) and if they also suffer from asthma they are diagnosed with NSAID exacerbated 
respiratory disease (NERD).  
These patients have the highest rates of exacerbation and hospital admissions and tend to have a 
poorer perception of control of disease, due to the persistence and severity of the associated 
sinonasal symptoms (23). Additionally, asthma symptoms tend to be more severe in these 
patients. 
Taking into account the high prevalence, the high disease burden and unmet need of NP patients 
who have co-morbid asthma or NERD, these patients will be allowed to enter the study (unless 
they present with any of the exclusion criteria described in the Exclusion Criteria Section 7.2). In 
addition, stratification at randomization for asthma and specific sub-group analysis will be 
performed to specifically assess efficacy in these subgroups. 
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NP patients who have persistent signs and symptoms or disease relapse after short course 
treatment with SCS or after a surgery for NP, represent a subgroup of patients with higher burden 
and unmet need, and therefore will be also analyzed. In addition, stratification at randomization 
for patients with prior surgery will be performed. 
4.4 
STUDY DESIGN 
This phase 3 multinational, multicenter, randomized, double-blind, placebo-controlled, parallel 
group study will evaluate the efficacy of dupilumab 300 mg administered subcutaneous (SC) q2w 
for 52 weeks on a background of INCS. The efficacy of dupilumab 300 mg q2w for 24 weeks 
followed by 300 mg every 4 weeks (q4w) up to Week 52 versus placebo will be also evaluated.  
The proposed study, allowing daily use of INCS and SCS courses and/or surgery as needed or 
other treatments considered standard of care will aim at evaluating a potential role for dupilumab 
in the existing treatment paradigm, for the treatment of nasal polyps.  
The clinical study consists of 3 periods: 
• 
Run-in period where the patients will receive MFNS for 4 weeks +/-3 days; 
• 
Randomized dupilumab/placebo treatment period (52 weeks) where approximately 
360 patients will be randomized, 120 p/Arm, to one of the following treatments: 
- 
Arm A: dupilumab 300 mg q2w SC until Week 52, 
- 
Arm B: dupilumab 300 mg q2w SC until Week 24, then 300 mg q4w until Week 52, 
- 
Arm C: placebo matching dupilumab SC q2w administration until Week 52. 
• 
Post treatment period - where patients will be followed for 12 weeks to evaluate systemic 
concentrations of functional dupilumab (PK), immunogenicity and safety after they are off 
the IMP.  
During the whole study duration, patients will continue MFNS stable dose started at Visit 1 (V1) 
except if dose is changed due to AE. 
In addition patients may receive rescue medications (including SCS) and/or undergo surgery for 
NP as deemed necessary by the Investigator and patient. Short courses of oral steroids are often 
used as adjunctive therapy to INCS or in cases NP patients who fail standard of care with INCS 
(15). Refer to Section 8.2.2 for additional details. 
Overall, this study will evaluate the potential real life benefit that dupilumab may provide for 
patients that failed currently available therapies. 
4.4.1 Endpoints rationale and description 
Clinically, NP is defined by long-term symptoms of nasal obstruction and congestion, reduction in 
or loss of sense of smell, and anterior and posterior rhinorrhea. The presence or absence of polyps 
is confirmed by performing endoscopy. These symptoms can impact greatly patient’s QoL.  
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Medical and surgical intervention decisions are mainly driven by the nasal polyp symptom burden 
and response to standard therapy with topical and SCS. Therefore, in this study, severity of 
symptoms will be scored daily by the patient (0-3). For nasal congestions/obstruction which is a 
major clinical symptom, the monthly average of the daily recorded symptom score will be 
assessed as co-primary endpoint along with the objective endoscopic assessment of NP score.  
Thus, the co-primary endpoints of this study are the change from baseline at Week 24 in: 
• 
Nasal congestion/obstruction symptom severity score consisting of the monthly average of 
the daily morning ante meridiem (AM) patient-assessed symptom severity (using a 0-3 
categorical scale). The NC is assessed by the patient on a daily basis from V1 and 
throughout the study, using an electronic diary (e-diary) using a 0-3 categorical scale 
(where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe 
symptoms). 
• 
The bilateral endoscopic NPS that ranges from 0-8 points and is the sum of the right and 
left scores (from 0 = no polyps; 1=small polyps in the middle meatus not reaching below 
the inferior border of the middle turbinate; 2 = polyps reaching below the lower border of 
the middle turbinate; 3= large polyps reaching the lower border of the inferior turbinate or 
polyps medial to the middle turbinate; 4 = large polyps causing complete obstruction of the 
inferior nasal cavity) (17, 18, 24).  
For Japan, in addition to the 2 co-primary endpoints above, the following will also be a  
co-primary endpoint: 
• 
Change from baseline in sinus opacifications assessed by CT scans using the Lund 
Mackay (LMK) score at Week 24.  
Key secondary endpoints of the study include: 
• 
Change from baseline in total symptoms score (TSS): composite severity score consisting 
of the patient daily AM assessed Nasal congestion/obstruction, decreased/loss of sense of 
smell, anterior/posterior rhinorrhea at Week 24. 
• 
Change from baseline in University of Pennsylvania smell identification test (UPSIT) at 
Week 24. 
• 
Change from baseline in the severity of decreased/loss of smell daily assessed by the 
patient at Week 24.  
• 
Change from baseline in sinus opacifications assessed by CT scans using the LMK score 
at Week 24. (Note for Japan: this is considered as primary end point) 
• 
Change from baseline in 22-item sino-nasal outcome test (SNOT-22) at Week 24.  
• 
Proportion of patients receiving SCS and/or are planned for surgery of nasal polyps during 
the study treatment. 
• 
Change from baseline in NC for q2w (Arm A) versus placebo (Arm C) at Week 52. 
• 
Change from baseline in NPS for q2w (Arm A) versus placebo (Arm C) at Week 52. 
• 
Change from baseline in NC for q2w/q4w (Arm B) versus placebo (Arm C) at Week 52. 
• 
Change from baseline in NPS for q2w/q4w (Arm B) versus placebo (Arm C) at Week 52. 
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The proposed study design and endpoints will answer important clinical questions about the 
efficacy on symptoms and objective signs of the disease and the effect of dupilumab on reduction 
of SCS rescue therapy and surgery, which are the most relevant clinical-practice assessments and 
reflecting current standard of care.  
Other efficacy, safety and exploratory assessments in patient reported outcomes (PROs), HRQoL 
and condition specific and general medical questionnaires to evaluate the potential real life benefit 
will be evaluated too.  
These treatment approaches and endpoints reflects real-life clinical assessment and are in line 
with increasing focus in the medical field on the effects of medical conditions and treatments on 
the QoL of and functioning of patients (1).  
4.4.2 Dupilumab dose and regimen rationale  
The dose regimens are selected based on the totality of clinical evidence in the dupilumab 
program including data from Phase 2 efficacy and safety study (ACT12340) in patients with nasal 
polyps and symptoms of chronic sinusitis, the result of Phase 2b dose ranging study in patients 
with moderate to severe asthma (DRI12544), the Phase 2b dose ranging study (R668-AD-1021) 
and phase 3 studies (R668-AD-1334 and R668-AD-1416) in patients with moderate to severe 
atopic dermatitis (AD), as well as the supportive PK/pharmacodynamic [PD] analysis.  
While the clinical manifestations may be distinct across NP, asthma and AD indications, Th2 
mediated inflammation is implicated in the disease etiology and pathophysiology of all 
3 conditions. Dupilumab has demonstrated marked concentration dependent inhibition of the 
upstream and downstream Th2 inflammatory biomarkers including thymus and activation-
regulated chemokine (TARC) and IgE with a very similar PD profile and exposure-response 
relationship in AD, asthma, and NP patients. In asthma dose ranging study (DRI12544), 300 mg 
q2w regimen demonstrated a robust treatment effect across all relevant indices of drug action, 
while less frequent regimens 200 mg q2w and 300mg q4w showed less effect in some endpoints 
including SNOT-22. Both dose-response and exposure-response analyses indicated that 
therapeutic responses (eg, improvement in forced expiratory volume in 1 second [FEV1] at 
Week 12) and biomarker responses (including fractional exhaled nitric oxide and TARC) 
plateaued by 300 mg q2w. Thus, a further increase in dose above 300 mg q2w is unlikely to 
achieve additional clinical benefit. The 300 mg q2w regimen is being currently evaluated as the 
higher dose regimen in the asthma Phase 3 pivotal study.  
In the AD dose ranging study (R668-AD-1021), similar treatment effect between 300 mg qw and 
300 mg q2w was also observed for most of efficacy endpoints (eg, IGA [Immunoglobulin A] and 
EASI [Eczema Area and Severity Index]). Consistently, results from the Phase 3 efficacy and 
safety studies in AD patients (R668-AD-1334 and R668-AD-1416) confirmed the highly similar 
clinical efficacy for the 300 mg qw and 300 mg q2w regimens across all endpoints. 
In the Phase 2 POC study in NP patients with chronic symptoms of sinusitis (ACT12340), the 
300 mg qw regimen demonstrated a robust, clinically and statistically significant treatment 
response on the primary and secondary efficacy endpoints for NP and chronic sinusitis at the end 
of the 16 week treatment period. PK/PD analysis of ACT12340 efficacy endpoints predicted a 
superior therapeutic benefit at both 300 mg q2w and 300 mg qw regimens, including clinical 
significant reduction in bilateral NPS (>1 point from baseline) and significant improvement in 
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symptoms of NC and decrease/loss of smell. The exposure-response analysis of SNOT-22 by 
leveraging both ACT12340 and the dose ranging data from DRI12544 NP patients consistently 
supports significant clinical benefits of 300 mg q2w regimen in improving SNOT-22 outcome 
(total score and selected nasal components of loss of smell and nasal blockage) and limited 
additional benefit with further increase in dose beyond 300 mg q2w. Thus, the available efficacy 
data from asthma, AD and NP trials collectively indicate a high potential for achieving an optimal 
treatment effect at 300 mg q2w in NP patients. 
Nasal polyposis is an inflammatory disorder of upper airways of chronic and recurring nature 
requiring the use of long-term anti-inflammatory treatment to achieve a maintenance state (25).  
In the ACT12340 study, a gradual development of treatment response was observed for bilateral 
NPS and NP symptoms of NC and sense of smell. The PD steady-state for the above endpoints 
was not reached at the end of treatment (EOT) at Week 16, suggesting additional therapeutic 
benefit with longer treatment duration. The time-course PK/PD analysis predicts 24 weeks to be 
the optimal treatment duration to assess the maximal symptomatic effect for NPS, NC, and other 
key secondary efficacy endpoints. In addition, a persistent off-treatment effect for dupilumab was 
also observed, where clinically relevant improvement in the primary and secondary endpoints as 
compared to the baseline was sustained at the end of the 16-week follow-up when dupilumab 
concentration already became undetectable. This suggested that a dose regimen given less 
frequently might sustain a full treatment response. Therefore, the current study will assess both 
the long term efficacy of the 300 mg q2w treatment for a 52-week period, as well as the 
maintenance of efficacy at a less frequent 300 mg q4w dosing regimen starting after an initial  
24-week "induction" treatment period with 300 mg q2w and continuing until completion of a total 
treatment duration of 52 weeks.  
In the ACT12340, a single loading dose of 600 mg was used on Day 1 to rapidly achieve an 
efficacious concentration range for a potentially earlier onset of significant response. Consistent 
with the observed PK and PD profile of NP response (gradual development of response as well as 
slow offset of response during off-treatment), PK/PD simulation of co-primary endpoints of NPS 
and NC showed minimal difference in the development of treatment effect and steady-state 
response of NPS and NC in the presence and absence of a loading dose of 600 mg on Day 1. 
Therefore, no loading dose is included in the present study. 
In summary, the present clinical evidence from the 3 related Th2 disease populations of CRSwNP, 
AD, and asthma supports selection of 300 mg q2w as the potential efficacious dose regimen to be 
evaluated for benefit risk in the Phase 3 study. 
4.5 
OVERALL BENEFITS AND RISKS ASSESSMENT 
Polyps are generally comprised of eosinophilic infiltrate and associated with a Th2 orchestrated 
inflammatory state characterized by high IgE, increased Th2 cytokines such as IL-5 and IL-13, 
and decreased T-regulatory function.  
Dupilumab prevents IL-4 and IL-13 binding and activation of their respective receptors involved 
in signaling pathways that play key roles in the pathophysiology of NP. A Phase 2a study in 
patients with NP and symptoms of sinusitis, demonstrated efficacy of dupilumab with 
improvements in endoscopic, radiographic, and clinical measures of disease as well as 
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improvements in lung function and disease control in patients with comorbid asthma. Based on 
the POC data and the mechanism of action, dupilumab may provide an effective treatment for 
patients suffering from NP despite maximal treatment with available therapy.  
Overall, 7408 subjects have been enrolled into the dupilumab development program (completed 
and ongoing studies) as of 30 September 2016.  
Based upon the currently available data for dupilumab and the review of the data by an 
independent data monitoring committee (IDMC), systemic hypersensitivity has been identified as 
an important potential risk. Use in patients with helminthic infections is considered missing 
information based on mechanism of action and evidence of the role of IL-4 in helminth repulsion 
in animal studies published in literature. Other theoretical risks based on immune-modulating 
properties of IL-4 are being managed conservatively through: 
• 
Exclusion of patients with immunosuppressed status or receiving systemic 
immunosupressants, and/or having active bacterial, viral or parasitic infection, or at high 
risk for developing or reactivating infections. 
• 
Monitoring of safety data, including periodic blinded safety monitoring team review and 
unblinded IDMC review. 
The total number of patients exposed to dupilumab is over 5000.  Data from these patients showed 
that dupilumab is well tolerated and has a favorable safety profile. This, together with the efficacy 
demonstrated in ACT12340 study in patients with NP, show a favorable benefit risk balance, and 
support continued development of dupilumab in NP. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is to evaluate the efficacy of dupilumab 300 mg every 2 weeks 
compared to placebo on a background of MFNS in reducing nasal congestion (NC)/obstruction 
severity and endoscopic nasal polyposis score (NPS) in patients with bilateral nasal polyposis 
(NP). 
5.2 
SECONDARY OBJECTIVES 
• 
To evaluate the efficacy of dupilumab in improving TSS. 
• 
To evaluate the efficacy of dupilumab in improving sense of smell.  
• 
To evaluate the efficacy of dupilumab in reducing CT scan opacification of the sinuses 
(for Japan, this is part of the primary objective).  
• 
To evaluate the ability of dupilumab in reducing the proportion of patients who require 
treatment with systemic corticosteroids (SCS) or surgery for NP. 
• 
To evaluate the effect of dupilumab on patient reported outcomes (PROs) and health 
related quality of life (HRQoL).  
• 
To evaluate the efficacy of dupilumab 300 mg q2w up to Week 52. 
• 
To evaluate the efficacy of dupilumab 300 mg q2w up to Week 24 followed by 300 mg 
every 4 weeks (q4w) up to Week 52.  
• 
To evaluate the effect of dupilumab in the subgroups of patients with prior surgery and co-
morbid asthma (including NERD). 
• 
To evaluate the safety of dupilumab in patients with bilateral NP.  
• 
To evaluate functional dupilumab concentrations (systemic exposure) and incidence of 
treatment emergent anti-drug antibodies (ADA). 
5.3 
EXPLORATORY OBJECTIVES  
• 
To explore the effects of dupilumab on biomarkers of type 2/TH2 inflammation in blood, 
. 
• 
To evaluate the effect of dupilumab on healthcare resource utilization. 
• 
To evaluate the effect of dupilumab on SNOT-22 items: “decreased sense of smell/taste”, 
“difficulty falling asleep”, “'wake up at night”, “lack of a good night's sleep”, “wake up 
tired”, “fatigue”, and “reduced productivity”. 
• 
To assess the effect of dupilumab in improving sense of taste. 
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
EFC14280 is a multinational, multicenter, randomized, double-blind, phase 3 placebo-controlled, 
parallel arm study to evaluate dupilumab in patients with bilateral NP. All patients will enter a 
run-in period of 4 weeks +/- 3 days receiving MFNS of 2 actuations (50 µg/actuation) in each 
nostril twice daily (BID), total daily dose of 400 µg, starting at V1, unless they are unable to 
tolerate or there is a specific regulatory requirement preventing use of this dose in which case, 
they can stay on a lower dose regimen (200 µg) of MFNS.  
Approximately 360 patients with bilateral NP at multiple centers will be randomized 1:1:1 
(120 patients per Arm) into 3 treatment groups as follows:  
• 
 Arm A: dupilumab 300 mg q2w SC until Week 52. 
• 
Arm B: dupilumab 300 mg q2w SC until Week 24 then 300 mg q4w until Week 52. 
• 
Arm C: placebo matching dupilumab SC q2w administration until Week 52. 
Patients will be included in approximately 130 sites and will be randomized according to asthma 
status (history of asthma or not), prior NP surgery (yes or no), and country. 
In order to have adequate number of patients for the subgroup analysis of patients with 
asthma/NERD, prior surgery, enrollment of the following categories of patients will be limited as 
follows (see rationale Section 4.2): 
• 
Patients without asthma and/or NERD history will be limited to 180 patients (out of the 
total 360 randomized patients). 
• 
Patients without prior surgery will be limited to 180 patients (out of the total 
360 randomized patients). 
These patients may fall in more than one category without limitation in numbers. 
During the randomized treatment period, patients will continue the stable dose of intranasal 
MFNS stabilized during the run-in period except if dose is changed due to AE. For a schematic 
study design refer to Section 1.2. 
During the study patients who report deterioration requiring medical/surgical intervention may 
come to the site for an endoscopy and clinical evaluation. An unscheduled visit may be used for 
this purpose and if necessary the Investigator may consider one of the treatment alternatives 
described in Section 8.2.2. If surgery is scheduled after the planned end of study, EOS visit will 
not be delayed. A follow up contact(s) should be performed around the time of planned surgery to 
document the surgery date and outcome (see Section 9.2.1.5). Surgery data will be collected until 
e-CRF closure of the trial. 
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6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The clinical trial will consist of 3 periods: 
• 
Run-in period (4 weeks, +/- 3 days): to determine a patient’s eligibility and for  
run-in/standardization of background INCS (MFNS) prior to randomization. 
• 
Randomized dupilumab/placebo treatment period (52 weeks +/- 3 days): to randomize the 
patient into a treatment arm and treat with dupilumab or placebo dose regimen. 
• 
Post treatment period (12 weeks +/- 3 days): to continue to collect data for PK, 
immunogenicity, safety, and efficacy after the patient has completed the study drug 
treatment period. If surgery is scheduled after the planned end of study, EOS visit will not 
be delayed. A follow up contact(s) should be performed around the time of planned 
surgery to document the surgery date and outcome (see Section 9.2.1.5). Surgery data will 
be collected until e-CRF closure of the trial. 
The total duration of study participation for patients that complete the randomized treatment 
period and post treatment follow up is approximately 68 weeks. The schedule of the visits is 
described in the specific flow chart in Section 1.2. 
6.2.2 Determination of end of clinical trial (all patients) 
The last patient last visit will occur when the last randomized patient has completed the end of his 
or her 12-week follow-up period or prematurely discontinues from the study. The end of the 
clinical trial is defined as the last patient’s last visit.  
6.3 
FIRST STEP ANALYSIS 
A first step analysis may be performed when all patients complete the Week 24 visit, including 
early dropouts. The co-primary endpoints and other 24-week endpoints and proportion of patients 
with SCS rescue or surgery for NP (actual or planned) will be analyzed at this first step analysis as 
the final analysis for these endpoints, and 52-week endpoints will not be analyzed at this first step 
analysis. No decision on the conduct of the study will be made based on the first step analysis (in 
particular, no decision to prematurely stop the study). 
In both cases, specific steps will be taken to maintain the blind of the study to all individuals 
involved in the conduct of the study and/or analysis, and to protect the overall blinding and 
integrity of the study data given the first step analysis as further described in Section 11.5. 
Individuals involved in the first step analysis of the study will not be involved in the conduct of 
the study afterwards; individual patient identification will not be released to anyone who is 
directly involved in the conduct of the study. 
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6.4 
STUDY COMMITTEES 
6.4.1 Data monitoring committee 
A data monitoring committee (DMC) with members independent from sponsor and Investigators 
is commissioned for the dupilumab clinical development program. This committee is comprised 
of externally-based individuals with expertise in the diseases under study, biostatistics, or clinical 
research. The DMC will monitor the safety data of patients (serious adverse events [SAE], 
treatment emergent adverse events [TEAE] and/or adverse events of special interest [AESI]) at 
regular intervals and is responsible for providing recommendations for protecting the safety and 
ensuring the welfare of these patients and provide Sanofi with appropriate recommendations in a 
timely manner to ensure the welfare and safety of the study patients. The DMC review is blinded 
with the ability to be unblinded at DMC request. 
The detailed DMC procedures and safety data to be reviewed are described in the DMC charter. 
In the above capacities, the DMC is advisory to the Sponsor. The Sponsor is responsible for 
promptly reviewing and for taking into account in a timely manner the recommendations of the 
DMC in terms of trial continuation with or without alterations or of potential trial termination. 
6.4.2 Clinical advisory committee 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
Patients with bilateral sino-nasal polyposis that despite prior treatment with SCS anytime within 
the past 2 years; and/or have a medical contraindication/intolerance to SCS; and/or had prior 
surgery for NP at the screening visit have: 
I 01. An endoscopic bilateral NPS at V1of at least 5 out of a maximum score of 8 (with a 
minimum score of 2 in each nasal cavity).  
I 02. Ongoing symptoms (for at least 8 weeks before V1) of: 
•  Nasal congestion/ blockade/obstruction with moderate or severe (symptom severity score 2 
or 3) at V1 and a weekly average severity of greater than 1 at time of randomization (V2). 
AND  
• 
Another symptom such as loss of smell, rhinorrhea (anterior/posterior).  
I 03. Signed written informed consent. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Patients <18 years of age. 
E 02. Patient who has previously been treated in dupilumab studies. 
E 03. Patient who has taken: 
• 
Biologic therapy/systemic immunosuppressant to treat inflammatory disease or 
autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary 
cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) within 2 months before 
V1 or 5 half-lives, whichever is longer. 
• 
Any experimental mAB within 5 half-lives or within 6 months before V1 if the half-life is 
unknown. 
• 
Anti-immunoglobulin E therapy (omalizumab) within 130 days prior to V1. 
• 
Patients who are receiving leukotriene antagonists/modifiers at V1 unless they are on a 
continuous treatment for at least 30 days prior to V1. 
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E 04. Initiation of allergen immunotherapy within 3 months prior to V1 or a plan to begin 
therapy or change its dose during the run-in period or the randomized treatment period. 
E 05. Patients who have undergone any and/or sinus intranasal surgery (including polypectomy) 
within 6 months before V1. 
E 06. Patients who have had a sino-nasal surgery changing the lateral wall structure of the nose 
making impossible the evaluation of NPS. 
E 07. Patients with conditions/concomitant diseases making them non evaluable at V1 or for the 
primary efficacy endpoint such as: 
• 
Antrochoanal polyps. 
• 
Nasal septal deviation that would occlude at least one nostril. 
• 
Acute sinusitis, nasal infection or upper respiratory infection. 
• 
Ongoing rhinitis medicamentosa. 
• 
Allergic granulomatous angiitis (Churg-Strauss syndrome), granulomatosis with 
polyangiitis (Wegener’s granulomatosis), Young’s syndrome, Kartagener’s syndrome or 
other dyskinetic ciliary syndromes, concomitant cystic fibrosis. 
• 
Radiologic suspicion, or confirmed invasive or expansive fungal rhinosinusitis 
E 08. Patients with nasal cavity malignant tumor and benign tumors (eg, papilloma, blood boil 
etc). 
E 09. Patients with forced expiratory volume (FEV1) 50% or less of predicted normal. 
E 10. Patients receiving concomitant treatment prohibited in the study (see Section 8.8.1). 
E 11. Patient is the Investigator or any Sub-Investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol. 
E 12. NIMP noncompliance at V2 (<80%) or any condition that could make the patient 
noncompliant with the study procedures and daily assessment in the e-diary. 
7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 13. Patients meet any contraindications or warning on National Product labeling for MFNS. 
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7.2.3 Exclusion criteria related to the current knowledge of Sanofi compound  
E 14. Pregnant or intent to become pregnant during the study, or breast-feeding women. 
E 15. Women of childbearing potential (WOCBP) (pre-menopausal female biologically capable 
of becoming pregnant) who do not fulfill:  
• 
A confirmed negative serum beta-human chorionic gonadotrophin (β-hCG) test at V1. 
AND either: 
• 
An established use of an acceptable contraceptive method: 
- 
Oral, injected, inserted or implanted hormonal contraceptive, 
- 
Intrauterine device (IUD) with or intrauterine system (IUS) with progestogen, 
- 
Barrier contraceptive (condom, diaphragm or cervical/vault caps) used with spermicide 
(foam, gel, film, cream or suppository), if allowed by local regulation. Note for Japan: 
oral contraceptive, intrauterine system with progestogen, barrier contraceptive 
(condom and diaphragm) used with spermicide are available in Japan. 
OR 
• 
Female sterilization (eg, tubal occlusion, hysterectomy or bilateral salpingectomy). 
• 
True abstinence in keeping with the preferred and usual lifestyle and if allowed by local 
regulation; periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods) is not an acceptable method of contraception. 
• 
Postmenopausal women (defined as at least 12 consecutive months with no menses 
without an alternative medical cause) are not required to use additional contraception. 
E 16. Diagnosed active parasitic infection (helminthes); suspected or high risk of parasitic 
infection, unless clinical and (if necessary) laboratory assessments have ruled out active 
infection before randomization. 
E 17. History of human immunodeficiency virus (HIV) infection or positive HIV screen  
(Anti HIV-1 and HIV-2 antibodies) at V1. 
E 18. A subject with a history of clinically significant renal, hepatic, cardiovascular, metabolic, 
neurologic, hematologic, ophthalmologic, respiratory, gastrointestinal, cerebrovascular or 
other significant medical illness or disorder which, in the judgment of the Investigator, 
could interfere with the study or require treatment that might interfere with the study. 
Specific examples include but are not limited to uncontrolled diabetes, uncontrolled 
hypertension, active hepatitis.  
E 19. Known or suspected history of immunosuppression, including history of invasive 
opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, aspergillosis), despite infection resolution; or unusually frequent, 
recurrent or prolonged infections, per Investigator’s judgment. 
E 20. Active tuberculosis, latent untreated tuberculosis or a history of incompletely treated 
tuberculosis or non-tuberculous mycobacterial infection will be excluded from the study 
unless it is well documented by a specialist that the patient has been adequately treated and 
can now start treatment with a biologic agent, in the medical judgment of the Investigator 
and/or infectious disease specialist. Tuberculosis testing would be performed on a country 
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by country basis according to local guidelines if required by regulatory authorities or ethic 
committees.  
E 21. Evidence of acute or chronic infection requiring treatment with systemic antibacterials, 
antivirals, antifungals, antiparasitics, or antiprotozoals within 4 weeks before V1 or during 
the run-in period, or significant viral infections within 4 weeks before V1 that may not 
have received antiviral treatment. 
E 22. Live attenuated vaccinations within 4 weeks prior to Visit 1 or planned live attenuated 
vaccinations during the study (Refer to Appendix A). 
E 23. Patients with active autoimmune disease and/or patients using immunosuppressive therapy 
for autoimmune disease (eg, Hashimoto’s thyroiditis, Graves’ disease, inflammatory bowel 
disease, primary biliary cirrhosis, systemic lupus erythematous, multiple sclerosis, and 
other neuro-inflammatory disease, psoriasis vulgaris, rheumatoid arthritis), or patients with 
high titer autoantibodies at V1 who are suspected of having high risk for developing 
autoimmune disease at the discretion of the Investigator or the Sponsor. 
E 24. History of malignancy within 5 years before V1, except completely treated in situ 
carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal 
cell carcinoma of the skin.  
E 25. Known or suspected alcohol and/or drug abuse. 
E 26. Patients with a history of a systemic hypersensitivity reaction, other than localized 
injection site reaction, to any biologic drug. 
E 27. Active hepatitis or patients with positive or indeterminate hepatitis B surface antigen 
(HBsAg), hepatitis B core antibody (HBcAb) (confirmed with presence of hepatitis B virus 
[HBV] deoxyribonucleic acid [DNA]), or positive hepatitis C virus antibody (HCVAb) 
(confirmed with presence of HCV ribonucleic acid [RNA]) at V1. 
E 28. Patients with the following liver injury related criteria at V1:  
• 
Clinically significant/active underlying hepatobiliary disease. 
OR, 
• 
Alanine aminotransferase (ALT) >3 upper limit of normal (ULN). 
E 29. Abnormal laboratory values at V1: 
• 
Creatine phosphokinase (CPK) >10 ULN  
OR, 
• 
Platelets <100 000 cells/mm3.  
OR, 
• 
Eosinophils >1500 cells/mm3. 
E 30. Conditions/Situations such as: Patients considered by the Investigator or any  
sub-Investigator as inappropriate for this study for any reason, eg,: 
• 
Those deemed unable to meet specific protocol requirements, such as scheduled visits. 
• 
Those deemed unable to administer or tolerate long-term injections as per the patient or 
the Investigator. 
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• 
Presence of any other conditions (eg, geographic, social….) actual or anticipated, that the 
Investigator feels would restrict or limit the patient’s participation for the duration of the 
study. 
7.2.4 Additional exclusion criteria during or at the end of the run-in period 
E 31. Patient who has withdrawn consent before enrollment/randomization. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
8.1.1 Dupilumab 
Sterile dupilumab 150 mg/mL will be provided in pre-filled syringes (2.25 total volume) to 
deliver 300 mg in 2 mL.  
8.1.2 Placebo for dupilumab 
Sterile placebo for dupilumab will be provided in identically matching pre-filled syringes to 
deliver 2 mL. 
8.1.3 Preparation of investigational medicinal product 
Dupilumab in pre-filled syringes will be dispensed to the patients, if required for home 
administration. 
8.1.4 Dosing schedule 
Regardless of the treatment arm, all randomized patients will receive q2w SC administrations of 
either dupilumab or placebo on D1 (V2). For Arm B, after Week 24, dupilumab administration 
will be alternated by placebo matched injection every other week up to Week 50 (last 
investigational medicinal product [IMP] administration). Every other week IMP administrations 
must be separated by at least 11 days.  
At V2, the Investigator (or delegate) will perform the injection. After V2, every other week 
administration of IMP will be performed at the investigational site up to at least Week 8 (V6). The 
IMP will be administered following clinic procedures and blood collection. Patients will be 
monitored at the study site for at least 30 minutes or minimum time required by your local 
regulator after injections for signs of hypersensitivity reaction.  
From Week 10, every other week home administration of IMP (by patient, caregiver, or health 
care professional) is possible if the patient (or caregiver) has been trained for 4 injections. 
Training must be documented when completed successfully and training injections must be 
recorded in the source documents. When IMP is administered at home, the patients must be 
advised by the site staff to self-monitor for potential signs and symptoms that may suggest a 
hypersensitivity reaction for at least 30 minutes after administration or minimum time required by 
your local regulator. If the patient (or caregiver) is unable or unwilling to administer IMP, 
arrangements must be made for qualified site personnel and/or healthcare professionals to 
administer IMP for the doses not scheduled to be given at the study site. If the patient, or 
caregiver(s) do not develop the comfort to inject the investigational drug at home, or the 
Investigator determines that patient (or caregiver) injection at home is not appropriate, injections 
can be performed at the site by way of unscheduled visits. 
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Subcutaneous injection sites should be alternated among the 4 quadrants of the abdomen 
(avoiding navel and waist areas), the upper thighs or the upper arms, so that the same site is not 
injected twice consecutively. Injection in the upper arms could be done only by a trained person 
(caregiver trained by Investigator or Delegate) or health care professional but not the patients 
themselves.  
Detailed instructions for transport, storage, preparation, and administration of IMP are provided to 
the patient. For doses not given at the study site patients will complete a paper dosing diary to 
document compliance with self-injection (or caregiver) of IMP, location of injection, and any 
symptoms. The diary will be kept as source data in the patient’s study file.  
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
8.2.1 Intranasal corticosteroid background therapy 
On a daily basis throughout the study, the patient will use an e-diary to record daily use of 
mometasone furoate nasal spray (MFNS) (NASONEX) 50 µg/actuation nasal spray, suspension 
(refer to the package insert & SmPC for a description, administration details and precautions for 
use). MFNS is provided in a bottle that contains 18 g (140 actuations) of product formulation. The 
sponsor will provide the MFNS to the Investigator sites for dispensing to the patients. If patient is 
unable to tolerate 200 micrograms twice a day (total dose 400 micrograms) due to experiencing 
adverse event, patient may reduce dose to 200 micrograms once per day. 
Detailed instructions for transport, storage, preparation, and administration of NIMP are provided 
to the patient. Patients will complete the e-diary to document compliance. The e-diary will be kept 
as source data in the patient’s study file.  
8.2.1.1 Run-in period 
After V1, once patient eligibility for study entry has been confirmed, all patients will enter a run-
in period of 4 weeks where they will receive starting at V1 MFNS:  
• 
Two actuations (50 µg/actuation) in each nostril BID (total daily dose of 400 µg), unless 
they are unable to tolerate the BID regimen or this dose is not approved in specific 
countries, in which case, they will follow a once daily (QD) regimen.  
MFNS will be self-administered by the patient, and at each visit the Investigator must ensure that 
the patient has the necessary doses up to the next visit, knowing that one MFNS device (1 bottle) 
contains sufficient doses for either 2 weeks of bi-daily treatment/regimen or 4 weeks of once daily 
treatment/regimen. 
Patients who receive rescue medication including INCS drops or systemic (oral, intravenous [IV], 
intramuscular [IM]) steroids between V1 and V2 will not be randomized. They can be rescreened 
as described in Section 10.1. 
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8.2.1.2 Randomized treatment period 
During the randomized treatment period, all patients will continue on the MFNS stable dose 
initiated at V1. If they experience an AE during the treatment period, patients can reduce the 
frequency of MFNS administration. 
8.2.1.3 Post treatment period 
Upon completing the randomized treatment period (or following early discontinuation of IMP or 
discontinuation from the study), patients can continue treatment with the stable dose of MFNS 
maintained over the randomized treatment period until End of Study visit, or modify treatment 
based on medical judgment. 
If surgery is scheduled after the planned end of study, EOS visit will not be delayed. A follow up 
contact(s) should be performed around the time of planned surgery to document the surgery date 
and outcome (see Section 9.2.1.5). Surgery data will be collected until e-CRF closure of the trial. 
8.2.2 Rescue treatment  
During the study treatment period and off treatment follow-up, based on clinical evaluation, in 
case of worsening of signs and/or symptoms requiring medical intervention, the Investigator may 
consider rescue treatment with: 
• 
Nasal lavage with saline and/or systemic antibiotics (up to 2 weeks in case of acute 
infection). 
• 
Short course OCS (prednisone or prednisolone up to 2 weeks). 
• 
Sino-nasal surgery for nasal polyps. Based on previous observations from PoC study, 
8 weeks of IMP treatment is recommended prior to surgery to allow onset of treatment 
effect. 
Patients receiving rescue treatment other than surgery during the study should continue on study 
drug unless the Investigator decides to withdraw the study treatment. Before starting treatment 
with SCS patients should come to the study site for the clinical assessments including endoscopy 
and PROs. 
For patients who undergo or are planned for surgery for NP the Investigator may decide to 
continue IMP up to the time of surgery or end of treatment whichever date comes first (see 
Section 9.2.1.5 for details). At the time of surgery patients will be permanently discontinued from 
study treatment and assessed as soon as possible using the procedures normally planned for the 
end-of-treatment (EOT) Visit as described in Section 10.3.1. 
In any case patients who prematurely discontinued the treatment will be encouraged to return to 
the study site for the efficacy and safety assessments planned at EOT visit and for additional visits 
as described in Section 10.3.1. 
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8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
Dupilumab and placebo will be provided in identically matching 2 mL pre-filled syringes. To 
protect the blind, each treatment kit of 2 mL (dupilumab/placebo) glass pre-filled syringes will be 
prepared such that the treatments (dupilumab and its matching placebo according to its dose) are 
identical and indistinguishable and will be labeled with a treatment kit number. The randomized 
treatment kit number list will be generated by Sanofi. Both the patient and Investigator will be 
blinded to assigned active drug or placebo for the whole study period. In addition, for Arm B after 
Week 24 to prevent differentiation between the regimens, dupilumab administration will be 
alterned by placebo matched injection every other week. For further details, see Section 8.5, 
Packaging and Labeling. 
Study patients, Investigators, and study site personnel will not have access to the randomization 
code list except under circumstances described in Section 8.3.2. 
Refer to Section 10.5 for suspected unexpected adverse drug reaction unblinding by the Sponsor. 
8.3.2 Randomization code breaking during the study 
In case of an adverse event (AE), the code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient.  
If possible, a contact should be initiated with the Monitoring Team before breaking the code. 
Code breaking can be performed at any time by using the proper module of the interactive voice 
response system (IVRS)/interactive web response system (IWRS) and/or by calling any other 
phone number provided by the Sponsor for that purpose. If the blind is broken, the Investigator 
should document the date, time of day and reason for code breaking. 
Patient withdrawal will only occur when the code break call is made at the site level, not the study 
level. This means that if the Emergency Unblinding transaction is performed by the Investigator 
(ie, at the site level), then the patient will be withdrawn from treatment. However, if the 
Emergency Unblinding transaction is performed by the Global Safety Officer (GSO) (ie, at the 
study level, as the GSO is not site based), it is not required to withdraw the patient from treatment. 
At the facilities where the PK measurements, ADA, and selected biomarkers are determined, the 
samples will be analyzed prior to data base lock leading to unblinding of responsible bioanalysts. 
Bioanalysts are excluded from the clinical trial team. 
The Data Monitoring Committee will receive blinded by treatment group or unblinded (if 
necessary) confidential reports from an independent statistician for review, which have to be 
handled strictly confidentially. None of these reports can be delivered to unauthorized persons. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
A randomized treatment kit number list will be generated centrally by Sanofi. The IMP 
(dupilumab or placebo) will be packaged in accordance with this list. 
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The Sanofi Clinical Supplies team will provide the randomized treatment kit number list and the 
Study Biostatistician will provide the randomization scheme to the centralized treatment 
allocation system. This centralized treatment allocation system will generate the patient 
randomization list according to which it will allocate the treatments to the patients. 
Patients who meet the entry criteria will be randomized to one of the following treatment arms 
using a 1:1:1 randomization ratio: 
• 
Arm A: dupilumab 300 mg q2w SC until Week 52. 
• 
Arm B: dupilumab 300 mg q2w SC until Week 24 then 300 mg q4w until Week 52. 
• 
Arm C: placebo matching dupilumab SC q2w administration until Week 52. 
Approximately 360 (120 patients/ Arm) patients shall be randomized. Randomization will be 
stratified based on asthma status (history of asthma or not), prior NP surgery (yes or no), and 
country.  
In order to have adequate number of patients for the subgroup analysis of patients with 
asthma/NERD, and prior surgery, enrollment of the following categories of patients will be 
limited as follows (see rationale Section 4.2): 
• 
Patients without asthma and/or NERD history will be limited to 180 patients (out of the 
total 360 randomized patients). 
• 
Patients without prior surgery will be limited to 180 patients (out of the total 
360 randomized patients). 
These patients may fall in more than one category without limitation in numbers. 
At randomization, IVRS will allocate to a patient a treatment number for dupilumab or placebo. A 
patient cannot be randomized more than once in the study. 
Patients who meet exclusion criteria may be re-screened and a different patient identification will 
be issued. There is no requirement for a waiting period between the screen-failure date and the re-
screening date. The IVRS/IWRS report will flag re-screened patients. Patients that are re-screened 
must sign a new consent form and all V1 procedures must be repeated. The Investigator obtains 
treatment kit numbers at randomization and subsequent scheduled visits via the IVRS/IWRS 
which will be available 24 hours a day. 
8.5 
PACKAGING AND LABELING 
From randomization (V2) up to Week 6 (V5), dupilumab 300 mg or placebo will be supplied as 
one glass pre-filled syringe packed in one patient kit box. From Week 8 (V6) on, dupilumab 
300 mg or placebo will be supplied as 2-glass pre-filled syringes packed in one patient kit box 
with individual cavities with number and arrow on the top of each cavity so that the order of 
dispensing for syringes is clear. The kits for Arm A (300 mg q2w administration) will contain 
only dupilumab 300 mg syringes and the kits for Arm C (placebo q2w administration) will 
contain only placebo syringes. Kits for Arm B (300 mg q2w/q4W administration) dispensed at 
Weeks 8 and 16 will contain 2 dupilumab 300 mg syringes and the kits dispensed at Weeks 24, 
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and 40 will contain a dupilumab 300 mg syringe (#1) followed sequentially by a placebo syringe 
(#2). 
MFNS will be supplied as commercial product of a box containing a bottle. Both bottle and box 
will be relabeled. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements.  
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Dupilumab and placebo IMPs should be stored at a temperature between 2°C and 8°C. MFNS 
storage conditions are specified on the bottle and its box. NASONEX should be stored at room 
temperature. 
All IMP and non-investigational medicinal product (NIMP) should be stored in an appropriate, 
locked room under the responsibility of the Investigator or other authorized persons 
(eg, pharmacists) in accordance with local regulations, policies, and procedures. 
Control of storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound should be 
managed according to the rules provided by the Sponsor. It is the responsibility of the 
Investigators to inform the patients regarding the mandatory storage requirements for the IMP. No 
temperature monitoring will be performed at the patients’ homes. 
8.7 
RESPONSIBILITIES  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMPs will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for direct-to-
patient shipment, for which a courier company has been approved by the Sponsor), allow the IMP 
to be used other than as directed by this clinical trial protocol, or dispose of IMP in any other 
manner. 
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8.7.1 Treatment accountability and compliance 
The Investigator or delegate will keep accurate records of the quantities of the IMP 
dispensed and returned, used and unused and NIMP dispensed and returned, used and unused by 
each patient.  
• 
Proper recording of treatment kit numbers as required on appropriate electronic case report 
form (e-CRF) page for accounting purposes. 
• 
All medication treatment kits (whether empty or unused) are returned by the patient at 
each visit when a treatment dispensing is planned and at EOT visit.  
• 
The completed patient diary (returned to the site at each visit), returned IMP treatment and 
NIMP kit boxes used and unused along with any unused prefilled syringes will be used for 
drug accountability purposes. Patients will also return used prefilled syringes to the site in 
a sharp container. 
• 
The Investigator (or designee) tracks treatment accountability/compliance by diary, and by 
counting the number of used and unused treatment kits and syringes and completes the 
appropriate page of the patient treatment log.  
• 
The monitor in charge of the study then checks the data entered on the IMP and NIMP 
administration page by comparing them with the IMP and NIMP that have been retrieved 
and the patient treatment log forms. Reconciliation will occur with paper and electronic 
diary as appropriate depending on study visit/period. 
8.7.2 Return and/or destruction of treatments 
Whenever possible all partially used, used or unused IMP and NIMP provided by the Sponsor will 
be destroyed on site according to the standard practices of the site. A detailed treatment log of the 
destroyed IMP and NIMP supplied by the Sponsor will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will 
not destroy any IMP and NIMP supplied by the Sponsor unless the Sponsor provides written 
authorization. When destruction at site cannot be performed, all IMP, and NIMP supplied by the 
Sponsor will be retrieved by the Sponsor. A detailed treatment log of the returned IMP and NIMP 
supplied by the Sponsor will be established with the Investigator (or the pharmacist) and 
countersigned by the Investigator and the monitoring team. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s) or 
NIMP. 
8.8.1 Prohibited concomitant medication  
The following concomitant treatments are not permitted during the run-in period and the 
randomized treatment period: 
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• 
Any systemic immunosupressive treatment including but not limited to methotrexate, 
cyclosporine, mycophenolate, tacrilomus, gold, penicillamine, sulfasalazine, 
hydroxychloroquine, azathioprine, and cyclophosphamide. 
• 
Anti-IgE therapy (omalizumab). 
• 
Mepolizumab or Reslizumab 
• 
Allergen immunotherapy (except if initiated more than 3 months prior to V1 and dose 
stable 1 month prior to V1). 
• 
Intranasal corticosteroid drops. 
• 
Use of intranasal decongestants except for preparation of nasal endoscopy  
• 
Long term courses (>2 weeks) of systemic steroids. 
• 
Short term courses (≤2 weeks) of IV, IM, SC SCS except as indicated treatment of NP or 
to treat other serious coexisting disease (such as asthma).  
• 
Short course courses (≤2 weeks) of SCS only between V1 and V2. 
• 
Live, attenuated vaccines (Appendix A). 
• 
mAB. 
Patients who between V1 and V2 receive any of the prohibited treatments, or treatment with 
systemic (oral, IV, IM) steroids or undergo surgery will not be randomized. They may however be 
rescreened following the procedures described in Section 10.1.  
8.8.2 Permitted concomitant medication 
The following treatments are allowed:  
• 
MFNS during the run-in period and throughout the whole study. 
• 
Nasal normal saline lavage (only considered rescue if initiated after V2). 
• 
Single topical decongestants administration for example oxymetazoline hydrochloride (to 
reduce the swelling and widen the path for the endoscope), as well as a topical anesthetic 
for example lidocaine are allowed before endoscopy. 
• 
Short term use of antibiotics (<2 weeks) are allowed during the study. 
• 
SABA, LABA, and LAMA. 
• 
Methylxanthines (for example theophylline, aminophyllines), 
• 
Inhaled corticosteroids. 
• 
Systemic antihistamines. 
• 
Leukotriene antagonists/modifiers are permitted during the study, only for patients who 
were on a continuous treatment for ≥30 days prior to V1. 
• 
Allergen immunotherapy in place for ≥3 months prior to V1 is permitted.  
• 
Rescue medication including short courses of SCS for treatment of NP as described in 
Section 8.2.2 or short courses of SCS to treat other serious co-existing diseases (such as 
asthma exacerbation) are allowed.  
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CYP substrates 
The impact of dupilumab on CYP enzymes activity has not been studied and the effect on 
dupilumab on the levels of IL4 and IL13 cytokines has not been fully characterized. 
However, literature data of studies in human hepatocytes indicate that the IL-4 was able to 
upregulate CYP450 2E1, 2B6, 3A4 mRNA expression or down regulate CYP1A2 mRNA  
(26, 27). Another study in human peripheral blood mononuclear cells (PBMC) incubated with 
various Th2 cytokines, reports that Th2 cytokines IL-4 and IL-13 generally increased the protein 
expression of CYP2B6 and CYP3A4 (28). 
A drug-drug interaction study (R668-AD-1433) designed to examine the effects of dupilumab on 
the PK of selected CYP450 substrates in adult patients with moderate to severe AD was 
completed recently.  The data indicated no clinically meaningful effect of dupilumab on CYP1A2, 
CYP3A4, CYP2C19 or CYP2D6 activity. 
During the study and at least up to the end of follow-up, caution should be used for drugs with 
narrow therapeutic index that are metabolized via these CYP450 isoforms. 
This means that unless the drug is prohibited in the study Section 8.8.1, close clinical observation 
and/or laboratory monitoring as applicable are required in order to enable early detection of toxic 
manifestations or lack of activity/efficacy of these drugs, followed by dose adjustment or their 
withdrawal if needed. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
Investigators must make their best efforts educating their patients on the importance of sticking to 
visit schedules, study required procedures and assessments up to the end of the study. 
Investigators must make best efforts to prevent missing data, in order that a high level of quality 
can be achieved for the study. 
9.1 
CO-PRIMARY ENDPOINTS 
There are 2 co-primary endpoints for this study for countries other than Japan:  
1. Change from baseline in the nasal congestion/obstruction at Week 24: The NC is 
assessed by the patient on a daily basis from V1 and throughout the study, using an e-diary 
using a 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate 
symptoms and 3 = severe symptoms) (2):  
Nasal congestion/obstruction will be scored as a reflective score (evaluation of symptom severity 
over the past 24 hours) by the patient: 
 
Scale 
Symptoms 
0 
No symptoms 
1 
Mild symptoms (symptoms clearly present, but minimal awareness and easily tolerated) 
2 
Moderate symptoms (definite awareness of symptoms that is bothersome but tolerable) 
3 
Severe symptoms (symptoms that are hard to tolerate, cause interference with activities 
or daily living) 
 
The e-diary is dispensed at V1 and information is downloaded from this device on the other 
indicated days.  
A severity ≥2 on V1 and a weekly average severity greater than 1 at time of randomization (V2) is 
required and will be provided to the site to determine patient eligibility. If there are 4 or more 
measurements collected within 7 days prior to randomization, the baseline will be the average of 
these measurements; if less than 4 measurements are collected, the baseline will be the average of 
the most recent 4 prior to randomization. 
For the baseline to EOT analysis, 4 weeks average of the symptom scores will be used. 
2. Change from baseline in the NPS at Week 24: The NPS (17, 18, 24) is assessed by 
central video recordings of nasal endoscopy. The score (NPS) is the sum of the right 
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and left nostril scores, as evaluated by means of nasal endoscopy. NP is graded based on 
polyp size described in Table 1. 
Table 1 - Endoscopic nasal polyp score 
Polyp Score 
Polyp Size 
0 
No polyps 
1 
Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate 
2 
Polyps reaching below the lower border of the middle turbinate  
3 
Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate 
4 
Large polyps causing complete obstruction of the inferior nasal cavity 
 
Nasal endoscopy should be performed at the end of the scheduled visits before the administration 
of IMP and preceded by local administration of anesthetic drugs in combination with a 
decongestant. 
Standard video sequences will be downloaded or sent to centralized reader. Centralized imaging 
data assessments and scoring by independent physician reviewer(s) for the imaging data will be 
performed for all endoscopies. To confirm eligibility at V2, only the V1 central reading will be 
made available to the site. In addition at V2 the investigator will perform the NE to confirm 
eligibility score and enter the result in the e-CRF. Thus the patient is considered eligible based on 
a V1 central reading followed by a V2 local reading NPS score of 5 or more and at least 2 each 
side. The final results of central reading from Visit 2 onward will be made available after the 
study. 
For the analysis of primary endpoint, central reading of V2 will be used for comparison with 
Week 24 reading. The sites will remove patient-identifying information from the imaging data 
header prior to sending the imaging data to the central reader. 
Further details on nasal endoscopy will be available in a separate operational manual provided to 
the sites. 
3. Lund-Mackay score 
For Japan, in addition to the two co-primary endpoints above, the following will also be a co-
primary endpoint: 
The LMK system is based on localization with points given for degree of opacification:  
0 = normal, 1 = partial opacification, 2 = total opacification. These points are then applied to the 
maxillary, anterior ethmoid, posterior ethmoid, sphenoid, frontal sinus on each side. The OC is 
graded as 0 = not occluded, or 2 = occluded deriving a maximum score of 12 per side. This 
scoring system has been validated in several studies (29, 30, 31). 
For patients in whom the OC is missing (because of a previous surgery) the reader should 
consider the location of the former OC and provide a scoring (as if the OC was there). 
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CT scan should be performed anytime during the run-in period before a first administration of 
IMP and at Visit 8 (Week 24). Whenever possible a cone beam CT scan should be utilized. In 
countries for which a specific approval procedure for the CT scan is required by a different 
committee than the local independent ethic committee (IEC)/institutional review board (IRB), 
patients may be enrolled using a CT available in the previous year or perform an MRI of the 
sinuses between V1 and V2. These countries will be exempted from all the planned study CT 
scans until approval from these committees is received. A Week 52 CT scan may be performed if 
approved by local ethics committees in order to assess the change from baseline to Week 52 using 
the 2 different treatment regimens of dupilumab 300 mg q2w for up to Week 52 and dupilumab 
300 mg q2w/q4w up to Week 52. 
Details for CT will be available in a separate operational manual provided to the sites. 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Key secondary efficacy endpoints  
For the analysis of key secondary endpoints see Section 11.4.2.2. 
9.2.1.1 Disease specific daily symptom assessment and total symptom score (TSS) 
On a daily basis from V1 and throughout the study, the patient will use an e-diary to: 
• 
Respond to the morning individual rhinosinusitis symptom questions using a 0 to 
3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms 
and 3 = severe symptoms) (3):  
- 
Congestion and/or obstruction. 
- 
Loss of sense of smell. 
- 
Anterior rhinorrhea (runny nose). 
- 
Posterior rhinorrhea (postnasal drip). 
The TSS is a composite score (ranging between 0 and 9) consisting of the sum of the following 
symptoms assessed daily in the morning: nasal congestion/obstruction, decreased/loss of sense of 
smell, rhinorrhea (average of anterior/posterior nasal discharge). 
9.2.1.2 Smell test: University of Pennsylvania Smell Identification Test (UPSIT)  
The UPSIT (UPSIT 40 odorant test) is a rapid and easy-to-administer method to quantitatively 
assess human olfactory function. The UPSIT shows a high test-retest reliability (r: 0.981) and 
scores on this test are strongly correlated with the detection threshold for phenyl ethyl alcohol in 
the same individuals. When the UPSIT is administered in the standardized manner, clinical 
subjects show a high degree of uniformity in UPSIT performance when tested in different 
laboratories. 
The test will be dispensed to the patient by the study site personnel and consists of 4 booklets, 
each containing 10 odorants with one odorant per page. The test-time is about 15 min. The stimuli 
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are embedded in 10-50 (mu) diameter plastic microcapsules on brown strips at the bottom of each 
page. Above each odorant strip is a multiple-choice question with four alternative words to 
describe the odor. The subject is asked to release the odorant by rubbing the brown-strip with the 
tip of a pencil and to indicate which of four words best describes the odor. Thus each subject 
receives a score out of 40 possible correct answers. The final score will be recorded in the e-CRF. 
The odorants of the UPSIT test utilized in this study will take into account cultural differences. 
The 40-odorant UPSIT is used in over 1500 clinics and laboratories throughout the United States, 
Canada, South America, and Europe, and has been administered to nearly 200 000 people since its 
development in the early 1980s. A particular strength of this test is that it provides an olfactory 
diagnosis based on comparing the patient's test score with normative data, providing a percentile 
score of an individual relative to his or her age-matched normal group. Furthermore, a clinician 
can distinguish patients with a normal sense of smell ("normosmia") from those with different 
levels of reduction ("mild, moderate, and severe microsmia") or loss ("anosmia") (32). 
9.2.1.3 Decreased/loss of sense of smell 
The decreased/loss of sense of smell severity is assessed by the patient on a daily basis from V1 
and throughout the study, using an e-diary to using a 0-3 categorical scale (where 0 = no 
symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms). 
9.2.1.4 Lund-Mackay score 
Lund-Mackay score is a secondary efficacy endpoint in countries other than Japan. Details of this 
endpoint are presented in Section 9.1.  
9.2.1.5 Proportion of patients during the treatment period who receive SCS rescue or are 
planned to undergo surgery for NP 
SCS rescue 
Oral steroids for rescue treatment of nasal polyps or for another reason will be prescribed to the 
patient by the site depending on local legislation/regulation. PROs and a nasal endoscopy should 
be performed before starting treatment with SCS. The Investigator (or designee) records the date 
and dosing information (daily dose, duration, INN) on the appropriate page(s) of the e-CRF. 
Indication for SCS use will be also captured by selecting one or more of the following categories:  
1. Nasal polyposis. 
2. Asthma. 
3. Other respiratory disease (specify).  
4. Other ear, nose or throat disease (specify). 
5. Other reason (specify).  
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Surgery (actual or planned) for NP  
For patients who undergo or are planned for sino-nasal surgery for NP, the reason (worsening 
signs and/or symptoms during the study), the expected and real surgery date, the type and 
outcome of surgery will be recorded in a specific CRF page. If surgery  
• 
Is performed during the study treatment period, patient and Investigator may decide to 
continue IMP up to the time of surgery or EOT whichever date comes first. At the time of 
surgery patients will be permanently discontinued from study treatment and assessed as 
soon as possible using the procedures normally planned for the EOT Visit and will be 
instructed to return to the study site as described in Section 10.3.1. An AE or serious 
adverse event (SAE) page will be completed.  
• 
Is performed during the follow-up the patients will be assessed according to the 
procedures normally planned for the EOS Visit and will be instructed to return to the study 
site as described in Section 10.1.15. An AE or SAE page will be completed.  
• 
If surgery is scheduled after the planned end of study, EOS visit will not be delayed. A 
follow up contact(s) should be performed around the time of planned surgery to document 
the surgery date and outcome. Surgery data will be collected until e-CRF closure of the 
trial. 
9.2.1.6 22-Item sino-nasal outcome test (SNOT-22) 
The SNOT-22 is a validated questionnaire to assess the impact of chronic rhinosinusitis on 
HRQoL (Appendix B). The SNOT-22 has 22 items on a 5-category scale applicable to sino-nasal 
conditions and surgical treatments. The range of the global score is 0-110 and a minimal 
important difference (MID), the smallest difference between clinical trial arms mean change from 
baseline (point estimates) that will be interpreted as important of 8.9 (33). Lower scores indicate 
less impact and the recall period is past 2 weeks. There are 5 domains that can be described within 
SNOT-22, including nasal, ear, sleep, general and practical, and emotional.  
9.2.2 Other secondary endpoints  
For the assessment of other secondary endpoints see analyses of efficacy endpoints,  
(Section 11.4.2.4). 
9.2.2.1 SCS dose and number of courses 
Total SCS rescue dose prescribed (in mg/year) during the study period and total SCS rescue 
intake in days and courses during the study period could be derived based on SCS dose prescribed 
and intake days of SCS during the study, recorded in eCRF pages. 
A course of SCS is considered continuous if treatment is separated by less than 7 days. Various 
doses of systemic corticosteroids will be converted to prednisone-equivalent OCS. 
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9.2.2.2 Visual analogue scale  
The visual analogue scale (VAS) for rhinosinusitis is used to evaluate the total severity (2). 
Rhinosinusitis disease can be divided into MILD, MODERATE and SEVERE based on total 
severity VAS score (0 to 10 cm): 
• 
MILD = VAS 0 to 3.  
• 
MODERATE = VAS >3 to 7.  
• 
SEVERE = VAS >7 to 10.  
• 
The patient is asked to indicate on a VAS the answer to the question below:  
“How troublesome are your symptoms of your rhinosinusitis” 
The VAS ranks from 0 (Not troublesome) to 10 (Worst thinkable troublesome) (Appendix D). 
9.2.2.3 Nasal peak inspiratory flow 
Nasal peak inspiratory flow (NPIF) evaluation represents a physiologic measure of the air flow 
through both nasal cavities during forced inspiration expressed in liters per minute. The NPIF is 
the best validated technique for the evaluation of nasal flow through the nose. Nasal inspiration 
correlates most with the subjective feeling of obstruction and is the best validated technique for 
monitoring nasal flow in clinical trials. 
On V1 patients will be issued an NPIF meter for recording morning (AM) NPIF. Patients will be 
instructed on the use of the device, and written instructions on the use of the NPIF meter will be 
provided to the patients. In addition, the Investigator will instruct the patients on how to record the 
following variables in the e-diary on a daily basis. 
• 
AM NPIF performed within 15 minutes after arising (before 12 noon) prior to taking 
MFNS.  
Three NPIF efforts will be performed by the patient; all 3 values will be recorded by the patient in 
the e-diary, and the highest value will be used for evaluation. The procedure takes about 
5 minutes. 
Baseline AM NPIF will be the mean AM measurement recorded for the 7 days prior to the first 
dose of IMP. If less than 4 measurements are collected during the 7 days, the average of the most 
recent 4 prior to randomization during the run-in period will serve as the baseline.  
The NPIF will be performed daily from V1 to Week 24 (V8). After V8 the NPIF will be 
performed every 4 weeks. 
The nasal flow is expressed in liter per minute, and consecutive measurements are performed. 
Taking the best of 3 outcomes with less than 10% variation is considered to be the best means of 
expression of the result (32). 
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9.2.2.4 Asthma Control Questionnaire, 6-question version (ACQ-6) in those patients 
comorbid with asthma 
The asthma control questionnaire-6 (ACQ-6) was designed to measure both the adequacy of 
asthma control and change in asthma control which occurs either spontaneously or as a result of 
treatment. Only patients with co-morbid asthma will be asked to complete the questionnaire in the 
e-diary during clinic visits. Patients should complete the questionnaire before the spirometry test. 
The asthma control questionnaire-6 (ACQ-6) has 6 questions which assess the most common 
asthma symptoms: 
• 
Frequency in past week awoken by asthma during the night. 
• 
Severity of asthma symptoms in the morning.  
• 
Limitation of daily activities due to asthma.  
• 
Shortness of breath due to asthma. 
• 
Frequency of wheezing, and 
• 
Short-acting bronchodilator use.  
Patients are asked to recall how their asthma has been during the previous week and to respond to 
the symptom questions on a 7-point scale (0 = no impairment, 6 = maximum impairment)  
(see Appendix E). 
A global score is calculated: the questions are equally weighted and the ACQ-6 score is the mean 
of the 6 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). 
Higher score indicates lower asthma control. Patients with a score below 1.0 reflect adequately 
controlled asthma and patients with scores above 1.0 reflect inadequately controlled asthma. On 
the 7-point scale of the ACQ-6, a change or difference in score of 0.5 is the smallest change that 
can be considered clinically important, corresponding to the Minimal Clinically Important 
Difference (MCID) defined by the developer. 
Measurement properties such as reliability, ability to detect change have been documented in the 
literature (34). 
9.2.2.5 Health related quality of life (HRQoL) 
9.2.2.5.1 Euro-QOL-5D 
The European quality of life-5D scale (EQ-5D) (Appendix C) is a standardized HRQoL 
questionnaire developed by the EuroQol Group in order to provide a simple, generic measure of 
health for clinical and economic appraisal (35). EQ-5D is designed for self-completion by 
patients. 
The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ VAS. The 
EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the 
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respondent’s self-rated health on a vertical VAS. The EQ VAS ‘thermometer’ has endpoints of 
100 (best imaginable health state) at the top and 0 (worst imaginable health state) at the bottom. 
9.3 
EXPLORATORY ENDPOINTS: 
• 
Healthcare resource utilization. 
• 
Proportion and time-to-event of patients with SCS rescue for nasal polyps. 
• 
Proportion and time-to-event of patients who have or are planned for surgery of nasal 
polyps. 
• 
Change from baseline in decreased/loss of sense of taste symptom severity. 
• 
SNOT-22 items: “decreased sense of smell/taste”, “difficulty falling asleep”, ”wake up at 
night”, “lack of a good night's sleep”, “wake up tried”, ”fatigue”, and “reduced 
productivity”. 
• 
Pharmacodynamic biomarkers in blood and urine. 
• 
 
 
• 
 
• 
FEV1, FVC and FEF 25-75 in patients with asthma. 
• 
Efficacy endpoints for the sub-group of patients with SCS use in the year prior to study 
Visit 1. 
• 
Patient reported outcomes including HRQoL scale (EQ5D-5L, Index Score) 
9.3.1 Spirometry 
Spirometry will be performed at local level (study site or another facility) in the morning after 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 
6 hours. FEV1, forced vital capacity (FVC) and forced expiratory flow at 25% to 75% of forced 
vital capacity (FEF 25-75) will be determined at the designated treatment visits. The results of 
FEV1 (% of predicted normal), FVC and FEF 25-75 should be recorded in the e-CRF anytime 
during run-in period (before V2) for all patients and in patients with asthma for the other 
scheduled visits during the randomized treatment period.  
Whenever possible, the same spirometer and standard spirometric techniques, including 
calibration, will be used to perform spirometry at all visits and, the same person should perform 
the measurements. 
9.4 
SAFETY ENDPOINTS 
9.4.1 Adverse events 
Refer to Section 10.4 to Section 10.6 for details. 
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9.4.2 Laboratory safety variables 
The clinical laboratory data consist of blood and urine analysis (including serum hematology and 
clinical chemistry). Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables. 
• 
Hematology includes: hemoglobin, hematocrit, platelet count, total white blood cell count 
with 5-part differential count, differential count, and total red blood cell count.  
• 
Serum chemistry includes: creatinine, blood urea nitrogen, glucose, uric acid, total 
cholesterol, total protein, albumin, total bilirubin (in case of values above the normal 
range, differentiation in conjugated and non-conjugated bilirubin), ALT, aspartate 
aminotransferase, alkaline phosphatase, lactate dehydrogenase, electrolytes (sodium, 
potassium, chloride), bicarbonate, and CPK.  
• 
HIV screening (Anti-HIV-1 and HIV-2 antibodies)  
• 
Anti-nuclear antibody (ANA). Note: Anti-ds DNA antibody will be tested if ANA is 
positive (≥1:160 titer). 
9.4.3 Hepatitis screening  
Hepatitis screening: HBsAg, hepatitis B surface antibody (HBsAb), HBcAb including HBcAb 
IgM and total, hepatitis C virus antibodies (HCVAb). In case of results showing HBsAg 
(negative) and HBcAb total or HBcAb IgM (positive), a HBV DNA testing must be performed 
prior to randomization to determine eligibility. In case of results showing HCVAb (positive), a 
HCV RNA testing must be performed prior to randomization to determine eligibility.  
For patients in Japan (or other countries/regions if there is local regulatory requirement) who are 
HBsAg negative and HBsAb positive at V1, Hepatitis B viral load will be tested at V2, V7, V8, 
and V10.  
9.4.4 Pregnancy test 
A serum pregnancy test (β-hCG) will be performed at run-in (V1) in women of childbearing 
potential, and a urine dipstick pregnancy test will be performed at V2 prior to randomization and 
every 4 weeks. A negative result must be obtained at V1 and V2 prior to randomization. In case of 
positive urinary test the study treatment will be withheld and a serum pregnancy test to confirm 
the pregnancy should be performed as soon as possible. Pregnancy will lead to definitive 
treatment discontinuation in all cases. 
9.4.5 Vital signs 
Vital signs include: blood pressure (mmHg), heart rate (beats per minute), respiration rate (breaths 
per minute), body temperature (degrees Celsius) and body weight (kg). Height (cm) will be 
measured on V1 only. Vital signs will be measured in the sitting position using the same Arm 
(preferably) at each visit, and will be measured prior to receiving IMP at the clinic visits. 
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9.4.5.1 Physical examination 
Physical examinations will include an assessment of general appearance, skin, eyes, 
ear/nose/throat, heart, chest, abdomen, reflexes, lymph nodes, spine, and extremities. All 
deviations from normal will be recorded, including those attributable to the patient’s disease. 
9.4.6 Electrocardiogram variables 
A standard 12-lead electrocardiogram (ECG) will be performed at the sites at the time points 
noted in the Study Flowchart (Section 1.2) to monitor any potential abnormality. In case of an 
abnormal ECG finding, the Investigator should enter details into the e-CRF. At V2, the 
Investigator should use their medical judgment to consider whether the patient is eligible for the 
study. 
9.5 
OTHER ENDPOINTS 
9.5.1 Functional dupilumab concentration and anti-drug antibodies in serum 
9.5.1.1 Sampling time  
Predose blood samples will be collected for determination of functional dupilumab 
(pharmacokinetics, or PK) in serum and anti-dupilumab antibodies at timepoints designated in the 
study flow chart (see Section 1.2). The date of collection should be recorded in the patient e-CRF. 
The date and time also will be collected on the central laboratory requisition form and entered into 
the database through data transfers from the central laboratory. 
In the event of any SAE or any AESI of anaphylactic reactions or systemic allergic reactions that 
are related to IMP and require treatment, or severe injection site reaction lasting longer than  
24 hours, samples will be collected near the onset and resolution of the event for any additional 
analysis if required or for archival purposes. An unscheduled systemic drug concentration page in 
the e-CRF must be completed as well. 
Patients who are ADA positive at their last study visit (early termination or planned end of study 
[EOS]), may be asked to return to the clinic to have additional ADA samples collected for 
analysis based on the overall clinical presentation at the time of discontinuation.  
9.5.1.2 Handling procedures 
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of handling procedures for samples used in the determination 
of functional dupilumab serum concentration and anti-drug antibodies is provided in Table 2.  
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Table 2 - Summary of handling procedures for SAR231893 (dupilumab) 
Sample type 
Functional dupilumab serum 
concentration 
Anti-dupilumab antibody 
Matrix 
Serum 
Serum 
Blood sample 
volume 
5 mL 
5 mL 
Anticoagulant 
None 
None 
Blood handling 
procedures 
 See Operational Manual 
See Operational Manual 
Serum aliquot split 
Storage conditions 
Serum shipment 
condition 
Two aliquots 
<6 months: below -20°C 
≥6 months: below -80°C (preferred) 
In dry ice 
Two aliquots 
<6 months: below -20°C 
≥6 months: below -80°C (preferred) 
In dry ice 
 
 
9.5.1.3 Bioanalytical methods  
Serum samples will be assayed using validated methods as described in Table 3.  
Table 3 - Summary of bioanalytical methods for dupilumab and anti-dupilumab antibody 
Analyte 
Functional dupilumab 
concentration 
Anti-dupilumab antibody 
Matrix 
Serum 
Serum 
Analytical technique 
ELISA 
Electrochemiluminescence 
 
 
9.5.1.4 Functional dupilumab concentration and anti-drug antibody measurement and 
samples 
Predose functional dupilumab concentrations in serum at V2 (Day 1), dupilumab trough 
concentrations at Week 2, Week 4, Week 16, Week 24, Week 40, Week 52/EOT Visit, and post 
treatment at Week 64/EOS Visit will be provided.  
Anti-dupilumab antibody status (negative or titer value) will be provided for samples collected at 
timepoints as specified in the Study Flow Chart. 
Patients who are ADA positive at their last study visit (early termination or planned EOS), will be 
considered for follow-up based on the overall clinical presentation at that time. 
Unused samples collected for drug concentration or ADA analyses may be used for exploratory 
analyses if the specific Future Use of Samples Informed Consent is signed (see Section 9.6). 
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9.5.2 Pharmacodynamics 
Several biomarkers related to CRSwNP and Th2 polarization will be assessed for their value in 
predicting therapeutic response and/or in documenting the time course of drug response.  
Patients, Investigators and site personnel will not have access to assay results for total IgE, TARC, 
periostin, and eotaxin-3 while the study is ongoing, as the related data are not essential for patient 
care and have the potential for unblinding the study treatments.  
Sample collection will be performed as per the study flow chart (Section 1.2) and assay 
methodologies are briefly summarized below. In general, duplicate aliquots of each sample for 
pharmacodynamic biomarkers should be stored to assure generation of a complete set of assay 
results. More detailed information on the collection, handling, transport and preservation of 
samples (eg, minimum volumes required for blood collection and for aliquots for each biomarker 
assay) will be provided in a separate laboratory manual. 
9.5.2.1 Serum biomarkers 
Total IgE will be measured using quantitative methods (eg, ImmunoCAP® FEIA), approved for 
diagnostic testing.  
Thymus and activation-regulated chemokine will be assayed with a validated enzyme 
immunoassay (eg, Human TARC Quantikine ELISA kit; R&D Systems). 
Concentrations of periostin will be assayed with a validated immunoassay. 
9.5.2.2 Plasma biomarkers 
Eotaxin-3 will be measured in heparinized plasma with a validated enzyme immunoassay. 
9.5.2.3 Urine biomarkers 
Leukotriene E4 and a metabolite of prostaglandin D2 (PGDM) will be measured in morning spot 
urine samples using validated quantitative assays. Assay results will be reported per mg of 
creatinine. 
9.5.2.4 
  
 
 
 
 
 
 
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9.5.3 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
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9.6 
FUTURE USE OF SAMPLES  
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For patients who have consented to it, the samples that are archived, unused or left 
over after planned testing may be used for additional research purposes 
 
 For patients who have consented to it, archival 
blood samples will be collected at the visit specified in the study flow chart, 10 mL each, will be 
collected into a dry, red topped tube with clotting activator (or into smaller tubes of equivalent 
total volume) kept at room temperature for 30 minutes and then centrifuged at approximately 
1500 g for 10 minutes at room temperature. The serum will then be transferred, in equal portions, 
into 3 storage tubes, which will be immediately capped and frozen in an upright position at -20°C 
or colder. 
These archived serum samples, and any residual or leftover serum, plasma or blood remaining 
from planned laboratory work, may be used for research purposes related to airway disease, 
response to dupilumab treatment, additional drug safety assessments or development and 
validation of bioassay methods beyond those defined in the present protocol. 
These samples will remain labelled with the same identifiers as the ones used during the study 
(ie, Subject ID, Sample ID). They will be transferred to a Sanofi site (or a subcontractor site) 
which can be located outside of the country where the study is conducted. The Sponsor has 
included safeguards for protecting patient confidentiality and personal data (see Section 14.3 
and Section 14.5). 
9.7 
APPROPRIATENESS OF MEASUREMENTS  
Refer to Section 4.4.1 for rationale on the co-primary endpoints. The proposed study design and 
endpoints will answer important clinical questions about the efficacy on symptoms and objective 
signs of the disease and the effect of dupilumab on reduction of SCS rescue therapy and surgery, 
which are the most relevant clinical practice assessments and reflect current standard of care.  
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10 
STUDY PROCEDURES 
Medical history should be recorded consistent with Good Clinical and local practice.  This would 
typically include atopic medical history (including asthma history, hypersensitivity to aspirin or 
NSAIDs, NERD, allergy/atopy history), history of surgeries, concomitant medications, etc. 
10.1 
VISIT SCHEDULE  
This section describes how the visits are carried out, in chronological order (according to the flow 
chart Section 1.2 and identical to the order shown in the e-CRF): 
The clinical trial consists of three periods, using an add-on therapy approach to INCS: 
• 
Run-in Period (28 days+/- 3 days; V1).  
• 
Randomized treatment period (up to 52 weeks +/- 3 days; Visits 2-10).  
• 
Post-treatment Period (12 weeks; +/- 3 days V11).  
The study visits occur on the planned dates (relative to the first injection), as scheduled. The visit 
schedule should be adhered to within the ± 3 day visit window. 
If a patient is prematurely discontinued from treatment, every attempt should be made for the 
patient to return to the study site as soon as possible after last IMP administration to perform all 
assessments planned at the EOT visit and patients will be asked and encouraged to return to the 
study site for the visit scheduled as described in Section 10.3.1 (early discontinuation) for a  
12-week follow up.  
Prior to all screening assessments, after discussion of participation in the study, the written 
consent form
 
 must be signed and dated (see Section 12.2). At 
selected sites, requirements for collection of samples for a nasal biomarkers substudy will be 
included in a separate written informed consent. 
Although the screening assessments for this study are grouped under the heading of a single visit 
in this protocol, it is possible for them to be performed over more than 1 site visit if necessary, as 
long as the run-in period window prior to Day 1 (V2) is respected. These patients do not need to 
sign a new consent form and be allocated a new patient number within this same window.  
Rescreening 
Patients that fail screening between V1 and V2 may be rescreened for study eligibility only once 
for the following criteria: 
• 
They do not meet the inclusion criteria for a weekly average NC >1 at V2  
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• 
They had an acute illness such as acute sinusitis, nasal infection or upper respiratory 
infection (E07). These patients can be rescreened only after complete resolution of 
symptoms 
• 
They took one of the prohibited treatments listed in Section 8.8.1 between V1 and V2.  
Patients that are re-screened must sign a new consent form and all of the V1 procedures must be 
repeated (refer to Section 8.4 for further instructions related to re-screening) unless a prior 
assessment is performed within the time frame permitted prior to study entry or the V1 baseline 
CT scan of sinuses and spot urine for biomarker sampling were performed. Patients with positive 
test for HIV or hepatitis will not be allowed for rescreening. 
Note, no waivers will be approved for randomization; all patients must fulfil all eligibility criteria 
before randomization into the study. 
If certain dynamic laboratory tests do not meet the eligibility criteria, these laboratory assessments 
may be repeated, at the discretion of the investigator, if it is judged to be likely to return to 
acceptable range for study inclusion within the screening visit window. 
For patients who do not fulfil other exclusion criteria, rescreening should be discussed with the 
Sponsor. In all cases, a given patient can only be re-screened only once. 
Order of assessments 
During the treatment and post treatment period, if necessary, it is possible to perform the study 
procedures within a 3 day period as long as these days are within the scheduled visit window and 
the order of procedures is maintained. 
It is recommended that assessments/procedures at a site visit are performed in the following order 
if applicable: 
1. Patient-reported outcomes and other questionnaires: 
- 
Daily symptoms of NC, loss of smell and anterior and posterior rhinorrhea, 
- 
SNOT-22, 
- 
VAS Rhinosinusitis,  
- 
Reduced sense of taste symptom severity score, 
- 
QoL (EQ-5D), 
- 
ACQ-6 (in patients with asthma),  
- 
Other questionnaires. 
2. Procedures. 
3. Safety and laboratory assessments. 
4. IMP administration. 
NIMP boxes should be collected at all visits following provision during all study periods. 
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IMP boxes should be collected at all visits following provision for home dosing during treatment 
period. 
10.1.1 Visit 1 (Week -4/Day -28 ±3 days): Run-in period 
Following a discussion of participation in the clinical trial, signed informed consent must be 
obtained and documented. 
The following procedures will then be performed: 
• 
Call IVRS/IWRS to assign patient number, register V1, and obtain first NIMP 
(NASONEX) box(es).  
• 
Interview to collect patient demographic information, NP information, other medical 
history (including asthma history, hypersensitivity to aspirin or NSAIDs, NERD, 
allergy/atopy history, surgical history (including number, type and dates of previous 
surgery for nasal polyps in the past), and prior and concomitant medications (including 
background therapy for NP and asthma), courses of SCS in the previous 2 years (number of 
SCS courses, route of administration doses and duration in the previous 2 years will be 
entered in the e-CRF), long term antibiotics use [>2 weeks] in the previous year will be 
also entered in the e-CRF); inform if patient is considered eligible for nasal polyp surgery 
at study entry. 
• 
Review entry criteria to assess eligibility, with special attention to verify and document the 
following:  
- 
Use of SCS for NP within 2 years prior to V1; and/or contraindication/intolerance to 
SCS; and or prior surgery for NP (whenever in the past), 
- 
Nasal polyps score of 5 or greater (and at least 2 in each side), 
- 
Presence of nasal congestion (blockade/obstruction) severity ≥2 on V1 and loss or 
reduction of smell and/or rhinorrhea/nasal discharge (anterior/posterior nasal drip),  
- 
Patients have not received any of the prohibited medications described in E 03 and/or 
Section 8.8.1.  
• 
Measure vital signs: blood pressure, heart rate, respiration rate, body temperature, weight, 
height. 
• 
Perform physical examination. 
• 
Perform CT scan (within the time period between V1 and V2, prior to first administration 
of IMP). In countries for which a specific approval procedure for the CT scan is required 
by a different committee than the local EC/IRB, patients may be enrolled using a CT 
available in the previous year or perform an MRI of the sinuses between V1 and V2. 
• 
Perform urine sampling for biomarkers and creatinine. 
• 
Perform spirometry within the time period between V1 and V2, for all patients and ensure 
that patients with co-morbid asthma have FEV1>50%. Spirometry will be performed after 
the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol has been withheld for 
at least 6 hours. 
• 
Obtain blood samples for screening clinical laboratory determinations:  
- 
Hematology (see Section 9.4.2 for details), 
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- 
Serum chemistry (see Section 9.4.2 for details). 
• 
Obtain blood samples for hepatitis screen (HBsAg, HBsAb, HBcAb, HCVAb, HIV screen 
(Anti-HIV-1 and HIV-2 antibodies) and anti-nuclear antibody (ANA). In case of results 
showing HBsAg (negative), and HBcAb total or HBcAb IgM (positive), an HBV DNA 
testing may be performed prior to randomization to rule out a false positivity if the 
Investigator believes the patient is a false positive, or to clarify the serological status if the 
Investigator finds it unclear to interpret in absence of known HBV infection. In case of 
results showing HCV Ab (positive), an HCV RNA testing may be performed to rule out a 
false positivity, if the Investigator believes the patient is a false positive.  
- 
Note: Anti-ds DNA antibody will be tested if ANA is positive (≥1:160 titer). 
• 
Obtain serum β-HCG pregnancy test if WOCBP. 
• 
Perform chest X-ray if no chest imaging (X-ray, CT, MRI) available within the previous 
year as per local standard of care or if there is local requirement.  
- 
Note for Japan: According to the request from the health authority, chest X-ray should 
be performed at V1 if there is no chest imaging (Chest X-ray, CT, MRI) available 
within 3 months prior to V1 to exclude patients with suspected active or untreated 
latent tuberculosis. 
• 
Perform nasal endoscopy and send to Central Reader. 
• 
Dispense e-diary/NPIF meter, provide instructions for daily use, and remind patient to 
bring the device to the next visit.  
• 
NIMP: 
- 
Dispense MFNS for use as mandatory background therapy throughout the study. 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Instruct patient on MFNS use and to record 
daily administration in the e-diary. 
• 
Start AE reporting. 
• 
Review and record all medication use with start date and dose in e-CRF.  
- 
Check for use of prohibited medications. 
• 
Advise patients with comorbid atopic conditions (such as asthma) not to adjust their 
treatment without consultation with their physicians. 
• 
Schedule appointment for the next visit. 
10.1.2 Visit 2 (Week 0): Randomization  
• 
PRO patient administration in the e-diary: Daily symptoms of NC, loss of smell and 
anterior and posterior rhinorrhea. 
• 
Inquire about AEs/SAEs and background therapy tolerability.  
• 
Review and record all medication use with start date and dose in e-CRF.  
- 
Check for use of prohibited medications. 
• 
Download e-diary/NPIF meter and check compliance with use of the mandatory 
background therapy (MFNS), as defined as:  
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- 
≥80% of total number of prescribed “stable dose” sprays taken during the run-in 
period. Compliance is verified based on MFNS use recorded in the patient e-diary. 
- 
Remind patient to bring the device to the next visit. 
• 
Confirm patient eligibility:  
- 
Review V1 nasal endoscopy results from central reader to confirm that patient has a 
score 5 or more and at least 2 each side. 
- 
Perform and review local endoscopy to confirm that patient has still a score 5 or more 
and at least 2 each side and record result in e-CRF. If the patient does not have the 
required scores at the V2 nasal endoscopy, the inclusion criteria are not fulfilled and 
the patient should not be randomized. 
- 
Record symptoms of sinusitis, and check the severity average of the last 7 days before 
visit 2 is >1 for the symptoms: nasal congestion/obstruction.  
- 
Record spirometry result from V1 and record FEV1 (liters and predicted), FVC and 
FEF 25-75 result in the e-CRF. Confirm eligibility for patients with FEV1 >50%. 
- 
Check patient compliance with daily diary. 
• 
Investigator to assess eligibility for nasal polyp surgery.  
• 
Perform ECG (refer to Section 9.4.6).  
• 
Obtain urine β-HCG pregnancy test if WOCBP. In case of positive test a serum pregnancy 
test to confirm the pregnancy should be performed as soon as possible. Pregnancy will 
lead to definitive screen failure. 
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight).  
• 
Review all Inclusion/Exclusion Criteria to reconfirm eligibility. 
- 
Reminder that patients receiving prohibited medications described in Section 8.8.1, 
including rescue with intranasal corticosteroid drops, SCS, or surgery for NP during 
the run-in period, are NOT eligible for randomization. 
If entry criteria are not met, call IVRS/IWRS to register the visit and screen-fail the patient. 
Refer to Section 8.4 for details regarding re-screening. 
If the patient meets all inclusion and does not meet any exclusion criteria: 
• 
Call IVRS/IWRS to register visit to randomize the patient and receive the first IMP kit 
number assignment and NIMP (NASONEX) boxes if needed.  
• 
Administer SNOT-22, VAS (for rhinosinusitis), reduced sense of taste severity, QoL  
(EQ-5D), and ACQ-6 (for patients with asthma). 
• 
 Health care resource utilization via e-CRF.  
• 
Administer smell test (UPSIT).  
• 
Obtain blood samples (prior to IMP) for:  
- 
Hematology laboratories (see Section 9.4.2 for details),  
- 
Note: Anti-ds DNA antibody will be tested if ANA is positive (≥1:160 titer). 
- 
Serum dupilumab concentration, and anti-drug antibodies, 
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- 
Hepatitis B viral load for patients in Japan (or other countries/regions if there is local 
regulatory requirement) who are HBsAg negative and HBsAb positive at V1,  
- 
Tuberculosis test if required by local regulation, 
- 
Stored DNA sampling, stored serum, and stored whole blood RNA, for those patients 
who have signed a specific informed consent form. 
• 
Perform urine sampling for biomarkers and creatinine. 
• 
Obtain serum and plasma for biomarkers, see Section 9.5.2. 
• 
 
  
• 
 
 
• 
Perform blood sampling for total IgE.  
• 
Remind patient to bring the e-diary/NPIF meter to the next visit. 
• 
Reminder: sexually active female patients of reproductive potential are required to practice 
an acceptable contraception (as defined in E 15 or local protocol amendment in case of 
specific local requirement) during the entire study duration, while taking dupilumab and 
for 12 weeks after the last IMP dose. Sexually active male patients should be reminded 
that if their partner is a woman of childbearing potential, their partner should consider 
protection by acceptable method(s) of birth control.  
• 
Administer IMP:  
- 
Patients are monitored for at least 30 minutes (or minimum time required by your local 
regulator) after the end of administration of IMP for any signs or symptoms of a 
hypersensitivity reaction, 
- 
Throughout the study, SC injection sites will be alternated between the 4 quadrants of 
the abdomen (avoiding navel and waist areas) or upper thighs or upper arms, so that the 
same site is not injected twice consecutively. Injection in the upper arms can only be 
performed by a person trained for 4 injections (caregiver trained by Investigator or 
delegate) or health care professional, but not the patient themselves. This instruction 
pertains to the day of the first dose is injected as well as the administration of q2w 
injections. Detailed instructions for transport, storage, preparation, and administration 
of IMP are provided to the patient, 
• 
NIMP:  
- 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Dispense MFNS if needed. Instruct patient to 
record usage in the e-diary. 
• 
Advise patients with comorbid atopic conditions (such as asthma) not to adjust their 
treatment without consultation with their physicians. 
• 
Schedule appointment for next visit. 
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10.1.3 Visit 3 (Week 2) 
• 
PRO Patient administration in the e-diary: 
- 
Daily symptoms of NC, loss of smell and anterior and posterior rhinorrhea, 
- 
VAS for rhinosinusitis,  
- 
Reduced sense of taste symptom severity score. 
• 
Administer smell test (UPSIT). 
• 
Inquire about AEs/SAEs and background therapy tolerability. 
• 
Collect NIMP boxes  
• 
Record all medication use with start date and dose in the e-CRF. 
- 
Check for use of prohibited medications. 
- 
Complete rescue medication/surgery page (s) of e-CRF. Use of oral steroids for rescue 
treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date 
and dosing information (daily dose, duration, INN) will be informed. Details on 
planned date for surgery, type, and outcome (whenever possible) of surgery will be 
recorded in a specific e-CRF page. If surgery is performed during the study treatment 
period or follow-up an AE or SAE page will be completed. 
• 
Call IVRS/IWRS to register visit and obtain next IMP kit number assignment and NIMP 
(NASONEX) box(es) if needed or report potential definitive IMP stop. 
• 
Download e-diary/NPIF meter and review the data; remind patient to bring the device to the 
next visit. 
• 
Perform blood sampling for serum dupilumab concentration. 
• 
Administer IMP (one SC injection). 
- 
Patients will be monitored at the study site for a minimum of 30 minutes (or minimum 
time required by your local regulator) after the injection. 
• 
NIMP:  
- 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Dispense MFNS if needed. Instruct patient to 
record usage in the e-diary.  
• 
Schedule appointment for next visit. 
• 
Remind the patient to withhold the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours prior to arriving at V4. 
10.1.4 Visit 4 (Week 4) 
• 
PRO Patient administration in the e-diary: 
- 
Daily symptoms of NC, loss of smell, and anterior and posterior rhinorrhea, 
- 
SNOT-22,  
- 
VAS for rhinosinusitis,  
- 
Reduced sense of taste symptom severity score, 
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- 
ACQ-6 (for patients with asthma). 
• 
Inquire about AEs/SAEs and background therapy tolerability. 
• 
Collect NIMP boxes  
• 
Record all medication use with start date and dose in the e-CRF. 
- 
Check for use of prohibited medications, 
- 
Complete rescue medication/surgery page (s) of e-CRF. Use of oral steroids for rescue 
treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date 
and dosing information (daily dose, duration, INN) will be informed. Details on 
planned date for surgery, type, and outcome (whenever possible) of surgery will be 
recorded in a specific e-CRF page. If surgery is performed during the study treatment 
period or follow-up an AE or SAE page will be completed. 
• 
Call IVRS/IWRS to register visit and obtain next IMP kit number assignment and NIMP 
(NASONEX) box(es) if needed or report potential definitive IMP stop. 
• 
Download e-diary/NPIF meter and review the data; remind patient to bring the device to the 
next visit. 
• 
Perform spirometry (for patients with asthma) and record FEV1, FVC and FEF 25-75 
result in the e-CRF. 
• 
Administer smell test (UPSIT). 
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform nasal endoscopy and send to Central Reader. 
• 
Perform blood sampling for serum dupilumab concentration. 
• 
Obtain urine β-HCG pregnancy test if WOCBP. In case of positive urinary test the study 
treatment will be withhold and a serum pregnancy test to confirm the pregnancy should be 
performed as soon as possible. Pregnancy will lead to definitive treatment discontinuation 
in all cases. 
• 
Administer IMP (one SC injection). 
- 
IMP can be administered by the patient or caregiver under the supervision of the 
Investigator or the designee,  
- 
Patients will be monitored at the study site for a minimum of 30 minutes (or minimum 
time required by your local regulator) after the injection. 
• 
NIMP:  
- 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Dispense MFNS if needed. Instruct patient to 
record usage in the e-diary.  
• 
Schedule appointment for next visit. 
10.1.5 Visit 5 (Week 6) 
• 
Inquire about AEs/SAEs and background therapy tolerability. 
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• 
Collect NIMP boxes  
• 
Record all medication use with start date and dose in the e-CRF. 
- 
Check for use of prohibited medications, 
- 
Complete rescue medication/surgery page (s) of e-CRF. Use of oral steroids for rescue 
treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date 
and dosing information (daily dose, duration, INN) will be informed. Details on 
planned date for surgery, type, and outcome (whenever possible) of surgery will be 
recorded in a specific e-CRF page. If surgery is performed during the study treatment 
period or follow-up an AE or SAE page will be completed. 
• 
Call IVRS/IWRS to register visit and obtain next IMP kit numbers assignment and NIMP 
(NASONEX) box(es) if needed or report potential definitive IMP stop. 
• 
Download e-diary/NPIF meter and review the data; remind patient to bring the device to the 
next visit. 
• 
Administer IMP (one SC injection). 
- 
IMP can be administered by the patient or caregiver under the supervision of the 
Investigator or the designee,  
- 
Patients will be monitored at the study site for a minimum of 30 minutes (or minimum 
time required by your local regulator) after the injection. 
• 
NIMP:  
- 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Dispense MFNS if needed. Instruct patient to 
record usage in the e-diary.  
• 
Schedule appointment for next visit. 
10.1.6 Visit 6 (Week 8) 
• 
PRO Patient administration in the e-diary: 
- 
Daily symptoms of NC, loss of smell and anterior and posterior rhinorrhea, 
- 
SNOT-22,  
- 
VAS for rhinosinusitis,  
- 
Reduced sense of taste symptom severity score. 
• 
Inquire about AEs/SAEs and background therapy tolerability. 
• 
Collect NIMP boxes  
• 
Record all medication use with start date and dose in the e-CRF. 
- 
Check for use of prohibited medications, 
- 
Complete rescue medication/surgery page (s) of e-CRF. Use of oral steroids for rescue 
treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date 
and dosing information (daily dose, duration, INN) will be informed. Details on 
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planned date for surgery, type, and outcome (whenever possible) of surgery will be 
recorded in a specific e-CRF page. If surgery is performed during the study treatment 
period or follow-up an AE or SAE page will be completed. 
• 
Call IVRS/IWRS to register visit and obtain next IMP kit number assignment and NIMP 
(NASONEX) box(es) if needed or report potential definitive IMP stop. 
• 
Download e-diary/NPIF meter and review the data; remind patient to bring the device to the 
next visit. 
• 
Perform nasal endoscopy and send to Central Reader. 
• 
Obtain blood sample for ADA. 
• 
Obtain urine β-HCG pregnancy test if WOCBP. In case of positive urinary test the study 
treatment will be withheld and a serum pregnancy test to confirm the pregnancy should be 
performed as soon as possible. Pregnancy will lead to definitive treatment discontinuation 
in all cases. 
• 
Administer IMP (one SC injection). 
- 
IMP can be administered by the patient or caregiver under the supervision of the 
Investigator or the designee,  
- 
Patients will be monitored at the study site for a minimum of 30 minutes (or minimum 
time required by your local regulator) after the injection. 
• 
NIMP:  
- 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Dispense MFNS if needed. Instruct patient to 
record usage in the e-diary.  
• 
In case of home administration for next IMP injection remind the patient to return IMP 
treatment and NIMP kit boxes along with any unused prefilled syringes that will be used 
for drug accountability purposes. Patients will also return used prefilled syringes to the site 
in a sharp container. 
• 
WOCBP are reminded to perform at Week 12 urinary pregnancy test and bring back the 
test for the next visit. In case of positive urinary test the study treatment will be withhold 
and a serum pregnancy test to confirm the pregnancy should be performed as soon as 
possible. Pregnancy will lead to definitive treatment discontinuation in all cases. In case of 
positive test at home, contact site immediately. 
• 
Remind the patient to withhold the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours prior to arriving at V7. 
• 
Supply IMP for patients who will have off-site visits on Week 10, 12, and 14.  
• 
Schedule appointment for next visit.  
10.1.7 Optional visits (Week 10, 12, 14) 
Optional visits can be scheduled at Week 10, 12, 14 for IMP/NIMP supply or IMP administration. 
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From Week 10, q2w home administration of IMP (by patient, caregiver, or health care 
professional) is possible if the patient (or caregiver) has been sufficiently trained. When IMP is 
administered at home, the patients must be advised by the site staff to self-monitor for potential 
signs and symptoms that may suggest a hypersensitivity reaction for at least 30 minutes (or 
minimum time required by your local regulator) after administration. Patients will complete a 
dosing diary to document compliance with self-injection of IMP (or injection by a caregiver), 
including anatomic site of administration and any adverse reactions). 
If the patient (or caregiver) is unable or unwilling to administer IMP, arrangements must be made 
for qualified site personnel and/or healthcare professionals to administer IMP for the doses not 
scheduled to be given at the study site. 
• 
Urinary pregnancy test to be performed at Week 12. 
• 
Patient should be informed to record home administration of the IMP in the diary. 
10.1.8 Visit 7 (Week 16) 
• 
PRO Patient administration in the e-diary: 
- 
Daily symptoms of NC, loss of smell and anterior and posterior rhinorrhea,  
- 
SNOT-22,  
- 
VAS for rhinosinusitis,  
- 
Reduced sense of taste symptom severity score, 
- 
QoL (EQ-5D), 
- 
ACQ-6 (for patients with asthma). 
• 
Health care resource utilization via e-CRF.  
• 
Inquire about AEs/SAEs and background therapy tolerability. 
• 
Collect IMP and NIMP boxes  
• 
Record all medication use with start date and dose in the e-CRF. 
- 
Check for use of prohibited medications, 
- 
Complete rescue medication/surgery page (s) of e-CRF. Use of oral steroids for rescue 
treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date 
and dosing information (daily dose, duration, INN) will be informed. Details on 
planned date for surgery, type and outcome (whenever possible) of surgery will be 
recorded in a specific e-CRF page. If surgery is performed during the study treatment 
period or follow-up an AE or SAE page will be completed. 
• 
Call IVRS/IWRS to register visit and obtain next IMP kit numbers assignment and NIMP 
(NASONEX) box(es) if needed or report potential definitive IMP stop. 
• 
Download e-diary/NPIF meter and review the data; remind patient to bring the device to the 
next visit. 
• 
Perform spirometry (for patients with asthma) and record FEV1, FVC and FEF 25-75 
result in the e-CRF. 
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• 
Perform nasal endoscopy and send to Central Reader. 
• 
Administer smell test (UPSIT). 
• 
Obtain blood samples for (prior to IMP):  
- 
Hematology (see Section 9.4.2 for details), 
- 
Serum chemistry (see Section 9.4.2 for details). 
• 
Perform blood sampling for Hepatitis B viral load (for patients in Japan [or other 
countries/regions if there is local regulatory requirement] who are HBsAg negative and 
HBsAb positive at V1). 
• 
Perform blood sampling for serum dupilumab concentration. 
• 
Perform serum sampling for ADA.  
• 
Perform urine sampling for biomarkers and creatinine. 
• 
 
• 
Obtain urine β-HCG pregnancy test if WOCBP. 
• 
Administer IMP (one SC injection). 
- 
IMP can be administered by the patient or caregiver under the supervision of the 
Investigator or the designee,  
- 
Patients will be monitored at the study site for a minimum of 30 minutes (or minimum 
time required by your local regulator) after the injection. 
• 
NIMP:  
- 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Dispense MFNS if needed. Instruct patient to 
record usage in the e-diary.  
• 
Schedule appointment for next visit.  
• 
Remind the patient to withhold the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours prior to arriving at V8. 
• 
Remind patient to return IMP treatment and NIMP kit boxes along with any unused 
prefilled syringes that will be used for drug accountability purposes. Patients will also 
return used prefilled syringes to the site in a sharp container. 
• 
WOCBP are reminded to perform at Week 20 the urinary pregnancy test and bring back 
the test for the next visit. In case of positive urinary test the study treatment will be 
withhold and a serum pregnancy test to confirm the pregnancy should be performed as 
soon as possible. Pregnancy will lead to definitive treatment discontinuation in all cases. 
• 
Supply IMP for optional visits can be scheduled at Week 18, 20, and 22. 
10.1.9 Optional visits (Week 18, 20, 22) 
Optional visits can be scheduled at Week 18, 20, 22 for IMP/NIMP supply or IMP administration. 
• 
Urinary pregnancy test to be performed at Week 20. 
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• 
Patient should be informed to record home administration of the IMP in the diary. 
10.1.10 
Visit 8 (Week 24) 
• 
PRO Patient administration in the e-diary: 
- 
Daily symptoms of NC, loss of smell and anterior and posterior rhinorrhea,  
- 
SNOT-22,  
- 
VAS for rhinosinusitis,  
- 
Reduced sense of taste symptom severity score, 
- 
QoL (EQ-5D), 
- 
ACQ-6 (for patients with asthma). 
• 
Health care resource utilization via e-CRF.  
• 
Inquire about AEs/SAEs and background therapy tolerability. 
• 
Collect IMP and NIMP boxes  
• 
Record all medication use with start date and dose in the e-CRF. 
- 
Check for use of prohibited medications, 
- 
Complete rescue medication/surgery page (s) of e-CRF. Use of oral steroids for rescue 
treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date 
and dosing information (daily dose, duration, INN) will be informed. Details on 
planned date for surgery, type and outcome (whenever possible) of surgery will be 
recorded in a specific e-CRF page. If surgery is performed during the study treatment 
period or follow-up an AE or SAE page will be completed. 
• 
Call IVRS/IWRS to register visit and obtain next IMP kit numbers assignment and NIMP 
(NASONEX) box(es) if needed or report potential definitive IMP stop. 
• 
Download e-diary/NPIF meter and review the data; remind patient to bring the device to the 
next visit. 
• 
Perform spirometry (for patients with asthma) and record FEV1, FVC and FEF 25-75 
result in the e-CRF. 
• 
Perform nasal endoscopy and send to Central Reader. 
• 
Administer smell test (UPSIT). 
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Perform CT scan. 
• 
Obtain blood samples for (prior to IMP):  
- 
Hematology (see Section 9.4.2 for details), 
- 
Serum chemistry (see Section 9.4.2 for details). 
• 
Perform blood sampling for Hepatitis B viral load (for patients in Japan [or other 
countries/regions if there is local regulatory requirement] who are HBsAg negative and 
HBsAb positive at V1). 
• 
Perform blood sampling for serum dupilumab concentration. 
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• 
Perform serum sampling for ADA.  
• 
Perform blood sampling for stored serum for those patients who have signed a specific 
informed consent form. 
• 
Perform blood sampling for total IgE. 
• 
Perform urine sampling for biomarkers and creatinine. 
• 
 
• 
 
 
• 
Obtain urine β-HCG pregnancy test if WOCBP. In case of positive urinary test the study 
treatment will be withhold and a serum pregnancy test to confirm the pregnancy should be 
performed as soon as possible. Pregnancy will lead to definitive treatment discontinuation 
in all cases. 
• 
Administer IMP (one SC injection). 
- 
IMP can be administered by the patient or caregiver under the supervision of the 
Investigator or the designee  
- 
Patients will be monitored at the study site for a minimum of 30 minutes (or minimum 
time required by your local regulator) after the injection. 
• 
NIMP:  
- 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Dispense MFNS if needed. Instruct patient to 
record usage in the e-diary.  
• 
Schedule appointment for next visit.  
• 
Remind the patient to withhold the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours prior to arriving at V9. 
• 
Remind the patient to return IMP treatment and NIMP kit boxes along with any unused 
prefilled syringes that will be used for drug accountability purposes. Patients will also 
return used prefilled syringes to the site in a sharp container. 
• 
Remind the patient to perform NPIF at Week 28, 32, and 36 and record the value in the  
e-diary.  
• 
WOCBP are reminded to perform at Week 28, 32, 36 the urinary pregnancy test and bring 
back the tests for the next visit. In case of positive urinary test the study treatment will be 
withhold and a serum pregnancy test to confirm the pregnancy should be performed as 
soon as possible. Pregnancy will lead to definitive treatment discontinuation in all cases. 
• 
Supply IMP for optional visits at Week 26, 28, 30, 32, 34, 36, and 38. 
10.1.11 
Optional visits (Week 26, 28, 30, 32, 34, 36, 38) 
Optional visits can be scheduled at Week 26, 28, 30, 32, 34, 36, 38 for IMP/NIMP supply or IMP 
administration. 
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• 
Urinary pregnancy test to be performed at Week 28, 32, 36. 
• 
Perform NPIF at Week 28, 32, 36, and record the value in the e-diary  
• 
Patient should be informed to record home administration of the IMP in the diary. 
10.1.12 
Visit 9 (Week 40) 
• 
PRO Patient administration in the e-diary: 
- 
SNOT-22,  
- 
VAS for rhinosinusitis,  
- 
QoL (EQ-5D), 
- 
ACQ-6 questionnaire in patients with asthma. 
• 
Health care resource utilization via e-CRF.  
• 
Inquire about AEs/SAEs and background therapy tolerability. 
• 
Collect IMP and NIMP boxes  
• 
Record all medication use with start date and dose in the e-CRF. 
- 
Check for use of prohibited medications. 
- 
Complete rescue medication/surgery page (s) of e-CRF. Use of oral steroids for rescue 
treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date 
and dosing information (daily dose, duration, INN) will be informed. Details on 
planned date for surgery, type, and outcome (whenever possible) of surgery will be 
recorded in a specific e-CRF page. If surgery is performed during the study treatment 
period or follow-up an AE or SAE page will be completed. 
• 
Call IVRS/IWRS to register visit and obtain next IMP kit numbers assignment and NIMP 
(NASONEX) box(es) if needed or report potential definitive IMP stop. 
• 
Download e-diary/NPIF meter and review the data; remind patient to bring the device to the 
next visit. 
• 
Perform spirometry (for patients with asthma) and record FEV1, FVC and FEF 25-75 
result in the e-CRF. 
• 
Perform nasal endoscopy and send to Central Reader. 
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Obtain blood samples for (prior to IMP):  
- 
Hematology (see Section 9.4.2 for details), 
- 
Serum chemistry (see Section 9.4.2 for details). 
• 
Sampling for serum dupilumab concentration. 
• 
Obtain urine β-HCG pregnancy test if WOCBP. In case of positive urinary test the study 
treatment will be withheld and a serum pregnancy test to confirm the pregnancy should be 
performed as soon as possible. Pregnancy will lead to definitive treatment discontinuation 
in all cases. 
• 
Administer IMP (one SC injection). 
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- 
IMP can be administered by the patient or caregiver under the supervision of the 
Investigator or the designee,  
- 
Patients will be monitored at the study site for a minimum of 30 minutes (or minimum 
time required by your local regulator) after the injection. 
• 
NIMP:  
- 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Dispense MFNS if needed. Instruct patient to 
record usage in the e-diary.  
• 
Schedule appointment for next visit. 
• 
Remind the patient to withhold the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours prior to arriving at V10. 
• 
Remind the patient to return IMP treatment and NIMP kit boxes along with any unused 
prefilled syringes that will be used for drug accountability purposes. Patients will also 
return used prefilled syringes to the site in a sharp container. 
• 
Remind the patient to perform NPIF at Week 44, 48 and record the value in the e-diary. 
• 
WOCBP are reminded to perform at Week 44, 48 the urinary pregnancy test and bring 
back the tests for the next visit. In case of positive urinary test the study treatment will be 
withhold and a serum pregnancy test to confirm the pregnancy should be performed as 
soon as possible. Pregnancy will lead to definitive treatment discontinuation in all cases. 
• 
Supply IMP for optional visits Week 42, 44, 46, 48 and 50. 
10.1.13 
Optional visits (Week 42, 44, 46, 48, and 50) 
Optional visits can be scheduled at Week 42, 44, 46, 48 and 50 for IMP/NIMP supply or IMP 
administration. 
• 
Urinary pregnancy test to be performed at Week 44, 48. 
• 
Perform NPIF at Week 44, 48 and record the value in the e-diary.  
• 
Patient should be informed to record home administration of the IMP in the diary. 
10.1.14 
Visit 10 (Week 52): End of treatment 
• 
PRO Patient administration in the e-diary: 
- 
Daily symptoms of NC, loss of smell and anterior and posterior rhinorrhea,  
- 
SNOT-22,  
- 
VAS for rhinosinusitis,  
- 
Reduced sense of taste symptom severity score, 
- 
QoL (EQ-5D), 
- 
ACQ-6 (for patients with asthma). 
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• 
Health care resource utilization via e-CRF.  
• 
Inquire about AEs/SAEs and background therapy tolerability. 
• 
Collect IMP and NIMP boxes  
• 
Record all medication use with start date and dose in the e-CRF. 
- 
Check for use of prohibited medications, 
- 
Complete rescue medication/surgery page (s) of e-CRF. Use of oral steroids for rescue 
treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date 
and dosing information (daily dose, duration, INN) will be informed. Details on 
planned date for surgery, type, and outcome (whenever possible) of surgery will be 
recorded in a specific e-CRF page. If surgery is performed during the study treatment 
period or follow-up an AE or SAE page will be completed. 
• 
Call IVRS/IWRS to register visit and obtain NIMP (NASONEX) box(es) if needed. 
• 
Download e-diary and review the data; remind patient to bring the device to the next visit. 
• 
Perform blood sampling for serum dupilumab concentration. 
• 
Perform spirometry (for patients with asthma) and record FEV1, FVC and FEF 25-75 
result in the e-CRF. 
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Perform ECG (refer to Section 9.4.6). 
• 
Perform CT scan (unless not approved by local ethics committee). 
• 
Perform nasal endoscopy and send to Central Reader. 
• 
Administer smell test (UPSIT). 
• 
Obtain blood samples for (prior to IMP):  
- Hematology (see Section 9.4.2 for details), 
- Serum chemistry (see Section 9.4.2 for details). 
• 
Perform blood sampling for Hepatitis B viral load (for patients in Japan [or other 
countries/regions if there is local regulatory requirement] who are HBsAg negative and 
HBsAb positive at V1). 
• 
Perform serum sampling for ADA.  
• 
Obtain serum and plasma for biomarkers, see Section 9.5.2 
• 
Perform blood sampling for stored serum for those patients who have signed a specific 
informed consent form. 
• 
Perform blood sampling for total IgE. 
• 
Obtain urine β-HCG pregnancy test if WOCBP. In case of positive urinary test the study 
treatment will be withhold and a serum pregnancy test to confirm the pregnancy should be 
performed as soon as possible. Pregnancy will lead to definitive treatment discontinuation 
in all cases. 
• 
Perform urine sampling for biomarkers and creatinine. 
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• 
NIMP:  
- 
Ensure that the patient has sufficient quantity for dosing up until the next visit, 
knowing that one MFNS bottle contains sufficient doses for either 2 weeks of BID 
treatment or 4 weeks of QD treatment. Dispense MFNS if needed. Instruct patient to 
record usage in the e-diary.  
- 
Advise patients with comorbid atopic conditions (such as asthma) not to adjust their 
treatment without consultation with their physicians. 
10.1.15 
Visit 11 (Week 64): End of study 
• 
PRO Patient administration in the e-diary: 
- 
Daily symptoms of NC, loss of smell and anterior and posterior rhinorrhea,  
- 
VAS for rhinosinusitis,  
- 
Reduced sense of taste symptom severity score. 
• 
Inquire about AEs/SAEs and background therapy tolerability. 
• 
Collect NIMP boxes  
• 
Record all medication use with start date and dose in the e-CRF. 
- 
Check for use of prohibited medications. 
- 
Complete rescue medication/surgery page (s) of e-CRF. Use of oral steroids for rescue 
treatment of worsening nasal polyps or for another reason will be captured by the 
Investigator (or designee) on the appropriate page(s) of the e-CRF page and the date 
and dosing information (daily dose, duration, INN) will be informed. Details on 
planned date for surgery, type, and outcome (whenever possible) of surgery will be 
recorded in a specific e-CRF page. If surgery is performed during the study treatment 
period or follow-up an AE or SAE page will be completed. 
• 
Call IVRS/IWRS to register visit. 
• 
Download e-diary/NPIF meter and review the data; collect eDiary device. 
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Perform nasal endoscopy and send to Central Reader. 
• 
Obtain urine β-HCG pregnancy test if WOCBP. 
• 
Obtain blood samples:  
- 
Hematology (see Section 9.4.2 for details), 
- 
Serum chemistry (see Section 9.4.2 for details). 
• 
Perform blood sampling for serum dupilumab concentration. 
• 
Perform serum sampling for ADA.  
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10.2 
DEFINITION OF SOURCE DATA 
Source data is all information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents. Source documents are 
original documents, data and records such as hospital records, clinic and office charts, laboratory 
notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, etc. 
All the data collected in the e-CRF should be transcribed directly from source documents. Data 
downloaded from the study-associated central laboratories, endoscopy, CT scan, NPIF 
measurement, and patient diary will be considered source data. HCRU will be collected directly in 
the e-CRF. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, the 
patient should remain in the study as long as possible. 
10.3.1 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
Patients who discontinue treatment permanently during the treatment period will be assessed as 
soon as possible using all procedures normally planned for the End-of-treatment Visit with the 
exception of CT Scan. Patients who discontinue early during the post-treatment period will be 
assessed as soon as possible using all procedures normally planned for the end-of-study (EOS) 
Visit. 
For patients in whom the surgery date is scheduled after the planned end of study, a follow up 
contact(s) should be performed around the time of planned surgery to document the surgery date. 
Surgery data will be collected only until e-CRF Closure and EOS will not be delayed. 
Patients will also be instructed to: 
• 
Return to the study site for evaluations of NPS, SNOT-22, at: 
- 
Week 24, Week 52: If the ETD visit occurred between Week 0-Week 16, 
- 
Week 52: If the ETD visit occurred between >Week 16-Week 40, 
- 
Week 64 (EOS): If the ETD visit occurred between >Week 40-Week 52. 
• 
Return and have a CT Scan performed as scheduled at Week 24 and 52. 
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Patients who discontinue prior to week 40 will have the following assessed through week 52, 
patients who discontinue after week 40 will have the following assessed through week 64: 
• 
Perform PK and ADA sampling at the initially scheduled visits for these assessments 
• 
Continue to complete the e-diary for nasal congestion, loss of smell daily symptom and 
anterior/posterior rhinorrhea evaluation 
• 
Continue on MFNS stable dose but patients are not required to complete the INCS use 
daily in the e-diary after ETD. 
• 
Advise patients with comorbid atopic conditions (such as asthma) not to adjust their 
treatment without consultation with their physicians. 
• 
Report any AE up to the last scheduled visit (Week 52 or Week 64 depending on the 
discontinuation date). 
• 
Contact the Investigator during the post treatment period up to the EOS visit if the 
symptoms worsen requiring medical attention. 
- 
The Investigator will record in the corresponding e-CRF pages rescue medication 
prescribed or surgical interventions during the planned study treatment period. Use of 
oral steroids for rescue treatment of worsening nasal polyps or for another reason will 
be captured by the Investigator (or designee) on the appropriate page(s) of the e-CRF 
page and the date and dosing information (daily dose, duration, INN) will be informed. 
Details on planned date for surgery, type, and outcome (whenever possible) of surgery 
will be recorded in a specific e-CRF page. If surgery is performed during the study 
treatment period or follow-up an AE or SAE page will be completed. 
For patients undergoing surgery for NP, refer to Section 9.2.1.5 for details. 
10.3.2 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of AEs. Re-
initiation of treatment with the IMP will be made under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the AE is sufficiently resolved and unlikely to recur after resuming therapy with 
IMP.  
In addition, any of the following conditions will be a cause for temporary treatment 
discontinuation: 
• 
Infections or infestations that do not respond to medical treatment should have study drug 
discontinued until the infection is resolved 
• 
Any laboratory abnormality that meets temporary treatment discontinuation criteria as per 
Appendix G. 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the e-CRF. If the IMP is interrupted for more than 2 doses, then the 
patient should permanently discontinue the study treatment. 
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10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the e-CRF. 
Patients must be withdrawn from the study (ie, from any further IMP or study procedure) for the 
following reasons: 
• 
At their own request or at the request of their legally authorized representative (legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient’s participation in 
the procedure(s) involved in the research). 
• 
If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
patient’s well-being. 
In case of surgery for NP (refer to Section 9.2.1.5for details).  
• 
At the specific request of the Sponsor. 
• 
In the event of a critical protocol deviation, at the request of the Investigator or the 
Sponsor. 
• 
Any code broken requested by the Investigator will lead to permanent treatment 
discontinuation. 
• 
In the event of an anaphylactic systemic allergic reaction that is related to IMP and that 
requires treatment. 
• 
In the event that the patient is diagnosed with a malignancy during the study, excluding 
carcinoma in situ of the cervix or squamous or basal cell. 
• 
Pregnancy.  
• 
Any opportunistic infection, such as tuberculosis or other infections whose nature or 
course may suggest an immunocompromised status (refer to Appendix I). 
• 
Serum ALT >3 ULN and total bilirubin >2ULN. 
• 
Serum ALT >5 ULN if baseline ALT <2 ULN or ALT >8 ULN if baseline ALT >2 ULN.  
Stopping rules described in Appendix G should be applied. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last.  
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the IMP (EOT Visit). (Refer to 
Section 10.1.14 Visit 10 (Week 52): End of treatment). 
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Patients who discontinue early from treatment may be asked to return to the clinic to have 
additional ADA samples collected for analysis based on the overall clinical presentation at the 
time of discontinuation. 
Patients who permanently discontinue the study medication will be asked and encouraged to 
return to the clinic for and participate in follow-up assessments described in (Section 10.3.1). 
10.3.5 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. If 
possible, the patients should be assessed using the procedures normally planned at the end-of-
treatment visit. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the  
e-CRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator should make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter). A patient should only be designated as lost to follow-up if the site 
is unable to establish contact with the patient after 3 documented attempts via 2 different methods 
(phone, text, e-mail, certified letter, etc).  
The statistical analysis plan (SAP) will specify how these patients lost to follow-up for their 
primary endpoints will be considered.  
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
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An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, or. 
• 
Is life-threatening, or. 
• 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or. 
• 
Results in persistent or significant disability/incapacity, or. 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is not 
intended to be exhaustive: 
• 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm,  
- 
Anaphylaxis (refer to Appendix H for Definition of Anaphylaxis), 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
• 
Development of drug dependence or drug abuse. 
• 
ALT >3 x ULN + total bilirubin >2 x ULN. 
• 
Suicide attempt or any event suggestive of suicidality. 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling).  
• 
Bullous cutaneous eruptions. 
• 
Cancers diagnosed during the study or aggravated during the study. 
• 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study. 
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10.4.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added or removed during a study by protocol amendment. 
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described Section 10.4.4, even if not fulfilling a seriousness criterion.  
AESIs for this study include: 
• Anaphylactic or systemic allergic reactions that are related to IMP and that require 
treatment (refer to Appendix H for the definition of anaphylaxis).  
• Severe injection site reactions that last longer than 24 hours. 
• Any infection meeting at least 1 of the following criteria: 
- 
Any serious infection (SAE), 
- 
Requires parenteral (IV, IM, SC) antimicrobial therapy,  
- 
Requires oral antimicrobial therapy for longer than 2 weeks, 
- 
Is a parasitic infection,  
- 
Is an opportunistic infection (refer to Appendix I). 
Note: Antimicrobial therapy refers to antibiotic, antiviral, and antifungal agents. 
• Significant elevation of ALT. 
- 
ALT >5 × ULN in patients with baseline ALT <2 × ULN;  
or 
- 
ALT >8 × ULN if baseline ALT >2 × ULN 
• Pregnancy occurring in a female patient entered in the clinical trial or in a female partner 
of a male patient entered in the clinical trial. It will be qualified as an SAE only if it fulfills 
1 of the seriousness criteria (see Section 10.4.1.2). 
- 
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.  
• Symptomatic overdose (serious or non-serious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic 
syringes or pills count) and defined as at least twice the intended dose during an 
interval of less than 11 days. The circumstances (ie, accidental or intentional) should 
be clearly specified in the verbatim and symptoms, if any, entered on separate AE 
forms. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
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10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities 
Not applicable for this study. 
10.4.3 General guidelines for reporting adverse events 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that patient, are 
to be recorded on the corresponding page(s) or screen(s) of the e-CRF.  
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, intensity, action taken with respect to IMP, 
corrective treatment/therapy given, additional investigations performed, outcome, and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the IMP or by 
the study procedure(s). 
The Investigator should take appropriate measures to follow all AEs until clinical recovery is 
complete and laboratory results have returned to normal, or until progression has been stabilized, 
or until death, in order to ensure the safety of the patients. This may imply that observations will 
continue beyond the last planned visit per protocol, and that additional investigations may be 
requested by the monitoring team up to as noticed by the Sponsor.  
When treatment is prematurely discontinued, the patient’s observations will continue until the end 
of the study as defined in Section 10.3.1.  
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
• 
Symptomatic and/or,  
• 
Requiring either corrective treatment or consultation, and/or,  
• 
Leading to IMP discontinuation or modification of dosing, and/or,  
• 
Fulfilling a seriousness criterion, and/or, 
• 
Defined as an AESI. 
See Section 10.4.6 for a table summarizing reporting timelines. 
10.4.4 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designee must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay.  
• 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. Care 
should be taken to ensure that the patient's identity is protected and the patient's identifiers 
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in the clinical trial are properly mentioned on any copy of a source document provided to 
the Sponsor. For laboratory results, include the laboratory normal ranges.  
• 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge. In addition, every effort should be made to further 
document any SAE that is fatal or life threatening within a week (7 days) of the initial 
notification.  
• 
A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work.  
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team.  
10.4.5 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
Instructions for AE reporting are summarized in Table 4. 
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix G. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• 
Neutropenia. 
• 
Thrombocytopenia. 
• 
Increase in ALT. 
• 
Acute renal insufficiency. 
• 
Suspicion of rhabdomyolysis. 
In addition, on treatment eosinophil counts >3000 cells/µL (3.0 G/L) are to be reported as AEs. 
NOTE: In this clinical trial these laboratory abnormalities can be considered as AESIs  
(see Section 10.4.1.3). 
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Table 4 - Summary of adverse event reporting instructions 
Adverse event/laboratory abnormality 
Reporting timeframe 
Serious adverse event 
 
Within 24 hours 
Adverse Event (non-SAE, 
non-AESI)a  
 
Routine 
Pregnancyb 
 
Within 24 hours 
Overdose 
Symptomatic 
Within 24 hours 
 
Asymptomatic 
Routine 
ALT elevation 
ALT >5 ULN if baseline ALT is ≤2 ULN 
Within 24 hours 
 
ALT >8 ULN if baseline ALT is >2 ULN 
Within 24 hours 
Anaphylactic or systemic allergic reactions that are related to IMP and that require treatment 
Within 24 hours 
Severe injection site reactions that last longer than 24 hours 
Within 24 hours 
Infections as defined in Section 10.4.1.3 
 
ALT=alanine aminotransaminase; ULN=upper limit of normal. 
a For reporting of epistaxis as an AE, use both AE form and Safety complementary form to provide date, features and outcome of the event. 
b The drug exposure via parent form is not part of the Case Report Form, but needs to be completed for pregnancy 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• 
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, Institutional Review Board/Independent Ethics Committee as 
appropriate and to the Investigators.  
• 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations.  
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
For safety, the treatment code will be unblinded by the Sponsor for reporting to the Health 
Authorities. 
Authority of any suspected unexpected adverse drug reaction (SUSAR) and reasonably associated 
with the use of the IMP according to either the judgment of the Investigator and/or the Sponsor. 
In case of a SUSAR, Sanofi Global Pharmacovigilance and Epidemiology will utilize XGRID to 
reveal medication assignment for regulatory reporting requirements for the particular case. 
The Sponsor will report all safety observations made during the conduct of the trial in the CSR. 
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10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypersensitivity  
Allergic reaction is a potential risk associated with the administration of most therapeutic mAB 
treatments. 
Allergic reactions may be defined as allergic reaction-mediated signs and symptoms experienced 
by patients during or shortly after the pharmacologic or biologic agent is given. These reactions 
may present in a variety of ways, including dizziness, headache, anxiety, dyspnea, hypotension, 
tachycardia, pruritus, rash, urticaria/angioedema, flushing, nausea, or vomiting, and joint pain 
with fever. Allergic reactions may begin within a few hours and persist up to 24 hours post 
dosing. Refer to Appendix H “Definition of Anaphylaxis”, which describes the clinical criteria for 
the diagnosis of anaphylaxis. 
Patients should be monitored for at least 30 minutes (or minimum time required by your local 
regulator) after each study-site administered IMP administration for any signs or symptoms of a 
hypersensitivity reaction. Any instance of allergic reaction should be reported as an AESI. Any 
anaphylactic reactions or acute allergic reactions that require immediate treatment will be an AESI 
with immediate reporting (within 24 hours) and study medication must be permanently 
discontinued. Trained personnel and medications should be available to treat anaphylaxis or any 
severe allergic reaction if it occurs. Furthermore, the study patients will be advised, when the IMP 
is administered at home, to self-monitor for potential signs and symptoms that may suggest a 
hypersensitivity reaction for at least 30 minutes after administration. 
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require treatment 
must be reported as an adverse event of special interest (AESI) (within 24 hours, for further 
details, see AESI definition in Section 10.4.1.3 and Appendix H) and study medication must be 
permanently discontinued. ADA and PK samples will be collected near the onset and completion 
resolution of the AESI for any additional analysis 
10.6.2 Severe injection site reactions 
Based on the SC mode of administration of high doses of protein and on a higher incidence of 
local injection site reactions observed at the highest dose level (300 mg weekly) in dupilumab 
studies, severe injection site reactions, are considered as a potential risk. Patients who experience 
an injection site reaction must be closely monitored for the possibility of a more intense injection 
site reaction with a future injection. Any severe injection reaction that lasts over 24 hours will be 
reported as an AESI with immediate notification. ADA and PK samples will be collected near the 
onset and completion resolution of the AESI for any additional analysis. 
Prophylactic treatment/premedication for an injection site reaction is not permitted. 
10.6.3 Infections, including opportunistic and parasitic infections 
Some immuno-modulating biologics have been associated with an increased risk of infection, 
including opportunistic infection. Though dupilumab has not been shown to increase the 
frequency of severe or serious infections in general, as a precautionary measure, the Investigator 
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is required to carefully monitor for any signs or symptoms of infection such as, but not limited to, 
increased body temperature, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, 
or serious febrile systemic illness. 
Since dupilumab binds to IL-4Rα, preventing IL-4 and IL-13 binding and activation of their 
respective receptors, it inhibits the Th2 cytokines productions. Infections with a diversity of 
helminthic parasites elicit eosinophilia via stimulation of Th2-like lymphocyte responses. The 
TH2 response is characterized by production of IL-4 and IL-5, subsequently generating IgG1 
[Immunoglobulin Gamma 1] and IgE-secreting cells, and eliciting eosinophilia. Eosinophilia is 
prominent in a number of helminthic parasitic diseases. The eosinophilic response to helminths is 
determined both by the host's immune response and by the parasite, including its distribution, 
migration, and development within the infected host. Therefore patient with treatment of 
dupilumab may potentially have an increased risk of parasitic infection. 
Infections defined in Section 10.4.1.3 should be reported as AESIs within 24 hours. 
A complete diagnostic work-up should be performed (ie, cultures, histopathological or cytological 
evaluation, antigen detection and serum antibody titers). Patients should be referred to an 
infectious disease specialist if deemed necessary for diagnostic work up and appropriate 
treatment. 
Infections or infestations that do not respond to medical treatment should have study drug 
discontinued until the infection is resolved. 
 For any opportunistic infection, such as tuberculosis or other infections whose nature or course 
may suggest an immunocompromised status (See Appendix I), patients must be permanently 
discontinued from study medication. 
In order to minimize this risk, any patient with an active parasitic infection is excluded from the 
study. Similarly, patients with suspected parasitic infection, or those at high risk of parasitic 
infection are also excluded, unless clinical and (if necessary) laboratory assessments have ruled 
out active infection before randomization. During the study, appearance of signs or symptoms 
(such as abdominal pain, cough, diarrhea, fever, fatigue hepatosplenomegaly) that could be 
associated with a parasitic infection should be carefully evaluated, especially if there is a history 
of parasitic exposure through recent travel to/ or residence in endemic areas, especially when 
conditions are conducive to infection (eg, extended stay, rural or slum areas, lack of running 
water, consumption of uncooked, undercooked, or otherwise potentially contaminated food, close 
contact with carriers and vectors, etc.). Subsequent medical assessments (eg, stool exam, blood 
tests, etc.) must be performed in order to rule out parasitic infection/infestation. Confirmed 
parasitic infections during the study should be reported as AESI with immediate notification.  
10.6.4 Elevated liver function tests  
No pre-clinical or clinical data has suggested any hepatic toxicity of dupilumab; however, as a 
general consideration of clinical development, the administration of immunosuppressant or 
immunomodulating agents may represent an additional risk factor for hepatotoxicity. 
In order to closely follow liver function tests (LFT), assessment of total protein, albumin, total 
bilirubin, ALT, aspartate aminotransferase, and alkaline phosphatase are measured as part of the 
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clinical laboratory testing. Clinical laboratory testing at V1 adds hepatitis screen (HBsAg, 
HBsAb, HBcAb, HCVAb. Active hepatitis or patients with positive or indeterminate HBsAg, 
HBcAb or positive HCVAb at V1 are excluded from the study. 
Guidance for the investigation of elevated LFTs is provided in Appendix G. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final CSR. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size is chosen to enable an adequate characterization of the efficacy between 
dupilumab 300 mg q2w (pooled A and B arms) and placebo with regard to the 2 co-primary 
endpoints, changes from baseline in NC and NPS at Week 24. 
The observed mean NC reduction of the dupilumab group with qw dosing in ACT12340 is 0.95 
and the observed mean NC reduction of the placebo group is 0.26. To calculate power, a 
conservative estimate is used that assumes the placebo-adjusted NC reduction of the dupilumab 
300 mg q2w group is 80% of the dupilumab 300 mg qw group, the mean NC reduction of the 
dupilumab 300 mg q2w group is then assumed to be 0.81 = 0.8 *  
(0.95-0.26) + 0.26. Assuming normal distribution of the change in NC, a common standard 
deviation (SD) of 1.03, which has incorporated a 20% inflation from the observed SD in 
ACT12340, and a 25% dropout rate, with 240 patients for the q2w pool and 120 patients in 
placebo, the study will have 99% power to detect an effect size of 0.534 using a two-sided test 
with alpha = 0.05 for the change in NC at Week 24 in the dupilumab 300 mg q2w group.  
The observed mean NPS reduction of the dupilumab group with qw dosing in ACT12340 is 1.85 
and the observed mean NPS reduction of the placebo group is 0.30. Using same conservative 
approach that assumes the placebo-adjusted NPS reduction of the dupilumab 300 mg q2w group is 
80% of the dupilumab 300 mg qw, the mean NPS reduction of the dupilumab 300 mg q2w group 
is then assumed to be 1.54 = 0.8*(1.85-0.30)+0.30. Assuming normal distribution of the change in 
NPS, a common standard deviation (SD) of 2.11, which has incorporated a 20% inflation from the 
observed SD in ACT12340, and a 25% dropout rate, with 240 patients for the q2w pool and  
120 patients in placebo, the study will have 99% power to detect an effect size of 0.588 using a 
two-sided test with alpha = 0.05 for the change in NPS at Week 24 in the dupilumab 300 mg q2w 
group.  
Therefore, with a sample size of 240 patients for the q2w pool ( Arm A and B) at Week 24, the 
combined power of the two co-primary efficacy endpoints is at least 98% for dupilumab 300mg 
q2w group with alpha = 0.05 assuming no negative correlation between the 2 endpoints. 
The observed mean LMK reduction of the dupilumab group with qw dosing in ACT12340 is 9.07 
and the observed mean LMK reduction of the placebo group is 0.23. Using same conservative 
approach that assumes the placebo-adjusted LMK reduction of the dupilumab 300 mg q2w group 
is 80% of the dupilumab 300 mg qw, the mean LMK reduction of the dupilumab 300 mg q2w 
group is then assumed to be 7.30 = 0.8*(9.07-0.23)+0.23. Assuming normal distribution of the 
change in LMK, a common standard deviation (SD) of 5.50, which has incorporated a 20% 
inflation from the observed SD in ACT12340, and a 25% dropout rate, with 240 patients for the 
q2w pool and 120 patients in placebo, the study will have 99% power to detect an effect size of 
1.285 using a two-sided test with alpha = 0.05 for the change in LMK at Week 24 in the 
dupilumab 300 mg q2w group. 
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Therefore, with a sample size of 240 patients for the q2w pool ( Arm A and B) at Week 24, the 
combined power of the three co-primary efficacy endpoints for Japan is at least 97% for 
dupilumab 300mg q2w group with alpha = 0.05 assuming no negative correlation between the  
3 endpoints. 
The sample size is also chosen to enable an adequate characterization of the efficacy between 
dupilumab 300 mg q2w (pooled A and B arms) and placebo with regard to the key secondary 
endpoints at Week 24, the change from baseline in the TSS, UPSIT score, the daily loss of smell 
assessment, the LMK, and the SNOT-22 scores, as well as the proportion of patients receiving 
SCS and/or planned to undergo surgery for nasal polyps. 
Assuming the proportion of patients receiving SCS for NP and/or planned to undergo surgery for 
NP is 15% in the placebo group, and is 5% in the dupilumab group, with 240 patients for the q2w 
pool and 120 patients in placebo, the study will have 87% power to detect a hazard ratio of 0.316 
between the treatment groups using a two-sided log rank test with alpha = 0.05.  
With 240 patients for the q2w pool and 120 patients in placebo, the study will have greater than 
99% power to detect difference between the treatment groups for all other five key secondary 
endpoints at Week 24, using a similar assumption procedure as the change from baseline in NC 
and NPS at Week 24.  
The sample size calculations were performed using nQuery Advisor 7. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who signed the informed consent. 
Randomized patients consist of all patients who have been allocated a treatment kit based on a 
randomization process. It will consist of all patients with a treatment kit number allocated and 
recorded in IVRS/IWSR database, and regardless of whether the treatment kit was used or not. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population.  
11.3 
ANALYSIS POPULATIONS 
11.3.1  Efficacy populations 
The population considered for the efficacy analysis will be the intent-to-treat (ITT) population.  
11.3.1.1 Intent-to-treat population 
ITT population: all randomized patients analyzed according to the treatment group allocated by 
randomization regardless of whether the treatment kit is used or not.  
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11.3.2 Safety population 
The population considered for safety analysis will be the safety population. 
Safety population: all patients exposed to study medication, regardless of the amount of treatment 
administered. The safety analyses will be conducted according to the treatment patients actually 
received. 
Treatment emergent period for the safety population is defined as the time between the first 
administration of study medication to Week 12 of post treatment period. 
In addition:  
• 
Nonrandomized but treated patients will be part of the safety population.  
• 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized.  
11.3.3 Systemic drug concentration population 
The systemic drug concentration population will consist of all patients in the safety population 
with at least one evaluable functional dupilumab concentration result. Patients will be analyzed 
according to the treatment actually received. 
11.3.4 Anti-drug antibody population  
The anti-drug antibody population will consist of all patients in the safety population with at least 
one evaluable ADA serum sample that was assayed successfully in the ADA assay following the 
first dose of the study medication. Patients will be analyzed according to the treatment actually 
received. 
11.3.5 Nasal biomarker substudy population 
Selected clinical sites will participate in a substudy for the collection of nasal samples and 
evaluation of biomarkers of inflammation. 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized 
according to actual treatment received within the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
Duration of IMP exposure is defined as: last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations.  
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11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Percentage of compliance for a patient will be defined as the number of administrations the 
patient was compliant divided by the total number of administrations the patient was planned to 
take during the treatment period (ie, from the 1st to the last administration). 
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, Mean, SD, Median, Min, and Max). The percentage of patients with compliance 
is <80% will be summarized. In addition, number and percentage of patients with at least 1 above 
planned dosing administration will be given, as well as the number and percentage of patients 
with 0, (0, 20%], and >20% under-planned dosing administrations. 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of co-primary efficacy endpoint(s) 
11.4.2.1.1 Co-Primary efficacy variables 
The 2 co-primary efficacy variables are: change from baseline in NC and in NPS at Week 24. 
These variables will be assessed for dupilumab 300 mg q2w (pooled A and B arms) versus 
placebo (Arm C), respectively.  
For Japan only, in addition to the 2 co-primary endpoints above, the following will also be a  
co-primary endpoint: 
• 
Change from baseline in sinus opacifications assessed by CT scans using the LMK score 
at Week 24. 
The following null hypothesis and alternative will be tested for pooled dupilumab arms against 
placebo:  
• 
H0: No treatment difference between the dupilumab dose regimen and placebo.  
• 
H1: There is a treatment difference between the dupilumab dose regimen and placebo.  
11.4.2.1.2 Analysis of the co-primary efficacy variables 
Each of the 2 co-primary efficacy endpoints (3 co-primary efficacy endpoints for Japan) will be 
analyzed using a hybrid method of the worst-observation carried forward (WOCF) and the 
multiple imputation (MI). With this approach, for patients who undergo surgery for NP or receive 
SCS for any reason, data collected postsurgery or post SCS will be set to missing, and the worst 
postbaseline value on or before the time of surgery or SCS will be used to impute missing Week 
24 value (for patients whose postbaseline values are all missing, the baseline will be used to 
impute). For patients who discontinue the treatment without being rescued by surgery or receiving 
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SCS, a multiple imputation approach will be used to impute missing Week 24 value, and this 
multiple imputation will use all patients who have not been rescued by surgery or receiving SCS 
at Week 24 and data collected after treatment discontinuation will be included in the analysis. 
Each of the imputed complete data will be analyzed by fitting an ANCOVA model with the 
baseline covariate and factors for treatment, asthma status, prior surgery history, and regions. 
Statistical inference obtained from all imputed data will be combined using Rubin’s rule. 
Descriptive statistics including number of subjects mean, standard error, and least squares (LS) 
means will be provided. In addition, difference in LS means and the corresponding 95% 
confidence intervals (CI) will be provided along with the p-values. 
11.4.2.1.3 Sensitivity analyses 
The reason and pattern of missing data will be carefully examined and tipping point analyses and 
other sensitivity analyses will be performed. Details of the sensitivity analyses will be provided in 
the SAP. 
11.4.2.1.4 Subgroup analysis 
To assess the consistency in treatment effects across different subgroup levels, subgroup analyses 
will be conducted for the co-primary efficacy endpoints with respect to age group, gender, region, 
prior surgery history, race, INCS dose level, baseline NPS, baseline NC, baseline TSS, baseline 
LMK, prior SCS use, and asthma comorbidity/NERD. The details will be provided in the SAP. 
11.4.2.2 Analyses of key secondary efficacy endpoints  
11.4.2.2.1 Analysis of the change from baseline in TSS, UPSIT score, the daily loss of smell 
assessment, the LMK, and SNOT-22 scores at Week 24 for dupilumab 300 mg q2w 
versus placebo 
The change from baseline in TSS, SNOT-22, UPSIT score, daily loss of smell, LMK score at 
Week 24 will be assessed for dupilumab 300 mg q2w (pooled A and B arms) versus placebo and 
will be analyzed using the hybrid method of the WOCF and the MI in the same fashion as for the 
co-primary endpoints.  
Note: LMK will not be a secondary endpoint for Japan as it is already a co-primary endpoint. 
11.4.2.2.2 Analysis of proportion of patients with SCS rescue or surgery (actual or planned) for 
NP during the treatment period for dupilumab 300 mg q2w versus placebo 
Proportion of patients with first SCS rescue and/or surgery (actual or planned) for NP during the 
treatment period will be derived and analyzed using the Cox proportional hazards model and log 
rank test stratified by asthma status, prior surgery history, and regions, by considering the first 
SCS rescue use or surgery (actual or planned) for NP as the event. The entire treatment period in 
Arms A and the treatment period of 300 mg q2w in Arm B (that is, the first 24 weeks) will be 
pooled and used as the treatment period by dupilumab 300 mg q2w, and the entire treatment 
period in Arm C will be used as the treatment period by placebo. For this analysis of proportion of 
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patients with SCS rescue or surgery (actual or planned) for NP for dupilumab 300 mg q2w and 
placebo, patients in Arm B will be considered as censored at the end of 300mg q2w treatment. 
Descriptive statistics including number of patients with rescue or surgery and number of patients 
without rescue or surgery (censored) and the corresponding rates will be provided by treatment 
group. The estimates of the hazard ratio and corresponding 95% CI will be provided for 
dupilumab 300 mg q2w versus the placebo. 
11.4.2.2.3 Analysis of the change from baseline in NC and in NPS at Week 52  
The change from baseline in NC and in NPS at Week 52 will be assessed separately for 
dupilumab 300 mg q2w (Arm A) and dupilumab 300 mg q2w/q4w (Arm B) versus placebo and 
will be analyzed using the hybrid method of the WOCF and the MI in the same fashion as for the 
co-primary endpoints.  
11.4.2.3 Multiplicity considerations 
The multiplicity procedure is proposed to control the overall type-I error rate for testing the  
co-primary and selected secondary endpoints. The overall alpha is 0.05. The comparisons with 
placebo will be tested based on the hierarchical order below at 2-sided α = 0.05: 
Co-primary efficacy endpoints: 
In countries other than Japan: 
• 
Change from baseline in NC and in NPS at Week 24 for 300mg q2w versus placebo. 
In Japan: 
• 
Change from baseline in NC, in NPS, and in CT LMK at Week 24 for 300mg q2w versus 
placebo. 
 
Secondary efficacy endpoints:  
• 
Change from baseline in TSS at Week 24 for 300mg q2w versus placebo. 
• 
Change from baseline in UPSIT at Week 24 for 300mg q2w versus placebo. 
• 
Change from baseline in loss of smell daily symptoms at Week 24 for 300mg q2w versus 
placebo. 
• 
Change from baseline in SNOT-22 at Week 24 for 300mg q2w versus placebo. 
• 
Change from baseline in CT LMK score at Week 24 for 300mg q2w versus placebo (this 
will not be a secondary endpoint for Japan as it is already a co-primary endpoint). 
• 
Proportion of patients with SCS rescue or surgery (actual or planned) for nasal polyposis 
during the treatment period. 
• 
Change from baseline in NPS at Week 52 for q2w (Arm A) versus placebo (Arm C). 
• 
Change from baseline in NC at Week 52 for q2w (Arm A) versus placebo (Arm C). 
• 
Change from baseline in NPS at Week 52 for q2w/q4w (Arm B) versus placebo (Arm C). 
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• 
Change from baseline in NC at Week 52 for q2w/q4w (Arm B) versus placebo (Arm C). 
In countries other than Japan, the study is considered positive when both co-primary endpoints, 
the change from baseline in NC and in NPS at Week 24, achieve statistical significance. 
In Japan, the study is considered positive when all co-primary endpoints, the change from baseline 
in NC, in NPS, and in CT LMK at Week 24, achieve statistical significance. 
11.4.2.4 Analyses of other secondary efficacy endpoints  
11.4.2.4.1 Comparisons for other secondary efficacy endpoints 
• 
Comparisons at Week 24 will be made between pooled arms A and B versus placebo. 
• 
Comparisons at Week 52 will be made between Arm A and Arm B versus placebo, 
separately, and also between Arm A and Arm B. 
• 
Comparisons will be made for the following secondary endpoints: 
- 
Change from baseline and time course profiles in NC, NPS, TSS, UPSIT, daily 
assessed loss of smell, SNOT-22 and LMK at Week 52, 
- 
Change from baseline at Week 24 and Week 52 in: 
- VAS for overall rhinosinusitis, 
- NPIF, 
- In the severity of rhinorrhea (anterior/posterior nasal discharge) daily symptom 
score assessed by the patient, 
- 
Patient reported outcomes including HRQoL  
- 
Proportion of responders at Week 24 (defined as patients with improvement by at least 
1 point in NPS), 
- 
Proportion of patients with improvement by at least 1 point in NPS and 0.5 reductions 
in NC at Week 24 and Week 52, 
- 
Proportion and time-to-event of patients with SCS rescue for any airway exacerbated 
disease (included but not limited to NP, chronic rhinosinusitis, allergic rhinitis, and 
asthma), 
- 
Proportion of patients with minimal clinically important difference (MCID)(≥8.9) in 
SNOT-22 at Week 24, 
- 
Proportion of patients with overall rhinosinusitis severity VAS ≤7 at Week 24. 
In the sub-groups of patients with prior surgery, or co-morbid asthma or NERD history: 
• 
Change from baseline and time course profiles in NC, NPS, TSS, UPSIT, loss of smell 
daily symptoms, CT LMK score, SNOT-22 at Week 24 and 52. 
• 
Proportion of patients with SCS rescue and/or surgery (actual or planned) for nasal polyps 
during the treatment period. 
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• 
Proportion of patients with SCS rescue for airway exacerbated disease. 
• 
Proportion of patients with VAS ≤7 at Week 24 and Week 52. 
• 
Change from baseline in ACQ-6 (in patients with asthma/NERD only) at Week 24 and 
Week 52.Proportion of responders at Week 24 (defined as patients with improvement by at 
least 1 point in NPS). 
• 
Proportion of responders at Week 24 (defined as patients with improvement by at least 1 
point in NPS). 
• 
Proportion of patients with improvement by at least 1 point in NPS and 0.5 reductions in 
NC at Week 24 and Week 52. 
11.4.2.4.2 Analyses of efficacy endpoints for Arm A and Arm B versus placebo at Week 52 
The change from baseline in TSS, SNOT-22, UPSIT, daily loss of smell and LMK at Week 52 
will be assessed separately for dupilumab 300 mg q2w (Arm A) and dupilumab 300 mg q2w/q4w 
(Arm B) versus placebo and will be analyzed using the hybrid method of the WOCF and the MI in 
the same fashion as for the key secondary endpoints of change from baseline in NC and in NPS at 
Week 52. 
Proportion of patients with first SCS rescue or surgery (actual or planned) for NP during the 
treatment period up to Week 52 will be assessed separately for dupilumab 300 mg q2w (Arm A) 
and dupilumab 300 mg q2w/q4w (Arm B) versus placebo and will be analyzed using the same 
approach as those for the key secondary endpoint of the proportion of patients with SCS rescue or 
surgery (actual or planned) for NP during the treatment period for dupilumab 300 mg q2w versus 
placebo. With this approach, proportion of patients with first SCS rescue or surgery (actual or 
planned) during the treatment period will be derived and analyzed using the Cox proportional 
hazards model and log rank test stratified by asthma status, prior surgery history, and regions, by 
considering the first SCS rescue use or surgery (actual or planned) for NP as the event. The entire 
treatment period in Arms A, B, and C will be used in the analysis, and comparisons will be made 
between Arms A and C, and between Arms B and C, separately. Descriptive statistics including 
number of patients with rescue or surgery and number of patients without rescue or surgery 
(censored) and the corresponding rates will be provided by treatment group. The estimates of the 
hazard ratio and corresponding 95% CI will be provided for Arms A versus C and Arms B versus 
C, respectively. 
11.4.2.4.3 Analysis for Arms A versus B at week 52 
Comparisons between dupilumab 300mg q2w and dupilumab 300 mg q2w/q4w will be made at 
Week 52. For such comparisons, descriptive statistics will be provided, and no statistical testing 
will be conducted. In more details, for changes from baseline in continuous endpoints, descriptive 
statistics including number of subjects, mean, standard error, min, and max will be provided by 
treatment group; for proportions of responders, number and proportion of  
responders/non-responders will be provided by treatment group; for proportion of patients with 
SCS rescue or surgery for NP, descriptive statistics including number of patients with rescue or 
surgery and number of patients (actual or planned) without rescue or surgery (censored) and the 
corresponding rates will be provided by treatment group. In addition, corresponding 95% 
confidence intervals between Arms A and B will be provided. 
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Time course profile of the different efficacy endpoints over 52 weeks will be provided to estimate 
magnitude of effect loss after w24 potentially resulting from the switch to a lower dosing/regimen 
(q4w) in the Arm B of EFC14280 study 
11.4.2.4.4 Analysis of sub-groups with comorbid asthma/NERD and prior surgery 
For each subgroup factor, interaction tests will be carried out to investigate consistency of the 
dupilumab effect across different subgroups identified by that factor.  
In addition, for these subgroups, comparisons at Week 24 will be analyzed between dupilumab 
300mg q2w (pooled A and B arms) versus placebo, and comparisons at Week 52 will be analyzed 
separately between dupilumab 300mg q2w (Arm A) versus placebo, and between dupilumab 
300mg q2w/q4w (Arm B) versus placebo. Details of these analyses will be provided in the 
statistical analysis plan. 
In addition to the analysis in the current study, statistical analysis for subgroups with comorbid 
asthma and surgery will be further conducted using the pooled data of EFC14280 and EFC14146, 
and the details will be provided in the statistical analysis plan (SAP) for the Integrated Summary 
of Efficacy (ISE).  
11.4.2.4.5 Analysis of the responder endpoints  
For any responder type endpoints including the proportion of responders at Week 24, the 
proportion of patients with MCID≥8.9 in SNOT-22 at Week 24, and the proportion of patients 
with VAS ≤7 at Week 24, the Cochran-Mantel-Haenszel test stratified by asthma status, prior 
surgery history, and region will be used. Comparisons of the proportions of responders between 
dupilumab 300mg q2w and placebo and between dupilumab 300 mg q2w/q4w and placebo will be 
derived. Patients who are indicated for surgery for NP or receive SCS for any reason will be 
considered as non-responders for time points after using SCS or surgery. For patients who 
discontinue treatment without using SCS or surgery, data collected during the off- treatment 
period will be used to determine the responder/non- responder status. Missing data will be 
considered as non-responders. 
11.4.2.4.6 Analysis of the proportion and time-to-event of patients with SCS rescue for any airway 
exacerbated disease 
Proportion and time-to-event of patients with SCS rescue for any airway exacerbated disease will 
be analyzed using a similar approach as the key secondary endpoint of the proportion of patients 
with SCS rescue or surgery for NP. 
11.4.2.5 Analyses of exploratory efficacy endpoints 
Statistical analysis for exploratory efficacy endpoints will be provided in the final statistical 
analysis plan (SAP). 
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11.4.2.6 Missing data handling 
For all continuous efficacy endpoints, in the primary approach for missing data handling, for 
patients who are indicated to undergo surgery for NP or receive SCS for any reason, data 
collected postsurgery or post SCS will be set to missing, and the worst postbaseline value on or 
before the time of surgery or SCS will be used to impute missing value at the certain analyzed 
visit (for patients whose postbaseline values are all missing, the baseline will be used to impute), 
and for patients who discontinue the treatment without being rescued by surgery or receiving SCS 
on or before the analyzed visit, a multiple imputation approach will be used to impute missing 
value at the certain analyzed visit, and this multiple imputation will use all patients who have not 
been rescued by surgery or receiving SCS at that analyzed visit and data collected after treatment 
discontinuation will be included in the analysis. 
For responder type endpoints, patients who are indicated for surgery for NP or receive SCS for 
any reason will be considered as non-responders for time points after using SCS or surgery; for 
patients who discontinue treatment without using SCS or surgery, data collected during the off- 
treatment period will be used to determine the responder/non- responder status, and missing data 
will be considered as non-responders. 
In addition, the reason and pattern of missing data will be carefully examined and tipping point 
analyses and other sensitivity analyses will also be performed. 
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment groups. All safety analyses will be 
performed on the safety population using the following common rules:  
The baseline value is defined generally as the last available value before randomization.  
The following definitions will be applied to laboratory parameters, vital signs and ECG. 
• 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG.  
• 
PCSA criteria will determine which patients had at least 1 PCSA during the treatment 
emergent period, taking into account all evaluations performed during the on-treatment 
period, including unscheduled or repeated evaluations. The number of all such patients 
will be the numerator for the on-treatment PCSA percentage.  
11.4.3.1 Adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and  
percentage (%) of patients experiencing an AE. Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the safety population within each treatment group.  
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Proportion of patients with at least one treatment emergent adverse event (TEAE), serious TEAE 
and TEAE leading to permanent treatment discontinuation will be tabulated by treatment groups. 
In addition, TEAEs will be described according to maximum intensity and relation to the study 
drug. Serious AEs and AEs leading to study discontinuation that occur outside the treatment 
emergent period will be summarized separately.  
• 
An overview summary of the number (%) of patients with: 
- 
Any TEAE, 
- 
Any serious AE (regardless of treatment-emergent status), 
- 
Any treatment-emergent SAE, 
- 
Any AE leading to death, 
- 
Any TEAE leading to permanent study drug discontinuation, 
- 
Any TEAE by maximum intensity, corrective treatment, and final outcome, 
- 
Cumulative incidence at specified time points (K-M estimates at 1 week, 4 weeks, 
8 weeks, 24 weeks, 28 weeks, 36 weeks, 52 weeks). 
11.4.3.1.1 Adverse event of special interest (AESI) 
The following summaries will be generated:  
• 
Incidence of each AESI will be tabulated by treatment groups.  
• 
The time-to-first event analyzed using Kaplan-Meier (K-M) methods and displayed as K-
M plots (cumulative incidence [%] versus time based on K-M estimates) will be provided 
to depict the course of onset over time. When TEAE start date or worsening date is 
partially available, the maximum of the earliest possible TEAE start date and the treatment 
start date will be used. When TEAE start date or worsening date is completely missing, the 
treatment start date will be used.  
AESI definitions and the method to identify AESIs will be specified in the SAP. 
11.4.3.1.2 Death 
The following deaths summaries will be generated: 
• 
Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population by treatment received.  
• 
Death in nonrandomized patients or randomized and not treated patients.  
• 
TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT.  
Patient data listings will be provided for all AEs, TEAEs, SAE, AEs leading to permanent 
treatment discontinuation, AESIs and deaths. 
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11.4.3.1.3 Clinical laboratory evaluation, vital signs and electrocardiogram (ECG) data  
Results and change from baseline for the parameters will be summarized by treatment groups for 
baseline and each post baseline time point, endpoint, minimum and maximum value. Summary 
statistics will include number of patients, mean, SD, median, Q1, Q3, minimum and maximum.  
The proportion of patients who had at least one incidence of PCSA at any time during the 
treatment emergent period will be summarized by treatment groups within each treatment phase. 
Shift tables showing changes with respect to the baseline status will be provided. 
Listings will be provided with flags indicating clinically out-of range values, as well as PCSA 
values. 
11.4.4 Analyses of pharmacokinetic, anti-drug antibodies and pharmacodynamic variables 
11.4.4.1 Functional dupilumab concentration analysis 
Concentrations of functional dupilumab in serum will be summarized using arithmetic and 
geometric means, SD, standard error of the mean (SEM), coefficient of variation (CV%), 
minimum, median, and maximum by treatment arms per visit. 
Concentrations of functional dupilumab in serum will be used for population PK analysis by 
nonlinear mixed effects modeling if warranted. Additional details of the analysis plan and the 
results will be provided in a separate document.  
11.4.4.2 Anti-drug antibodies analysis 
Incidence of positivity in the ADA assay will be assessed on samples collected, as absolute 
occurrence (n) and percent of patients (%), presented by treatment groups. Listing of all ADA titer 
levels will be provided for patients positive in the ADA assay. Samples positive in the ADA assay 
will be further characterized for the presence of anti-dupilumab neutralizing antibodies. 
Plots of concentrations of functional dupilumab will be examined and the potential influence of 
ADA on individual concentration-time profiles will be evaluated. Assessment of the potential 
impact of ADA on safety and efficacy may be provided. 
ADA at baseline will be summarized by: 
• 
Number (%) of patients with a baseline sample negative in the ADA assay. 
• 
Number (%) of patients with a baseline sample positive in the ADA assay (Pre-existing 
immunoreactivity).  
Total subject number (%) will be provided for the following: 
• 
Number (%) of patients with treatment-emergent positive response in the ADA assay. 
(ADA incidence).  
• 
Number (%) of transient treatment-emergent positive patients.  
• 
Number (%) of persistent treatment-emergent positive patients.  
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• 
Number (%) of treatment-boosted positive patients. 
• 
Number (%) of undetermined treatment-emergent positive patients.  
Titer values (Titer value category). 
The minimum titer for samples positive in the ADA assay is based on the minimum required 
dilution of the assay. 
• 
Low (Titer <1000). 
• 
Moderate (1 000 ≤Titer ≤10 000).  
• 
High (Titer >10 000).  
Definitions of pre-existing immunoreactivity, treatment emergent, persistent response, transient 
response, treatment boosted, and undetermined response will be specified in the statistical analysis 
plan (SAP). 
11.4.4.3 Pharmacodynamics 
The values to be used as baselines will be those collected on Day 1 (predose assessments). If any 
of the scheduled assessments on Day 1 are technically disqualified (eg, insufficient sample) and 
the parameters are measured at any of the run-in period visits, then values determined at the run-in 
period visits can be used as baseline. 
For all parameters, raw data, changes from baseline and percent changes from baseline will be 
summarized in descriptive statistics by treatment arms and time points.  
Summary plots (mean +/- SEM) on raw data, changes from baseline and percent changes from 
baseline will be provided by treatment arms. 
11.4.5 Analyses of patient reported outcomes (Health-related Quality of Life/health 
economics variables) 
Change from baseline in the quantitative variables of EQ-5D-5L (index score) and EQ-5D VAS 
(self-rated health) will be analyzed using the hybrid method of the WOCF and the MI in the same 
fashion as for the co-primary endpoints. Descriptive statistics including number of patients, mean, 
standard error, and LS means will be provided. In addition, difference in LS means and the 
corresponding 95% CI will be provided along with the p-values.  
11.5 
FIRST STEP ANALYSIS 
A first step analysis may be performed when all patients complete the Week 24 visit, including 
early dropouts. The co-primary endpoints and other 24-week endpoints and proportion of patients 
with SCS rescue or surgery for NP (actual or planned) will be analyzed at this first step analysis as 
the final analysis for these endpoints, and 52-week endpoints will not be analyzed at this first step 
analysis. No decision on the conduct of the study will be made based on the first step analysis (in 
particular, no decision to prematurely stop the study). Specific steps will be taken to maintain the 
blind of the study to all individuals involved in the conduct of the study and/or analysis. 
Individuals involved in the first step analysis of the study will not be involved in the conduct of 
the study afterwards; individual patient identification will not be released to anyone who is 
directly involved in the conduct of the study. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the International Council for Harmonisation (ICH) guidelines for good clinical 
practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the IRB/IEC. All participants should be informed to the fullest extent possible about 
the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
 
 
 
 
 
 
 
 
  
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12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure Investigator’s 
curriculum vitae [CV], etc.) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure will be 
sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the e-CRF, discrepancy resolution form (DRF) or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, IRB/IEC, and the regulatory authorities to have direct access to original medical 
records which support the data in the e-CRFs (eg, patient's medical file, appointment books, 
original laboratory records, etc). These personnel, bound by professional secrecy, must maintain 
the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRFs) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the e-CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
IRB/IEC is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations.  
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party.  
• 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations.  
Patient race and ethnicity (Caucasian/white, Black, Asian/Oriental, others) will be collected in this 
study because these data are required by several regulatory authorities (eg, on afro-American 
population for Food and Drug Administration (FDA), on Japanese population for the 
Pharmaceuticals and Medical Devices Agency (PMDA) in Japan). 
 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/ risk ratio, efficacy and safety of the product(s). They may be further 
processed if they have been anonymized. 
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14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio.  
• 
Patient enrollment is unsatisfactory.  
• 
The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon.  
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• 
Non-compliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP.  
• 
The total number of patients is included earlier than expected.  
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
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