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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    2015-003101-42
    Trial protocol
    GB   HU   DE   NL   CZ   FR   PL   BG  
    Global end of trial date
    05 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jul 2019
    First version publication date
    20 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC14146
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02912468
    WHO universal trial number (UTN)
    U1111-1178-5390
    Sponsors
    Sponsor organisation name
    Sanofi
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    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 (NC)/obstruction severity and endoscopic nasal polyp score (NPS) in subjects with bilateral nasal polyposis (NP).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject was participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Bulgaria: 11
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Romania: 39
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Ukraine: 45
    Country: Number of subjects enrolled
    United States: 34
    Worldwide total number of subjects
    276
    EEA total number of subjects
    177
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    233
    From 65 to 84 years
    42
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Study subjects were involved in the study from 05 December 2016 to 05 July 2018 at 67 active centres in 13 countries. A total of 506 subjects were screened, of which 276 subjects were enrolled and randomised to receive dupilumab 300 mg or placebo. A total of 230 subjects failed screening mainly due to failure to meet inclusion criteria.

    Pre-assignment
    Screening details
    Randomisation was stratified by the presence of comorbid asthma and/or non-steroidal anti-inflammatory drug exacerbated respiratory disease (NSAID-ERD), prior NP surgery (yes or no), and country.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    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 MFNS at stable dose.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (matched to dupilumab 300 mg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 millilitre (mL), SC injection once q2w using a prefilled syringe for 24 weeks.

    Arm title
    Dupilumab 300 mg
    Arm description
    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.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 mL, SC injection once q2w using a prefilled syringe for 24 weeks.

    Number of subjects in period 1
    Placebo Dupilumab 300 mg
    Started
    133
    143
    Treated
    133
    142
    Safety Population
    132
    143
    Completed
    124
    138
    Not completed
    9
    5
         Randomised and not treated
    -
    1
         Consent withdrawn by subject
    6
    2
         Adverse Event
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    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 MFNS at stable dose.

    Reporting group title
    Dupilumab 300 mg
    Reporting group description
    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.

    Reporting group values
    Placebo Dupilumab 300 mg Total
    Number of subjects
    133 143 276
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.83 ± 13.21 50.17 ± 13.59 -
    Gender categorical
    Units: Subjects
        Female
    63 55 118
        Male
    70 88 158
    Ethnicity
    In the placebo arm, 131 subjects were only involved in the evaluation of the specified baseline measure.
    Units: Subjects
        Hispanic or Latino
    1 5 6
        Not Hispanic or Latino
    130 138 268
        Unknown
    2 0 2
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 1 1
        Asian
    0 1 1
        Black or African American
    7 2 9
        White
    126 138 264
        Unknown or Not Reported
    0 1 1
    Nasal Congestion/Obstruction Symptom Severity Score
    NC symptom severity was assessed by the subjects 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.
    Units: score on a scale
        arithmetic mean (standard deviation)
    2.45 ± 0.55 2.26 ± 0.57 -
    Nasal Polyp Score
    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 polyps) to 8 (large polyps), with higher score representing more severe disease. In the placebo arm, 132 subjects were only involved in the evaluation of the specified baseline measure.
    Units: score on a scale
        arithmetic mean (standard deviation)
    5.86 ± 1.31 5.64 ± 1.23 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    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 MFNS at stable dose.

    Reporting group title
    Dupilumab 300 mg
    Reporting group description
    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.

    Primary: Change From Baseline at Week 24 in Nasal Congestion/Obstruction Symptom Severity Score

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    End point title
    Change From Baseline at Week 24 in Nasal Congestion/Obstruction Symptom Severity Score
    End point description
    NC symptom severity was assessed by the subjects 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. The analysis was performed on intent-to-treat (ITT) population which included all randomised subjects who were analysed according to the treatment group allocated by randomisation.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: score on a scale
        least squares mean (standard error)
    -0.45 ± 0.07
    -1.34 ± 0.07
    Statistical analysis title
    Dupilumab 300 mg versus Placebo
    Statistical analysis description
    Data were analysed using a hybrid method of the worst-observation carried forward (WOCF) and multiple imputation (MI). The imputed completed data were analysed by fitting ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin’s rule.
    Comparison groups
    Dupilumab 300 mg v Placebo
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.07
         upper limit
    -0.71

    Primary: Change From Baseline at Week 24 in Nasal Polyp Score

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    End point title
    Change From Baseline at Week 24 in Nasal Polyp Score
    End point description
    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 centralised, blinded, independent review of the nasal endoscopy video recordings. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    132
    143
    Units: score on a scale
        least squares mean (standard error)
    0.17 ± 0.15
    -1.89 ± 0.14
    Statistical analysis title
    Dupilumab 300 mg versus Palcebo
    Statistical analysis description
    Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin’s rule.
    Comparison groups
    Dupilumab 300 mg v Placebo
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -2.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.43
         upper limit
    -1.69

    Secondary: Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund-Mackay Score

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    End point title
    Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund-Mackay Score
    End point description
    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 end point is not included as a secondary outcome measure and is instead one of the co-primary outcome measures. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    129
    141
    Units: score on a scale
        least squares mean (standard error)
    -0.74 ± 0.37
    -8.18 ± 0.34
    Statistical analysis title
    Dupilumab 300 mg versus Placebo
    Statistical analysis description
    Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin’s rule.
    Comparison groups
    Dupilumab 300 mg v Placebo
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -7.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.35
         upper limit
    -6.53
    Notes
    [1] - Hierarchical testing procedure was used to control type I error. For regions outside of Japan, this first secondary endpoint was not tested unless both co-primary endpoints were significant at the 0.05 level. Hierarchical testing continued only when previous endpoint was statistically significant. For Japan submission, LMK was instead a co-primary endpoint which also had to be met before secondary endpoints were tested in the hierarchy. Last endpoint in hierarchy is Week 24 SNOT-22.
    [2] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline at Week 24 in Total Symptom Score (TSS)

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    End point title
    Change From Baseline at Week 24 in Total Symptom Score (TSS)
    End point description
    The TSS was the sum of subject-assessed nasal symptom scores for NC/obstruction, decreased/loss of sense of smell, and rhinorrhea (anterior/posterior nasal discharge), each accessed on 0 to 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. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: score on a scale
        least squares mean (standard error)
    -1.17 ± 0.17
    -3.77 ± 0.16
    Statistical analysis title
    Dupilumab 300 mg versus Placebo
    Statistical analysis description
    Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin’s rule.
    Comparison groups
    Dupilumab 300 mg v Placebo
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.0001 [4]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -2.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.04
         upper limit
    -2.17
    Notes
    [3] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant).
    [4] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline at Week 24 in the University of Pennsylvania Smell Identification Test (UPSIT) Score

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    End point title
    Change From Baseline at Week 24 in the University of Pennsylvania Smell Identification Test (UPSIT) Score
    End point description
    The UPSIT was a 40-item test to measure the individual’s ability to detect odours. 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. The analysis was performed on ITT. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    140
    Units: score on a scale
        least squares mean (standard error)
    0.70 ± 0.71
    11.26 ± 0.67
    Statistical analysis title
    Dupilumab 300 mg versus Placebo
    Statistical analysis description
    Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin’s rule.
    Comparison groups
    Dupilumab 300 mg v Placebo
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.0001 [6]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    10.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.79
         upper limit
    12.34
    Notes
    [5] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant).
    [6] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline at Week 24 in Severity of Decreased/Loss of Smell as Assessed by Subject Daily

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    End point title
    Change From Baseline at Week 24 in Severity of Decreased/Loss of Smell as Assessed by Subject Daily
    End point description
    The severity of decreased/loss of sense of smell was reported by the subjects 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. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: score on a scale
        least squares mean (standard error)
    -0.29 ± 0.07
    -1.41 ± 0.07
    Statistical analysis title
    Dupilumab 300 mg versus Placebo
    Statistical analysis description
    Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin’s rule.
    Comparison groups
    Dupilumab 300 mg v Placebo
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001 [8]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.31
         upper limit
    -0.93
    Notes
    [7] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant).
    [8] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline at Week 24 in 22-item Sino-nasal Outcome Test (SNOT-22) Scores

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    End point title
    Change From Baseline at Week 24 in 22-item Sino-nasal Outcome Test (SNOT-22) Scores
    End point description
    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. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    131
    137
    Units: score on a scale
        least squares mean (standard error)
    -9.31 ± 1.62
    -30.43 ± 1.54
    Statistical analysis title
    Dupilumab 300 mg versus Placebo
    Statistical analysis description
    Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin’s rule.
    Comparison groups
    Dupilumab 300 mg v Placebo
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    < 0.0001 [10]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -21.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.17
         upper limit
    -17.06
    Notes
    [9] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant).
    [10] - Threshold for significance at 0.05 level.

    Secondary: Rescue Treatment Use: Estimate of Percentage of Subjects With >=1 Event by Week 24 Obtained Using Kaplan-Meier Method

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    End point title
    Rescue Treatment Use: Estimate of Percentage of Subjects With >=1 Event by Week 24 Obtained Using Kaplan-Meier Method
    End point description
    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 NP when there was worsening of signs and/or symptoms during the study. Estimate of percentage of subjects with event by Week 24 was obtained using Kaplan-Meier method. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: percentage of subjects with event
    number (confidence interval 95%)
        SCS treatment
    18.9 (12.7 to 26.0)
    6.5 (3.2 to 11.5)
        NP surgery
    7.5 (3.7 to 13.2)
    2.1 (0.6 to 5.6)
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Visual Analogue Scale (VAS) for Rhinosinusitis

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    End point title
    Change From Baseline at Week 24 in Visual Analogue Scale (VAS) for Rhinosinusitis
    End point description
    The VAS for rhinosinusitis was used to evaluate the total disease severity. Subjects were asked to indicate on a 10 centimetres (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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    130
    136
    Units: centimetres
        least squares mean (standard error)
    -1.34 ± 0.24
    -4.54 ± 0.23
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Nasal Peak Inspiratory Flow (NPIF)

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    End point title
    Change From Baseline at Week 24 in Nasal Peak Inspiratory Flow (NPIF)
    End point description
    NPIF evaluation represented a physiologic measure of the air flow through both nasal cavities during forced inspiration expressed in litres per minute. Higher NPIF values are indicative of better nasal air flow. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: litres per minute
        least squares mean (standard error)
    14.09 ± 3.97
    54.50 ± 3.73
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Rhinorrhea Daily Symptom Score

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    End point title
    Change From Baseline at Week 24 in Rhinorrhea Daily Symptom Score
    End point description
    Rhinorrhea was reported by the subjects 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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: score on a scale
        least squares mean (standard error)
    -0.42 ± 0.06
    -1.04 ± 0.06
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Forced Expiratory Volume in 1 Second (FEV1) for Subjects With Asthma

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    End point title
    Change From Baseline at Week 24 in Forced Expiratory Volume in 1 Second (FEV1) for Subjects With Asthma
    End point description
    FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with asthma.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    79
    82
    Units: litres
        least squares mean (standard error)
    -0.06 ± 0.05
    0.15 ± 0.05
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Asthma Control Questionnaire-6 (ACQ-6) Scores for Subjects With Asthma

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    End point title
    Change From Baseline at Week 24 in Asthma Control Questionnaire-6 (ACQ-6) Scores for Subjects With Asthma
    End point description
    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). Subjects 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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with the corresponding baseline value, treatment group, prior surgery, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with asthma and had available data for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    76
    75
    Units: score on a scale
        least squares mean (standard error)
    -0.24 ± 0.10
    -1.00 ± 0.10
    No statistical analyses for this end point

    Secondary: 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)

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    End point title
    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)
    End point description
    NC symptom severity was assessed by the subjects 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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: score on a scale
    least squares mean (standard error)
        Week 28
    -0.48 ± 0.07
    -1.36 ± 0.07
        Week 32
    -0.50 ± 0.07
    -1.33 ± 0.07
        Week 36
    -0.53 ± 0.07
    -1.05 ± 0.07
        Week 40
    -0.51 ± 0.08
    -0.83 ± 0.07
        Week 44
    -0.49 ± 0.08
    -0.77 ± 0.07
        Week 48
    -0.52 ± 0.08
    -0.77 ± 0.07
    No statistical analyses for this end point

    Secondary: Change From Baseline at Weeks 36 and 48 in Nasal Polyp Score (Assessments Performed 12 and 24 Weeks After End of Treatment)

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    End point title
    Change From Baseline at Weeks 36 and 48 in Nasal Polyp Score (Assessments Performed 12 and 24 Weeks After End of Treatment)
    End point description
    NPS: 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 inferior nasal cavity), with a lower score indicating smaller-sized polyps. Total NPS: 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 centralised, blinded independent review of the nasal endoscopy video recordings. Data were analysed using a hybrid method of the WOCF and MI. LS means and SE were obtained from ANCOVA model. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 36, Week 48 (post-baseline assessments performed 12 and 24 weeks after end of treatment)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    132
    143
    Units: score on a scale
    least squares mean (standard error)
        Week 36
    -0.06 ± 0.14
    -0.99 ± 0.13
        Week 48
    0.14 ± 0.13
    -0.66 ± 0.12
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 48 in Opacification of Sinuses Measured by Lund-Mackay Score (Assessment Performed 24 Weeks After End of Treatment)

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    End point title
    Change From Baseline at Week 48 in Opacification of Sinuses Measured by Lund-Mackay Score (Assessment Performed 24 Weeks After End of Treatment)
    End point description
    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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population. Here, ‘number of subjects analysed = subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48 (Post-baseline assessment performed 24 weeks after end of treatment)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    129
    141
    Units: score on a scale
        least squares mean (standard error)
    -0.82 ± 0.38
    -2.62 ± 0.36
    No statistical analyses for this end point

    Secondary: 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)

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    End point title
    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)
    End point description
    The TSS was the sum of subject-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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: score on a scale
    least squares mean (standard error)
        Week 28
    -1.18 ± 0.17
    -3.84 ± 0.16
        Week 32
    -1.25 ± 0.17
    -3.64 ± 0.17
        Week 36
    -1.31 ± 0.18
    -2.91 ± 0.17
        Week 40
    -1.27 ± 0.18
    -2.28 ± 0.17
        Week 44
    -1.20 ± 0.18
    -2.09 ± 0.17
        Week 48
    -1.28 ± 0.19
    -2.05 ± 0.18
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 48 in University of Pennsylvania Smell Identification Test (Assessment Performed 24 Weeks After End of Treatment)

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    End point title
    Change From Baseline at Week 48 in University of Pennsylvania Smell Identification Test (Assessment Performed 24 Weeks After End of Treatment)
    End point description
    The UPSIT was a 40-item test to measure the individual’s ability to detect odours. Total score ranges from 0 (anosmia) to 40 (normal sense of smell), lower score indicated severe smell loss. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48 (Post-baseline assessment performed 24 weeks after end of treatment)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    140
    Units: score on a scale
        least squares mean (standard error)
    0.21 ± 0.77
    4.20 ± 0.73
    No statistical analyses for this end point

    Secondary: 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)

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    End point title
    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)
    End point description
    The severity of decreased/loss of sense of smell was reported by the subjects 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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: score on a scale
    least squares mean (standard error)
        Week 28
    -0.28 ± 0.08
    -1.45 ± 0.07
        Week 32
    -0.31 ± 0.08
    -1.36 ± 0.07
        Week 36
    -0.33 ± 0.08
    -1.07 ± 0.07
        Week 40
    -0.30 ± 0.07
    -0.83 ± 0.07
        Week 44
    -0.28 ± 0.07
    -0.74 ± 0.07
        Week 48
    -0.30 ± 0.07
    -0.71 ± 0.06
    No statistical analyses for this end point

    Secondary: 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)

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    End point title
    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)
    End point description
    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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 36 and Week 48 (Post-baseline assessments performed 12 and 24 weeks after end of treatment)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    131
    137
    Units: score on scale
    least squares mean (standard error)
        Week 36
    -8.31 ± 1.75
    -20.87 ± 1.67
        Week 48
    -8.36 ± 1.88
    -17.66 ± 1.80
    No statistical analyses for this end point

    Secondary: Rescue Treatment Use: Estimate of Percentage of Subjects With >=1 Event by Week 48 Obtained Using Kaplan-Meier Method

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    End point title
    Rescue Treatment Use: Estimate of Percentage of Subjects With >=1 Event by Week 48 Obtained Using Kaplan-Meier Method
    End point description
    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 subjects with event by Week 48 was obtained using Kaplan-Meier method. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 48
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: percentage of subjects with event
    number (confidence interval 95%)
        SCS treatment
    28.8 (21.4 to 36.7)
    21.4 (15.0 to 28.5)
        NP surgery
    12.5 (7.5 to 18.9)
    6.3 (2.9 to 11.4)
    No statistical analyses for this end point

    Secondary: Change From Baseline at Weeks 36 and 48 in Visual Analog Scale for Rhinosinusitis (Assessments Performed 12 and 24 Weeks After End of Treatment)

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    End point title
    Change From Baseline at Weeks 36 and 48 in Visual Analog Scale for Rhinosinusitis (Assessments Performed 12 and 24 Weeks After End of Treatment)
    End point description
    The VAS for rhinosinusitis was used to evaluate the total disease severity. The subjects 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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 36 and Week 48 (Post-baseline assessments performed 12 and 24 weeks after end of treatment)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    130
    136
    Units: centimetres
    least squares mean (standard error)
        Week 36
    -1.36 ± 0.26
    -3.02 ± 0.25
        Week 48
    -1.17 ± 0.25
    -2.42 ± 0.24
    No statistical analyses for this end point

    Secondary: 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)

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    End point title
    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)
    End point description
    Rhinorrhea was reported by subjects 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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    133
    143
    Units: score on a scale
    least squares mean (standard error)
        Week 28
    -0.42 ± 0.06
    -1.04 ± 0.06
        Week 32
    -0.43 ± 0.06
    -0.97 ± 0.06
        Week 36
    -0.44 ± 0.07
    -0.80 ± 0.06
        Week 40
    -0.44 ± 0.07
    -0.63 ± 0.06
        Week 44
    -0.41 ± 0.07
    -0.58 ± 0.06
        Week 48
    -0.45 ± 0.07
    -0.58 ± 0.07
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 48 in Forced Expiratory Volume in 1 Second for Subjects With Asthma (Assessment Performed 24 Weeks After End of Treatment)

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    End point title
    Change From Baseline at Week 48 in Forced Expiratory Volume in 1 Second for Subjects With Asthma (Assessment Performed 24 Weeks After End of Treatment)
    End point description
    FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with asthma.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48 (Post-baseline assessment performed 24 weeks after end of treatment)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    79
    82
    Units: litres
        least squares mean (standard error)
    -0.11 ± 0.05
    -0.05 ± 0.05
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 48 in Asthma Control Questionnaire-6 Scores for Subjects With Asthma (Assessment Performed 24 Weeks After End of Treatment)

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    End point title
    Change From Baseline at Week 48 in Asthma Control Questionnaire-6 Scores for Subjects With Asthma (Assessment Performed 24 Weeks After End of Treatment)
    End point description
    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). Subjects 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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with the corresponding baseline value, treatment group, prior surgery, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with asthma and had available data for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48 (Post-baseline assessment performed 24 weeks after end of treatment)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    76
    75
    Units: score on a scale
        least squares mean (standard error)
    -0.09 ± 0.11
    -0.55 ± 0.11
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and TEAEs Leading to Treatment Discontinuation

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    End point title
    Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and TEAEs Leading to Treatment Discontinuation
    End point description
    Adverse Event (AE), any untoward medical occurrence that did not necessarily have to have a causal relationship with 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.. The analysis was performed on safety population which included all subjects who received at least 1 dose or part of a dose of the study drug, analysed according to the treatment actually received.
    End point type
    Secondary
    End point timeframe
    Baseline up to 98 days following the last administration of study drug (up to 36 weeks)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    132
    143
    Units: subjects
    number (not applicable)
        Any TEAE
    93
    93
        Any treatment emergent SAE
    19
    6
        TEAE leading to treatment discontinuation
    3
    5
    No statistical analyses for this end point

    Secondary: Functional Dupilumab Concentration in Serum

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    End point title
    Functional Dupilumab Concentration in Serum [11]
    End point description
    Analysis performed on pharmacokinetic population included all subjects who received at least 1 dose of study drug with at least 1 evaluable functional dupilumab concentration result. Here, ‘number analysed’ = number of subjects with available data for each specified category. Data for this end point was not planned to be collected and analysed for placebo.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, 16, 24, 36, End of study (Week 48)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to be analysed for Dupilumab arm only.
    End point values
    Dupilumab 300 mg
    Number of subjects analysed
    142
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n=139)
    0.00 ± 0.00
        Week 4 (n=138)
    31267.18 ± 13008.16
        Week 8 (n=141)
    48306.73 ± 20621.18
        Week 16 (n=138)
    63958.12 ± 29822.30
        Week 24 (n=136)
    69224.11 ± 36933.70
        Week 36 (n=136)
    356.53 ± 1501.69
        Week 48 (n=138)
    39.00 ± 0.00
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent And Treatment-Boosted Antidrug Antibodies (ADA) Response

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    End point title
    Number of Subjects With Treatment-Emergent And Treatment-Boosted Antidrug Antibodies (ADA) Response
    End point description
    ADA response was categorised 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. The analysis was performed on ADA population which included subjects who received at least 1 dose of study drug with at least one non-missing ADA assay result following the first dose of the study medication.
    End point type
    Secondary
    End point timeframe
    Baseline to End of study (Week 48)
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    132
    143
    Units: subjects
        With treatment-emergent ADA
    7
    22
        With treatment-boosted ADA
    0
    0
    No statistical analyses for this end point

    Secondary: Mean Total SCS Rescue Dose Prescribed During Treatment Period

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    End point title
    Mean Total SCS Rescue Dose Prescribed During Treatment Period
    End point description
    SCS included: Betamethasone, dexamethasone, dexamethasone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, prednisolone, prednisolone metasulfobenzoate sodium, prednisone, and triamcinolone. For every subject, total dose was calculated as (prescribed total daily dose*duration of SCS use). Then, mean of the total dose of 25 subjects (placebo group) and 9 subjects (Dupilumab group) was derived. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    25
    9
    Units: milligrams
        arithmetic mean (standard deviation)
    366.07 ± 247.07
    686.65 ± 1575.86
    No statistical analyses for this end point

    Secondary: Total Systemic Corticosteroids Rescue Intake Duration: Average Duration per Subject

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    End point title
    Total Systemic Corticosteroids Rescue Intake Duration: Average Duration per Subject
    End point description
    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. The analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    25
    9
    Units: days
        arithmetic mean (standard deviation)
    11.04 ± 6.79
    23.33 ± 50.13
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in European Quality of Life 5 Dimension (EQ-5D) Visual Analog Scale Score

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    End point title
    Change From Baseline at Week 24 in European Quality of Life 5 Dimension (EQ-5D) Visual Analog Scale Score
    End point description
    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 has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. EQ-VAS recorded the subject’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). The analysis was performed on ITT population. Here, ‘number of subjects analyzed’ = subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    130
    136
    Units: score on a scale
        least squares mean (standard error)
    1.74 ± 1.54
    12.00 ± 1.48
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Nasal Congestion Symptom Severity Score: Subgroup of Subjects With Asthma

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    End point title
    Change From Baseline at Week 24 in Nasal Congestion Symptom Severity Score: Subgroup of Subjects With Asthma
    End point description
    NC symptom severity was assessed by the subjects 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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates. Analysis was performed on a subset of subjects, which included all randomised subjects with asthma.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    79
    82
    Units: score on a scale
        least squares mean (standard error)
    -0.36 ± 0.09
    -1.48 ± 0.09
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Nasal Congestion Symptom Severity Score: Subgroup of Subjects With Prior Nasal Polyp Surgery

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    End point title
    Change From Baseline at Week 24 in Nasal Congestion Symptom Severity Score: Subgroup of Subjects With Prior Nasal Polyp Surgery
    End point description
    NC symptom severity was assessed by the subjects 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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, and regions as covariates. Analysis was performed on a subset of subjects, which included all randomised subjects with prior NP surgery history.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    99
    99
    Units: score on a scale
        least squares mean (standard error)
    -0.52 ± 0.09
    -1.41 ± 0.08
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Nasal Polyp Score: Subgroup of Subjects With Asthma

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    End point title
    Change From Baseline at Week 24 in Nasal Polyp Score: Subgroup of Subjects With Asthma
    End point description
    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 centralised, blinded, independent review of the nasal endoscopy video recordings. Data were analysed using a hybrid method of the WOCF and MI. LS mean and SE were obtained from ANCOVA model. Analysis was performed on a subset of subjects, which included all randomised subjects with asthma and had available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    78
    82
    Units: score on a scale
        least squares mean (standard error)
    0.27 ± 0.20
    -1.89 ± 0.20
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Nasal Polyp Score: Subgroup of Subjects With Prior Nasal Polyp Surgery

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    End point title
    Change From Baseline at Week 24 in Nasal Polyp Score: Subgroup of Subjects With Prior Nasal Polyp Surgery
    End point description
    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 assessed by centralised scoring of nasal endoscopy video recordings. NPS was assessed by centralised, blinded, independent review of the nasal endoscopy video recordings. Data were analysed using a hybrid method of the WOCF and MI. LS mean and SE were obtained from ANCOVA model. Analysis was performed on a subset of subjects, which included all randomised subjects with prior NP surgery history and had available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    98
    99
    Units: score on a scale
        least squares mean (standard error)
    0.14 ± 0.18
    -1.86 ± 0.18
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Subjects With Asthma

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    End point title
    Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Subjects With Asthma
    End point description
    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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates. Analysis was performed on a subset of subjects, which included all randomised subjects with asthma and had available data for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    78
    81
    Units: score on a scale
        least squares mean (standard error)
    -0.15 ± 0.47
    -7.97 ± 0.47
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Subjects With Prior Nasal Polyp Surgery

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    End point title
    Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Subjects With Prior Nasal Polyp Surgery
    End point description
    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 analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, and regions as covariates. Analysis was performed on a subset of subjects, which included all randomised subjects with prior NP surgery history and had available data for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Dupilumab 300 mg
    Number of subjects analysed
    97
    98
    Units: score on a scale
        least squares mean (standard error)
    -0.39 ± 0.42
    -7.60 ± 0.41
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to end of study regardless of seriousness or relationship to investigational product. Time frame for reporting of TEAE was up to 36 weeks.
    Adverse event reporting additional description
    Reported AEs are treatment emergent AEs that developed/worsened during the ‘on treatment period’ (from the first IMP administration to the last study drug administration + 98 days). Analysis was performed on safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for dupilumab), 1 SC injection q2w from Day 1 of Week 0 up to Week 24 added to background therapy of intranasal MFNS at stable dose.

    Reporting group title
    Dupilumab 300 mg
    Reporting group description
    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.

    Serious adverse events
    Placebo Dupilumab 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 132 (14.39%)
    6 / 143 (4.20%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Clavicle Fracture
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal Cancer
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic Valve Stenosis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Rhinosinusitis With Nasal Polyps
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal Polyps
         subjects affected / exposed
    7 / 132 (5.30%)
    2 / 143 (1.40%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Eosinophilic Granulomatosis With Polyangiitis
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal Tunnel Syndrome
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Radiculopathy
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vitreous Haemorrhage
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine Polyp
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot Deformity
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute Sinusitis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Dupilumab 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 132 (46.21%)
    55 / 143 (38.46%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    8 / 132 (6.06%)
    3 / 143 (2.10%)
         occurrences all number
    11
    3
    Cough
         subjects affected / exposed
    7 / 132 (5.30%)
    4 / 143 (2.80%)
         occurrences all number
    9
    4
    Epistaxis
         subjects affected / exposed
    4 / 132 (3.03%)
    11 / 143 (7.69%)
         occurrences all number
    7
    13
    Nasal Polyps
         subjects affected / exposed
    17 / 132 (12.88%)
    16 / 143 (11.19%)
         occurrences all number
    26
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 132 (8.33%)
    7 / 143 (4.90%)
         occurrences all number
    13
    7
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    12 / 132 (9.09%)
    8 / 143 (5.59%)
         occurrences all number
    30
    25
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 132 (6.06%)
    0 / 143 (0.00%)
         occurrences all number
    8
    0
    Nasopharyngitis
         subjects affected / exposed
    20 / 132 (15.15%)
    19 / 143 (13.29%)
         occurrences all number
    25
    25

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 May 2017
    Following amendment changes were made Clarification of early treatment discontinuation language, restesting of dynamic laboratory values during screening, analysis changed to systemic corticosteroids from oral corticosteroids, EQ-5D elevated from exploratory endpoint to secondary endpoint, clarified CT scan administration to be mandatory unless not approved by local ethics committee or institutional review board, intranasal decongestants added to list of prohibited medications except as needed for nasal endoscopy procedure, study procedures could be performed over 3 days if necessary as long as the visit window was respected, updated safety language throughout the protocol to be consistent with most current safety information per latest investigators brochure: male birth control no longer required, clarified that rescue therapy prescribed by the investigator will not be provided by the Sponsor.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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