A Controlled Clinical Study of Dupilumab in Patients With Bilateral Nasal Polyps (SINUS-24)

A Randomized, 24-Week Treatment, Double-blind, Placebo-controlled Efficacy and Safety Study of Dupilumab 300 mg Every Other Week, in Patients With Bilateral Nasal Polyposis on a Background Therapy With Intranasal Corticosteroids

Primary Objective:

To evaluate the efficacy of dupilumab 300 milligram (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 polyp score (NPS) in participants with bilateral nasal polyposis (NP). In addition for Japan participants, reduction in computed tomography (CT) scan opacification of the sinuses was a coprimary 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 (primary objective for Japan).
• To evaluate ability of dupilumab in reducing proportion of participants requiring treatment with systemic corticosteroids or NP surgery.
• To evaluate the effect of dupilumab on participant reported outcomes and health related quality of life outcome by sinonasal outcome test-22 (SNOT-22).
• To evaluate the effect of dupilumab in the subgroups of participants with prior surgery and co-morbid asthma (including non-steroid antiinflammatory drug [NSAID] exacerbated respiratory disease [ERD]).
• To evaluate residual effect in follow up.
• To evaluate the safety of dupilumab in participants with bilateral NP.
• To evaluate functional dupilumab concentrations (systemic exposure) and incidence of treatment-emergent anti-drug antibodies.

Study Overview

• Status: Completed
• Conditions: Chronic Rhinosinusitis Phenotype With Nasal Polyps (CRSwNP)
• Intervention / Treatment: Drug: Placebo; Drug: Mometasone furoate 50 micrograms; Drug: Dupilumab SAR231893 (REGN668)

Detailed Description

The total study duration per participant was expected to be up to 52 weeks that consisted of a 4-weeks run-in period, 24-weeks treatment period, and a 24-weeks post treatment period.

• Study Type: Interventional
• Enrollment (Actual): 276
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • Investigational Site Number 1000003
  • Sofia, Bulgaria, 1527
    • Investigational Site Number 1000002
  • Sofia, Bulgaria, 1606
    • Investigational Site Number 1000001
• Czechia
  • Hradec Kralove, Czechia, 50005
    • Investigational Site Number 2030001
  • Pardubice, Czechia, 53203
    • Investigational Site Number 2030002
  • Praha 2, Czechia, 12808
    • Investigational Site Number 2030004
• France
  • La Roche Sur Yon, France, 85925
    • Investigational Site Number 2500005
  • Lille, France, 59000
    • Investigational Site Number 2500007
  • Lyon, France, 69317
    • Investigational Site Number 2500003
  • Montpellier, France, 34000
    • Investigational Site Number 2500001
  • Nantes, France, 44035
    • Investigational Site Number 2500006
  • Toulouse, France, 31059
    • Investigational Site Number 2500002
  • Vandoeuvre-Les-Nancy, France, 54511
    • Investigational Site Number 2500004
• Germany
  • Berlin, Germany, 13353
    • Investigational Site Number 2760001
  • München, Germany, 81377
    • Investigational Site Number 2760003
  • Münster, Germany, 48149
    • Investigational Site Number 2760002
• Hungary
  • Budapest, Hungary, 1062
    • Investigational Site Number 3480006
  • Budapest, Hungary, 1083
    • Investigational Site Number 3480007
  • Budapest, Hungary, 1115
    • Investigational Site Number 3480004
  • Budapest, Hungary, 1125
    • Investigational Site Number 3480003
  • Debrecen, Hungary, 4032
    • Investigational Site Number 3480005
  • Pécs, Hungary, 7621
    • Investigational Site Number 3480002
  • Szeged, Hungary, 6725
    • Investigational Site Number 3480001
• Italy
  • Bologna, Italy, 40139
    • Investigational Site Number 3800007
  • Catania, Italy, 95123
    • Investigational Site Number 3800002
  • Milano, Italy, 20142
    • Investigational Site Number 3800006
  • Milano, Italy, 20132
    • Investigational Site Number 3800004
  • Pisa, Italy, 56124
    • Investigational Site Number 3800001
  • Rozzano, Italy, 20089
    • Investigational Site Number 3800005
  • Varese, Italy, 21100
    • Investigational Site Number 3800003
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Investigational Site Number 5280001
• Poland
  • Katowice, Poland, 40-611
    • Investigational Site Number 6160002
  • Lodz, Poland, 90-153
    • Investigational Site Number 6160001
  • Warszawa, Poland, 04-141
    • Investigational Site Number 6160003
• Romania
  • Brasov, Romania, 500283
    • Investigational Site Number 6420007
  • Brasov, Romania, 500283
    • Investigational Site Number 6420013
  • Bucuresti, Romania, 011172
    • Investigational Site Number 6420003
  • Cluj-Napoca, Romania, 400015
    • Investigational Site Number 6420009
  • Craiova, Romania, 200642
    • Investigational Site Number 6420008
  • Targu-Mures, Romania, 540098
    • Investigational Site Number 6420010
• Russian Federation
  • Moscow, Russian Federation, 119435
    • Investigational Site Number 6430004
  • Moscow, Russian Federation, 129090
    • Investigational Site Number 6430003
  • Saint-Petersburg, Russian Federation, 195030
    • Investigational Site Number 6430001
  • Saint-Petersburg, Russian Federation, 197022
    • Investigational Site Number 6430007
  • St-Petersburg, Russian Federation, 190013
    • Investigational Site Number 6430002
  • Yaroslavl, Russian Federation, 150003
    • Investigational Site Number 6430006
• Ukraine
  • Ivano-Frankivsk, Ukraine, 76000
    • Investigational Site Number 8040002
  • Kharkiv, Ukraine, 61166
    • Investigational Site Number 8040004
  • Kyiv, Ukraine, 01133
    • Investigational Site Number 8040005
  • Kyiv, Ukraine, 03680
    • Investigational Site Number 8040006
  • Poltava, Ukraine, 36011
    • Investigational Site Number 8040001
  • Ternopil, Ukraine, 46000
    • Investigational Site Number 8040008
• United Kingdom
  • Bradford, United Kingdom, BD9 6RJ
    • Investigational Site Number 8260001
  • Dundee, United Kingdom, DD1 9SY
    • Investigational Site Number 8260002
  • Great Yarmouth, United Kingdom, NR31 6LA
    • Investigational Site Number 8260007
  • London, United Kingdom, SE1 7EH
    • Investigational Site Number 8260006
  • Stockport, United Kingdom, SK2 7JE
    • Investigational Site Number 8260004
  • Wigan, United Kingdom, WN1 2NN
    • Investigational Site Number 8260005
• United States
  • California
    • Long Beach, California, United States, 90720
      • Investigational Site Number 8400009
    • Orange, California, United States, 92868
      • Investigational Site Number 8400004
    • San Diego, California, United States, 92123
      • Investigational Site Number 8400014
    • Stockton, California, United States, 95207
      • Investigational Site Number 8400002
  • Colorado
    • Centennial, Colorado, United States, 80112
      • Investigational Site Number 8400016
  • Florida
    • Tampa, Florida, United States, 33613
      • Investigational Site Number 8400013
  • Iowa
    • West Des Moines, Iowa, United States, 50265
      • Investigational Site Number 8400022
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Investigational Site Number 8400007
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Investigational Site Number 8400005
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Investigational Site Number 8400021
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Investigational Site Number 8400008
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Investigational Site Number 8400019
  • Oregon
    • Medford, Oregon, United States, 97504
      • Investigational Site Number 8400020
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Investigational Site Number 8400018
  • Tennessee
    • Nashville, Tennessee, United States, 37232-8695
      • Investigational Site Number 8400003
  • Texas
    • Dallas, Texas, United States, 75231
      • Investigational Site Number 8400001
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Investigational Site Number 8400015
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Investigational Site Number 8400010

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Participants with bilateral sinonasal polyposis that despite prior treatment with systemic corticosteroids (SCS) anytime within the past 2 years; and/or had a medical contraindication / intolerance to SCS; and/or had prior surgery for NP at the screening visit, had:
• An endoscopic bilateral NPS 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 prior to Visit [V] 1) 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 the time of randomization (V2), and another symptom such as loss of smell, rhinorrhea (anterior/posterior).
• Signed written informed consent.

Exclusion criteria:

• Participants <18 years of age.
• Participants who were previously treated in dupilumab studies.
• Participants who had 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 was longer.
• Any experimental monoclonal antibody (mAB) within 5 half-lives or within 6 months before V1 if the half-life was unknown.
• Anti-immunoglobulin E (IgE) therapy (omalizumab) within 130 days prior to V1.
• Participants who received leukotriene antagonists/modifiers at V1 unless they were on a continuous treatment for at least 30 days prior to V1.
• Initiated allergen immunotherapy within 3 months prior to V1 or planned to begin therapy or changed its dose during the run-in period or the randomized treatment period.
• Participants who undergone any intranasal and/or sinus surgery (including polypectomy) within 6 months prior to V1.
• Participants who had a sinonasal or sinus surgery changing the lateral wall structure of the nose making impossible the evaluation of NPS.
• Participants 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.
• Participants with nasal cavity malignant tumor and benign tumors (eg, papilloma, blood boil, etc).
• Participants with forced expiratory volume in 1 second (FEV1) 50% or less (of predicted normal).
• Participants who received concomitant treatment prohibited in the study.
• Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit.
• History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening.
• Positive with hepatitis B surface antigen (HBsAg) or hepatitis C antibody at the screening visit.
• Active chronic or acute infection requiring systemic treatment within 2 weeks before the baseline visit.
• Known or suspected history of immunosuppression.
• Pregnant or breastfeeding women, or women planned to become pregnant or breastfeed during the study.
• Women unwilling to use adequate birth control, if of reproductive potential and sexually active.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo (for dupilumab), 1 subcutaneous (SC) injection every 2 weeks (q2w) from Day 1 of Week 0 up to Week 24 added to background therapy of intranasal mometasone furoate nasal spray (MFNS) at stable dose.	Drug: Placebo; Pharmaceutical form: Solution Route of administration: Subcutaneous; Drug: Mometasone furoate 50 micrograms; Pharmaceutical form: Suspension (Nasal spray) Route of administration: Intranasal; Other Names: NASONEX®
Experimental: Dupilumab 300 mg; Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 24 added to background therapy of intranasal MFNS at stable dose.	Drug: Mometasone furoate 50 micrograms; Pharmaceutical form: Suspension (Nasal spray) Route of administration: Intranasal; Other Names: NASONEX®; Drug: Dupilumab SAR231893 (REGN668); Pharmaceutical form: Solution Route of administration: Subcutaneous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline at Week 24 in Nasal Congestion/Obstruction Symptom Severity Score	NC symptom severity was assessed by the participants on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. Least squares (LS) means and standard error (SE) were obtained from Analysis of covariance (ANCOVA) model described in Statistical Analysis Overview.	Baseline, Week 24
Change From Baseline at Week 24 in Nasal Polyp Score	NPS: sum of right, left nostril scores, evaluated by nasal endoscopy. For each nostril, NPS was graded based on polyp size from 0 = no polyps to 4 = large polyps causing complete obstruction of inferior nasal cavity; lower score = smaller-sized polyps. Total NPS: sum of right and left nostril scores; ranges from 0 (no polyps) to 8 (large polyps), higher score = more severe disease. NPS was assessed by centralized, blinded, independent review of the nasal endoscopy video recordings. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview.	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund-Mackay (LMK) Score	The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. NOTE: For Japan regulatory submission only, this endpoint is not included as a secondary outcome measure and is instead one of the co-primary outcome measures.	Baseline, Week 24
Change From Baseline at Week 24 in Total Symptom Score (TSS)	The TSS was the sum of participant-assessed nasal symptom scores for nasal congestion/obstruction, decreased/loss of sense of smell, and rhinorrhea (anterior/posterior nasal discharge), each accessed on 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms). Total score ranged from 0 (no symptoms) to 9 (severe symptoms). Higher score indicated more severe symptoms. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview.	Baseline, Week 24
Change From Baseline at Week 24 in the University of Pennsylvania Smell Identification Test (UPSIT) Score	The UPSIT was a 40-item test to measure the individual's ability to detect odors. Total score ranges from 0 (anosmia) to 40 (normal sense of smell), lower score indicated severe smell loss. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview.	Baseline, Week 24
Change From Baseline at Week 24 in Severity of Decreased/Loss of Smell as Assessed by Participant Daily	The severity of decreased/loss of sense of smell was reported by the participants using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), higher score indicated more severe symptoms. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview.	Baseline, Week 24
Change From Baseline at Week 24 in 22-item Sino-nasal Outcome Test (SNOT-22) Scores	The SNOT-22 is a validated questionnaire that was used to assess the impact of chronic rhinosinusitis phenotype with nasal polyps (CRSwNP) on health-related quality of life (HRQoL). It is a 22 item questionnaire with each item assigned a score ranging from 0 (no problem) to 5 (problem as bad as it can be). The total score may range from 0 (no disease) to 110 (worst disease), lower scores representing better health related quality of life. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview.	Baseline, Week 24
Rescue Treatment Use: Estimate of Percentage of Participants With >=1 Event by Week 24 Obtained Using Kaplan-Meier Method	Rescue treatment was defined as usage of systemic corticosteroids (SCS) or NP surgery (actual or planned) during the treatment period. Rescue treatment included: SCS: Betamethasone, dexamethasone, dexamethasone sodium phosphate, Hydrocortisone sodium succinate, methylprednisolone, prednisolone, prednisolone metasulfobenzoate sodium, prednisone, and triamcinolone.; Sino-nasal surgery for nasal polyps when there was worsening of signs and/or symptoms during the study. Estimate of percentage of participants with event by Week 24 was obtained using Kaplan-Meier method.	Baseline up to Week 24
Change From Baseline at Week 24 in Visual Analogue Scale (VAS) for Rhinosinusitis	The VAS for rhinosinusitis was used to evaluate the total disease severity. The participants were asked to indicate on a 10 centimeters (cm) VAS the answer to the question, "How troublesome are your symptoms of your rhinosinusitis?" The range of the VAS was from 0 (not troublesome) to 10 (worse thinkable troublesome), where higher score indicated worse thinkable troublesome. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 24
Change From Baseline at Week 24 in Nasal Peak Inspiratory Flow (NPIF)	NPIF evaluation represented a physiologic measure of the air flow through both nasal cavities during forced inspiration expressed in liters per minute. Higher NPIF values are indicative of better nasal air flow. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 24
Change From Baseline at Week 24 in Rhinorrhea Daily Symptom Score	Rhinorrhea was reported by the participants using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), where higher scores indicated more severe symptoms. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 24
Change From Baseline at Week 24 in Forced Expiratory Volume in 1 Second (FEV1) for Participants With Asthma	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates.	Baseline, Week 24
Change From Baseline at Week 24 in Asthma Control Questionnaire-6 (ACQ-6) Scores for Participants With Asthma	ACQ-6 had 6 questions which assessed the most common asthma symptoms (woken by asthma, symptoms on waking, activity limitation, shortness of breath, wheezing, puffs/inhalations use). Participants were asked to recall how their asthma had been during the previous week and to respond to the symptom questions on a 7-point scale ranged from 0 = no impairment to 6 = maximum impairment. The ACQ-6 score was the mean of the scores of all 6 questions and therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled), with higher scores indicated lower asthma control. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with the corresponding baseline value, treatment group, prior surgery, and regions as covariates.	Baseline, Week 24
Change From Baseline at Weeks 28, 32, 36, 40, 44 and 48 in Nasal Congestion Symptom Severity Score (Assessments Performed 4-24 Weeks After End of Treatment)	NC symptom severity was assessed by the participants on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 28, Week 32, Week 36, Week 40, Week 44 and Week 48 (Post-baseline assessments performed 4-24 weeks after end of treatment)
Change From Baseline at Weeks 36 and 48 in Nasal Polyp Score (Assessments Performed 12 and 24 Weeks After End of Treatment)	NPS was the sum of right and left nostril scores, as evaluated by means of nasal endoscopy. For each nostril, NPS was graded based on polyp size from 0 to 4 (0 = no polyps to 4 = large polyps causing complete obstruction of the inferior nasal cavity), with a lower score indicating smaller-sized polyps. Total NPS was the sum of right and left nostril scores and ranges from 0 (no polyp) to 8 (large polyp), with highest score representing more severe disease. NPS was assessed by centralized, blinded, independent review of the nasal endoscopy video recordings. Data were analyzed using a hybrid method of the WOCF and MI. LS mean and SE were obtained from ANCOVA model.	Baseline, Week 36, Week 48 (post-baseline assessments performed 12 and 24 weeks after end of treatment)
Change From Baseline at Week 48 in Opacification of Sinuses Measured by Lund-Mackay Score (Assessment Performed 24 Weeks After End of Treatment)	The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 48 (Post-baseline assessment performed 24 weeks after end of treatment)
Change From Baseline at Weeks 28, 32, 36, 40, 44 and 48 in Total Symptom Score (Assessments Performed 4-24 Weeks After End of Treatment)	The TSS was the sum of participant-assessed nasal symptom scores for NC/obstruction, decreased/loss of sense of smell, and rhinorrhea (anterior/posterior nasal discharge), each accessed on 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms). Total score ranged from 0 (no symptoms) to 9 (severe symptoms). Higher score indicated more severe symptoms. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 28, Week 32, Week 36, Week 40, Week 44 and Week 48 (Post-baseline assessments performed 4-24 weeks after end of treatment)
Change From Baseline at Week 48 in University of Pennsylvania Smell Identification Test (Assessment Performed 24 Weeks After End of Treatment)	The UPSIT was a 40-item test to measure the individual's ability to detect odors. Total score ranges from 0 (anosmia) to 40 (normal sense of smell), lower score indicated severe smell loss. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 48 (Post-baseline assessment performed 24 weeks after end of treatment)
Change From Baseline at Weeks 28, 32, 36, 40, 44 and 48 in Severity of Decreased/Loss of Smell as Assessed by Participant Daily (Assessments Performed 4-24 Weeks After End of Treatment)	The severity of decreased/loss of sense of smell was reported by the participants using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), higher score indicated more severe symptoms. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 28, Week 32, Week 36, Week 40, Week 44 and Week 48 (Post-baseline assessments performed 4-24 weeks after end of treatment)
Change From Baseline at Weeks 36 and 48 in 22-item Sino-nasal Outcome Test Scores (Assessments Performed 12 and 24 Weeks After End of Treatment)	The SNOT-22 is a validated questionnaire that was used to assess the impact of CRSwNP on HRQoL. It is a 22 item questionnaire with each item assigned a score ranging from 0 (no problem) to 5 (problem as bad as it can be). The total score may range from 0 (no disease) to 110 (worst disease), lower scores representing better health related quality of life. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 36 and Week 48 (Post-baseline assessments performed 12 and 24 weeks after end of treatment)
Rescue Treatment Use: Estimate of Percentage of Participants With >=1 Event by Week 48 Obtained Using Kaplan-Meier Method	Rescue treatment was defined as usage of SCS or NP surgery (actual or planned) during the study. Rescue treatment included: SCS: Betamethasone, dexamethasone, dexamethasone sodium phosphate, Hydrocortisone sodium succinate, methylprednisolone, prednisolone, prednisolone metasulfobenzoate sodium, prednisone, and triamcinolone.; Sino-nasal surgery for nasal polyps when there was worsening of signs and/or symptoms during the study. Estimate of percentage of participants with event by Week 48 was obtained using Kaplan-Meier method.	Baseline up to Week 48
Change From Baseline at Weeks 36 and 48 in Visual Analog Scale for Rhinosinusitis (Assessments Performed 12 and 24 Weeks After End of Treatment)	The VAS for rhinosinusitis was used to evaluate the total disease severity. The participants were asked to indicate on a 10 cm VAS the answer to the question, "How troublesome are your symptoms of your rhinosinusitis?" The range of the VAS was from 0 (not troublesome) to 10 (worse thinkable troublesome), where higher score indicated worse thinkable troublesome. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 36 and Week 48 (Post-baseline assessments performed 12 and 24 weeks after end of treatment)
Change From Baseline at Weeks 28, 32, 36, 40, 44 and 48 in Rhinorrhea Daily Symptom Score (Assessments Performed 4-24 Weeks After End of Treatment)	Rhinorrhea was reported by the participants using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), where higher scores indicated more severe symptoms. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates.	Baseline, Week 28, Week 32, Week 36, Week 40, Week 44 and Week 48 (Post-baseline assessments performed 4-24 weeks after end of treatment)
Change From Baseline at Week 48 in Forced Expiratory Volume in 1 Second for Participants With Asthma (Assessment Performed 24 Weeks After End of Treatment)	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates.	Baseline, Week 48 (Post-baseline assessment performed 24 weeks after end of treatment)
Change From Baseline at Week 48 in Asthma Control Questionnaire-6 Scores for Participants With Asthma (Assessment Performed 24 Weeks After End of Treatment)	ACQ-6 had 6 questions which assessed the most common asthma symptoms (woken by asthma, symptoms on waking, activity limitation, shortness of breath, wheezing, puffs/inhalations use). Participants were asked to recall how their asthma had been during the previous week and to respond to the symptom questions on a 7-point scale ranged from 0 = no impairment to 6 = maximum impairment. The ACQ-6 score was the mean of the scores of all 6 questions and therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled), with higher scores indicated lower asthma control. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with the corresponding baseline value, treatment group, prior surgery, and regions as covariates.	Baseline, Week 48 (Post-baseline assessment performed 24 weeks after end of treatment)
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and TEAEs Leading to Treatment Discontinuation	An Adverse Event (AE) was defined as any untoward medical occurrence that did not necessarily have to have a causal relationship with the study treatment. TEAEs were defined as AEs that developed or worsened in grade or became serious during TEAE period which was defined as the period from the time of first dose of study drug until 98 days following the last administration of study drug. Serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a medically important event.	Baseline up to 98 days following the last administration of study drug (up to 36 weeks)
Functional Dupilumab Concentration in Serum		Baseline, Week 4, 8, 16, 24, 36, End of study (Week 48)
Number of Participants With Treatment-Emergent And Treatment-Boosted Anti-drug Antibodies (ADA) Response	ADA response were categorized as: treatment emergent and treatment boosted response. 1) Treatment emergent was defined as a positive response in the ADA assay post first dose, when baseline results are negative or missing. 2) Treatment boosted was defined as: An ADA positive response in the assay post first dose that is greater-than or equal to 4-fold over baseline titer levels, when baseline results are positive.	Baseline to End of study (Week 48)
Mean Total Systemic Corticosteroids Rescue Dose Prescribed During Treatment Period	SCS included: Betamethasone, dexamethasone, dexamethasone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, prednisolone, prednisolone metasulfobenzoate sodium, prednisone, and triamcinolone. For every participant, total dose was calculated as (prescribed total daily dose*duration of SCS use). Then, mean of the total dose of 25 participants (placebo group) and 9 participants (Dupilumab group) was derived.	Baseline to Week 24
Total Systemic Corticosteroids Rescue Intake Duration: Average Duration Per Participant	Rescue treatment was defined as usage of SCS or NP surgery (actual or planned) during the treatment period. SCS rescue intake duration was defined as the duration (in days) from start of SCS rescue medication till the end of SCS rescue treatment.	Baseline to Week 24
Change From Baseline at Week 24 in European Quality of Life 5 Dimension (EQ-5D) Visual Analog Scale Score	The EQ-5D was a standardized HRQoL questionnaire consisting of EQ-5D descriptive system and EQ VAS. EQ-5D descriptive system comprised of 5 dimensions: mobility, selfcare, usual activities, pain/discomfort and anxiety/depression. Each dimension had 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. EQ-VAS recorded the participant's self-rated health on a vertical VAS that allowed them to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable).	Baseline, Week 24
Change From Baseline at Week 24 in Nasal Congestion Symptom Severity Score: Subgroup of Participants With Asthma	NC symptom severity was assessed by the participants on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates.	Baseline, Week 24
Change From Baseline at Week 24 in Nasal Congestion Symptom Severity Score: Subgroup of Participants With Prior Nasal Polyp Surgery	NC symptom severity was assessed by the participants on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, and regions as covariates.	Baseline, Week 24
Change From Baseline at Week 24 in Nasal Polyp Score: Subgroup of Participants With Asthma	NPS was the sum of right and left nostril scores, as evaluated by means of nasal endoscopy. For each nostril, NPS was graded from 0 to 4 (0 = no polyps to 4 = large polyps causing complete obstruction of the inferior nasal cavity), with a lower score indicating smaller-sized polyps. Total NPS was the sum of right and left nostril scores and ranges from 0 (no polyp) to 8 (large polyp), with highest score representing more severe disease. NPS was assessed by centralized, blinded, independent review of the nasal endoscopy video recordings. Data were analyzed using a hybrid method of the WOCF and MI. LS mean and SE were obtained from ANCOVA model.	Baseline, Week 24
Change From Baseline at Week 24 in Nasal Polyp Score: Subgroup of Participants With Prior Nasal Polyp Surgery	NPS was the sum of right and left nostril scores, as evaluated by means of nasal endoscopy. For each nostril, NPS was graded from 0 to 4 (0 = no polyps to 4 = large polyps causing complete obstruction of the inferior nasal cavity), with a lower score indicating smaller-sized polyps. Total NPS was the sum of right and left nostril scores and ranges from 0 (no polyp) to 8 (large polyp), with highest score representing more severe disease. NPS was assessed by centralized, blinded, independent review of the nasal endoscopy video recordings. Data were analyzed using a hybrid method of the WOCF and MI. LS mean and SE were obtained from ANCOVA model.	Baseline, Week 24
Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Participants With Asthma	The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates.	Baseline, Week 24
Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Participants With Prior Nasal Polyp Surgery	The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. Data were analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, and regions as covariates.	Baseline, Week 24

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Chong LY, Piromchai P, Sharp S, Snidvongs K, Webster KE, Philpott C, Hopkins C, Burton MJ. Biologics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2021 Mar 12;3(3):CD013513. doi: 10.1002/14651858.CD013513.pub3.
• Wechsler ME, Klion AD, Paggiaro P, Nair P, Staumont-Salle D, Radwan A, Johnson RR, Kapoor U, Khokhar FA, Daizadeh N, Chen Z, Laws E, Ortiz B, Jacob-Nara JA, Mannent LP, Rowe PJ, Deniz Y. Effect of Dupilumab on Blood Eosinophil Counts in Patients With Asthma, Chronic Rhinosinusitis With Nasal Polyps, Atopic Dermatitis, or Eosinophilic Esophagitis. J Allergy Clin Immunol Pract. 2022 Oct;10(10):2695-2709. doi: 10.1016/j.jaip.2022.05.019. Epub 2022 May 28.
• Khan AH, Reaney M, Guillemin I, Nelson L, Qin S, Kamat S, Mannent L, Amin N, Whalley D, Hopkins C. Development of Sinonasal Outcome Test (SNOT-22) Domains in Chronic Rhinosinusitis With Nasal Polyps. Laryngoscope. 2022 May;132(5):933-941. doi: 10.1002/lary.29766. Epub 2021 Aug 26.
• Peters AT, Han JK, Hellings P, Heffler E, Gevaert P, Bachert C, Xu Y, Chuang CC, Neupane B, Msihid J, Mannent LP, Guyot P, Kamat S. Indirect Treatment Comparison of Biologics in Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol Pract. 2021 Jun;9(6):2461-2471.e5. doi: 10.1016/j.jaip.2021.01.031. Epub 2021 Feb 4.
• Peters AT, Soler ZM, Kern RC, Heffler E, Maspero JF, Crampette L, Fujieda S, Lane AP, Zhang H, Nash S, Khan AH, Siddiqui S, Jacob-Nara JA, Rowe P, Deniz Y. Improvement in patient-reported "taste" and association with smell in dupilumab-treated patients with severe chronic rhinosinusitis with nasal polyps from the SINUS-24 and SINUS-52 trials. Clin Exp Allergy. 2022 Sep;52(9):1105-1109. doi: 10.1111/cea.14194. Epub 2022 Jul 12. No abstract available.
• Bachert C, Peters AT, Heffler E, Han JK, Olze H, Pfaar O, Chuang CC, Rout R, Attre R, Goga L, Jacob-Nara JA, Rowe PJ, Deniz Y, Chen Z, Kamat S, Siddiqui S. Responder analysis to demonstrate the effect of targeting type 2 inflammatory mechanisms with dupilumab across objective and patient-reported endpoints for patients with severe chronic rhinosinusitis with nasal polyps in the SINUS-24 and SINUS-52 studies. Clin Exp Allergy. 2022 Feb;52(2):244-249. doi: 10.1111/cea.14051. No abstract available.
• Lee SE, Hopkins C, Mullol J, Msihid J, Guillemin I, Amin N, Mannent LP, Li Y, Siddiqui S, Chuang CC, Kamat S, Khan AH. Dupilumab improves health related quality of life: Results from the phase 3 SINUS studies. Allergy. 2022 Jul;77(7):2211-2221. doi: 10.1111/all.15222. Epub 2022 Feb 1.
• Bachert C, Corren J, Lee SE, Zhang H, Harel S, Cunoosamy D, Khan AH, Jacob-Nara JA, Siddiqui S, Nash S, Rowe PJ, Deniz Y. Dupilumab efficacy and biomarkers in chronic rhinosinusitis with nasal polyps: Association between dupilumab treatment effect on nasal polyp score and biomarkers of type 2 inflammation in patients with chronic rhinosinusitis with nasal polyps in the phase 3 SINUS-24 and SINUS-52 trials. Int Forum Allergy Rhinol. 2022 Sep;12(9):1191-1195. doi: 10.1002/alr.22964. Epub 2022 Jan 31. No abstract available.
• Hellings PW, Peters AT, Chaker AM, Heffler E, Zhang H, Praestgaard A, Nash S, Khan AH, Siddiqui S, Jacob-Nara JA, Rowe PJ, Deniz Y. Rapid and sustained effects of dupilumab in severe chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2022 Jul;12(7):958-962. doi: 10.1002/alr.22944. Epub 2022 Jan 23. No abstract available.
• Han JK, Bachert C, Lee SE, Hopkins C, Heffler E, Hellings PW, Peters AT, Kamat S, Whalley D, Qin S, Nelson L, Siddiqui S, Khan AH, Li Y, Mannent LP, Guillemin I, Chuang CC. Estimating Clinically Meaningful Change of Efficacy Outcomes in Inadequately Controlled Chronic Rhinosinusitis with Nasal Polyposis. Laryngoscope. 2022 Feb;132(2):265-271. doi: 10.1002/lary.29888. Epub 2021 Dec 1.
• Chuang CC, Guillemin I, Bachert C, Lee SE, Hellings PW, Fokkens WJ, Duverger N, Fan C, Daizadeh N, Amin N, Mannent LP, Khan AH, Kamat S. Dupilumab in CRSwNP: Responder Analysis Using Clinically Meaningful Efficacy Outcome Thresholds. Laryngoscope. 2022 Feb;132(2):259-264. doi: 10.1002/lary.29911. Epub 2021 Nov 24.
• Mullol J, Laidlaw TM, Bachert C, Mannent LP, Canonica GW, Han JK, Maspero JF, Picado C, Daizadeh N, Ortiz B, Li Y, Ruddy M, Laws E, Amin N. Efficacy and safety of dupilumab in patients with uncontrolled severe chronic rhinosinusitis with nasal polyps and a clinical diagnosis of NSAID-ERD: Results from two randomized placebo-controlled phase 3 trials. Allergy. 2022 Apr;77(4):1231-1244. doi: 10.1111/all.15067. Epub 2021 Oct 1.
• Hopkins C, Wagenmann M, Bachert C, Desrosiers M, Han JK, Hellings PW, Lee SE, Msihid J, Radwan A, Rowe P, Amin N, Deniz Y, Ortiz B, Mannent LP, Rout R. Efficacy of dupilumab in patients with a history of prior sinus surgery for chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2021 Jul;11(7):1087-1101. doi: 10.1002/alr.22780. Epub 2021 Feb 21.
• Laidlaw TM, Bachert C, Amin N, Desrosiers M, Hellings PW, Mullol J, Maspero JF, Gevaert P, Zhang M, Mao X, Khan AH, Kamat S, Patel N, Graham NMH, Ruddy M, Staudinger H, Mannent LP. Dupilumab improves upper and lower airway disease control in chronic rhinosinusitis with nasal polyps and asthma. Ann Allergy Asthma Immunol. 2021 May;126(5):584-592.e1. doi: 10.1016/j.anai.2021.01.012. Epub 2021 Jan 16.
• Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, Mullol J, Greos LS, Bosso JV, Laidlaw TM, Cervin AU, Maspero JF, Hopkins C, Olze H, Canonica GW, Paggiaro P, Cho SH, Fokkens WJ, Fujieda S, Zhang M, Lu X, Fan C, Draikiwicz S, Kamat SA, Khan A, Pirozzi G, Patel N, Graham NMH, Ruddy M, Staudinger H, Weinreich D, Stahl N, Yancopoulos GD, Mannent LP. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019 Nov 2;394(10209):1638-1650. doi: 10.1016/S0140-6736(19)31881-1. Epub 2019 Sep 19. Erratum In: Lancet. 2019 Nov 2;394(10209):1618.

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2016
• Primary Completion (Actual): July 5, 2018
• Study Completion (Actual): July 5, 2018

Study Registration Dates

• First Submitted: September 21, 2016
• First Submitted That Met QC Criteria: September 21, 2016
• First Posted (Estimate): September 23, 2016

Study Record Updates

• Last Update Posted (Actual): July 25, 2019
• Last Update Submitted That Met QC Criteria: July 3, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Nasal polyposis, Chronic rhinosinusitis, Intranasal corticosteroids, Dupilumab, Human monoclonal antibody
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Pathological Conditions, Anatomical; Nose Diseases; Nasal Polyps; Polyps; Anti-Inflammatory Agents; Dermatologic Agents; Anti-Allergic Agents; Mometasone Furoate
• Other Study ID Numbers: EFC14146; 2015-003101-42 (EudraCT Number); U1111-1178-5390 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Not yet available