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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase 3 Efficacy and Safety Study Of Benralizumab in Patients with Severe Nasal Polyposis (OSTRO)

    Summary
    EudraCT number
    2017-003675-61
    Trial protocol
    DK   AT   BE   HU   PL   DE  
    Global end of trial date
    31 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Aug 2021
    First version publication date
    12 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D3252C00001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03401229
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Vastra Malarehamnen 9, Sodertalje, Sweden,
    Public contact
    AstraZeneca Information Center, AstraZeneca, +1 8002369933, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.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
    01 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of benralizumab on nasal polyp burden and patient reported nasal blockage (NB).
    Protection of trial subjects
    This study is conducted in accordance with the protocol and with the following: Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines; Applicable International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) Guidelines; Applicable laws and regulations.The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, and other relevant documents (e.g. advertisements) must be submitted to an Institutional Review Board/Independent Ethics Committee (IRB/IEC) by the Investigator and reviewed and approved by the IRB/IEC before the study is initiated. Any amendments to the protocol will require IRB/IEC approval before implementation of changes made to the study design, except for changes necessary to eliminate an immediate hazard to study patients. Where applicable as per relevant laws and regulations, amendments will also be submitted to, reviewed and approved by regulatory authorities/national competent authorities.
    Background therapy
    If a patient was using an alternative intranasal corticosteroids (INCS) product other than mometasone furoate nasal spray (MFNS) prior to visit 1, the Investigator would switch the INCS to MFNS at visit 1. Mometasone furoate (total daily dose of 400mcg) was required daily throughout the study.
    Evidence for comparator
    Placebo
    Actual start date of recruitment
    15 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Canada: 70
    Country: Number of subjects enrolled
    Denmark: 51
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    Hungary: 36
    Country: Number of subjects enrolled
    Poland: 73
    Country: Number of subjects enrolled
    United States: 78
    Worldwide total number of subjects
    410
    EEA total number of subjects
    262
    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)
    351
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    413 participants were randomized to receive treatment in study D3250C00001 (OSTRO) with benralizumab 30 mg or placebo. Of the 413 patients randomized, 410 (99.3%) received treatment with study drug. 207 (50.5%) patients received benralizumab 30 mg and 203 (49.5%) patients received placebo

    Pre-assignment
    Screening details
    In OSTRO, at the first visit, ie, the enrollment visit 1, patients were evaluated regarding the protocol mandated inclusion and exclusion criteria. After enrolment, eligible patients entered a 5-week screening/run in period on a stable dose of study provided Mometasone Furoate Nasal Spray (MFNS).

    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, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Benra 30 mg
    Arm description
    Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.
    Arm type
    Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    Benra
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.

    Arm title
    Placebo
    Arm description
    Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.

    Number of subjects in period 1
    Benra 30 mg Placebo
    Started
    207
    203
    Completed
    167
    166
    Not completed
    40
    37
         Consent withdrawn by subject
    29
    26
         Adverse event, non-fatal
    8
    6
         COVID-19
    -
    1
         Other
    1
    3
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Benra 30 mg
    Reporting group description
    Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.

    Reporting group title
    Placebo
    Reporting group description
    Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.

    Reporting group values
    Benra 30 mg Placebo Total
    Number of subjects
    207 203 410
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    181 170 351
        From 65-84 years
    26 33 59
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    50.1 ( 12.38 ) 50.2 ( 13.91 ) -
    Sex: Female, Male
    Units: Participants
        Female
    65 82 147
        Male
    142 121 263
    Race/Ethnicity, Customized
    Units: Subjects
        White
    197 190 387
        Black or African American
    4 8 12
        American Indian or Alaska Native
    0 1 1
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Asian
    3 1 4
        Other
    2 3 5
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients randomized and receiving any IP irrespective of their protocol adherence and continued participation in the study. Patients are analyzed according to their randomized treatment.

    Subject analysis sets values
    Full analysis set
    Number of subjects
    410
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    351
        From 65-84 years
    59
        85 years and over
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    50.2 ( 13.14 )
    Sex: Female, Male
    Units: Participants
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        White
        Black or African American
        American Indian or Alaska Native
        Native Hawaiian or Other Pacific Islander
        Asian
        Other

    End points

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    End points reporting groups
    Reporting group title
    Benra 30 mg
    Reporting group description
    Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.

    Reporting group title
    Placebo
    Reporting group description
    Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All patients randomized and receiving any IP irrespective of their protocol adherence and continued participation in the study. Patients are analyzed according to their randomized treatment.

    Primary: Change from baseline in total NPS at week 40

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    End point title
    Change from baseline in total NPS at week 40
    End point description
    Change from baseline in total nasal polyps score (NPS) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The total NPS was the sum of the right and left nostril scores and maximum total NPS is 8, as evaluated by nasal endoscopy and the left and right score were based on central read with scale from 0 to 4 where higher score reflects heavier bilateral nasal polyp burden. Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Primary
    End point timeframe
    Baseline to week 40
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    187
    187
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.36 ( 1.66 )
    0.17 ( 1.18 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.852
         upper limit
    -0.289
    Notes
    [1] - The primary analysis compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in total NPS and/or the change from baseline in NBS are similar between benralizumab and placebo. H1: Both of the change from baseline in total NPS and the change from baseline in NBS are different between benralizumab and placebo.
    [2] - To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate. Both of the co-primary endpoints were tested at 0.01 (two-sided).

    Primary: Change from baseline in NBS at week 40

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    End point title
    Change from baseline in NBS at week 40
    End point description
    Change from baseline in nasal blockage score (NBS) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The NBS was captured by an item in NPSD. Patients were asked to rate the severity of their worst nasal blockage over the past 24 hours using the following response options: 0–none; 1–mild; 2–moderate; 3–severe. The NBS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Primary
    End point timeframe
    Baseline to week 40
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    181
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.68 ( 1.02 )
    -0.41 ( 0.89 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.0048 [4]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.458
         upper limit
    -0.083
    Notes
    [3] - The primary analysis compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in total NPS and/or the change from baseline in NBS are similar between benralizumab and placebo. H1: Both of the change from baseline in total NPS and the change from baseline in NBS are different between benralizumab and placebo.
    [4] - To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate. Both of the co-primary endpoints were tested at 0.01 (two-sided).

    Secondary: Change from baseline in SNOT-22 at week 40

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    End point title
    Change from baseline in SNOT-22 at week 40
    End point description
    Change from baseline in SinoNasal outcome test (SNOT-22) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The SNOT-22 is a condition specific health-related quality of life assessment which captures patient-reported physical problems, functional limitations, and emotional consequences of sinonasal conditions. The total score is the sum of item scores and has a range from 0 to 110 (higher scores indicate poorer outcomes). Baseline was the last valid value on or prior to the date of randomization. Data collected after NP surgery and/or SCS_NP were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    193
    190
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -15.2 ( 30.47 )
    -10.7 ( 31.64 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.0821 [6]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -5.212
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.087
         upper limit
    0.664
    Notes
    [5] - This endpoint compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in SNOT-22 total score is similar between benralizumab and placebo. H1: The change from baseline in SNOT-22 total score is different between benralizumab and placebo.
    [6] - Since both primary endpoints were significant at significant level of 0.01 level, this endpoint was tested at significant level of 0.05.

    Secondary: Time to first NP surgery and/or SCS use for NP up to week 56

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    End point title
    Time to first NP surgery and/or SCS use for NP up to week 56
    End point description
    The time to first nasal polyposis (NP) surgery and/or systemic corticosteroids (SCS) use for NP up to week 56 was calculated based on the earliest occurrence of NP surgery and/or SCS use for NP and was calculated as follows: Time to first NP surgery and/or SCS use for NP = Earlier of (Start date of first NP surgery, Start date of first SCS use for NP) – date of randomization + 1. For patients who did not experience any surgery or SCS use for NP, the time to event was censored at earlier of (date of their week 56 visit, date of discontinuation).
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207
    203
    Units: participants
    72
    91
    Statistical analysis title
    Cox regression
    Statistical analysis description
    A Cox proportional hazards model including covariates treatment group, region (US/Non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.066 [8]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    1.02
    Notes
    [7] - This endpoint compared the rate of incidence of first NP surgery and/or SCS use for NP of benralizumab with placebo. H0: The rate is similar between benralizumab and placebo. H1: the rate is different between benralizumab and placebo. Hazard ratio is benralizumab vs placebo and HR less than 1 indicates longer time to event
    [8] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value is considered nominal because test for change from baseline in SNOT-22 at week 40 was not statistically significant.

    Secondary: Time to the first NP surgery up to week 56

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    End point title
    Time to the first NP surgery up to week 56
    End point description
    The time to first nasal polyposis (NP) surgery up to week 56 was calculated based on the earliest occurrence of NP surgery and was calculated as follows: Time to first NP surgery=Start date of first NP surgery – date of randomization + 1. For patients who did not experience any surgery, the time to event was censored at earlier of (date of their week 56 visit, date of discontinuation).
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207
    203
    Units: participants
    33
    37
    Statistical analysis title
    Cox regression
    Statistical analysis description
    A Cox proportional hazards model including covariates treatment group, region (US/Non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.5008 [10]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.36
    Notes
    [9] - The endpoint compared the rate of incidence of first NP surgery of benralizumab with placebo. H0: The rate is similar between benralizumab and placebo. H1: the rate is different between benralizumab and placebo. Hazard ratio (HR) is benralizumab vs placebo and HR less than 1 indicates longer time to event
    [10] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal.

    Secondary: Change from baseline in DSS at week 40

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    End point title
    Change from baseline in DSS at week 40
    End point description
    Change from baseline in difficulty with sense of smell (DSS) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The DSS is captured by an item in the NPSD. Severity of worst difficulty with sense of smell over the past 24 hours was rated with response options: 0–none; 1–mild; 2–moderate; 3–severe. The DSS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids use for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    181
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.34 ( 0.74 )
    -0.16 ( 0.65 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.0029 [12]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.218
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.361
         upper limit
    -0.074
    Notes
    [11] - This endpoint compared the changes from baseline DSS score of benralizumab with placebo. H0: The change from baseline in DSS score is similar between benralizumab and placebo. H1: The change from baseline in DSS score is different between benralizumab and placebo.
    [12] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal.

    Secondary: Change from baseline in NPS at week 56

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    End point title
    Change from baseline in NPS at week 56
    End point description
    Change from baseline in total nasal polyps score (NPS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The total NPS is the sum of the right and left nostril scores, as evaluated by nasal endoscopy and the left and right score are based on central read with scale from 0 to 4 where higher score reflects heavier bilateral nasal polyp burden. Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    161
    171
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.22 ( 1.76 )
    0.18 ( 1.44 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    332
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.0054 [14]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.475
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.81
         upper limit
    -0.141
    Notes
    [13] - This endpoint compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in NPS is similar between benralizumab and placebo. H1: The change from baseline in NPS is different between benralizumab and placebo.
    [14] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal.

    Secondary: Change from baseline in NBS at week 56

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    End point title
    Change from baseline in NBS at week 56
    End point description
    Change from baseline in nasal blockage score (NBS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The NBS is captured by an item in the NPSD. Patients were asked to rate the severity of their worst nasal blockage over the past 24 hours using the following response options: 0–none; 1–mild; 2–moderate; 3–severe. The NBS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    179
    175
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.68 ( 1.03 )
    -0.38 ( 0.91 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.0032 [16]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.287
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.477
         upper limit
    -0.096
    Notes
    [15] - This endpoint compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in NBS is similar between benralizumab and placebo. H1: The change from baseline in NBS is different between benralizumab and placebo.
    [16] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal.

    Secondary: Change from baseline in SNOT-22 at week 56

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    End point title
    Change from baseline in SNOT-22 at week 56
    End point description
    Change from baseline in SinoNasal outcome test (SNOT-22) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The SNOT-22 is a condition specific health-related quality of life assessment which captures patient-reported physical problems, functional limitations, and emotional consequences of sinonasal conditions. The total score is range from 0 to 110 (higher scores indicate poorer outcomes). Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    190
    184
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -15.1 ( 33.55 )
    -7.9 ( 33.22 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.0188 [18]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -7.492
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.741
         upper limit
    -1.243
    Notes
    [17] - This endpoint compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in SNOT-22 total score is similar between benralizumab and placebo. H1: The change from baseline in SNOT-22 total score is different between benralizumab and placebo.
    [18] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal.

    Secondary: Change from baseline in DSS at week 56

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    End point title
    Change from baseline in DSS at week 56
    End point description
    Change from baseline in difficulty with sense of smell (DSS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The DSS is captured by an item in the NPSD with response options: 0–none; 1–mild; 2–moderate; 3–severe to rate the severity of their worst difficulty with sense of smell over past 24 hours. The DSS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    179
    175
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.39 ( 0.79 )
    -0.21 ( 0.65 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.0023 [20]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.237
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.389
         upper limit
    -0.084
    Notes
    [19] - This endpoint compared the changes from baseline DSS score of benralizumab with placebo. H0: The change from baseline in DSS score is similar between benralizumab and placebo. H1: The change from baseline in DSS score is different between benralizumab and placebo.
    [20] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal.

    Secondary: Change from baseline in LMS at EOT/IPD

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    End point title
    Change from baseline in LMS at EOT/IPD
    End point description
    Change from baseline in CT Lund Mackay Score (LMS) at end of treatment (EOT)/investigational product discontinuation (IPD) was defined as the endpoint value at EOT/IPD minus the baseline value. The LMS evaluates the patency using a 0-2 scale (0‒normal; 1‒partial opacification; and 2‒total opacification) of each sinus (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, frontal sinus on each side). The osteomeatal complex is graded as 0- not occluded or 2‒occluded. The total CT score is the sum of the scores from all the sinus and ranges from 0 to 24. The analysis used the data collected after systemic corticosteroids for nasal polyposis (SCS_NP). A composite strategy was used for NP surgery. If a patient had NP surgery before EOT/IPD CT scan, the data was censored after the time of the first NP surgery and the worst possible value (WP) was imputed in its place.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT/IPD
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    81 [21]
    84 [22]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.93 ( 5.06 )
    -0.20 ( 4.20 )
    Notes
    [21] - 92 subjects started the arm to the computed tomography (CT) subset.
    [22] - 90 subjects started the arm to the computed tomography (CT) subset.
    Statistical analysis title
    Change from baseline in LMS at EOT/IPD, ANCOVA
    Statistical analysis description
    ANCOVA following WP (WP for NP surgery), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.2375 [24]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.856
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.281
         upper limit
    0.57
    Notes
    [23] - This endpoint compared the changes from baseline LMS score of benralizumab with placebo. H0: The change from baseline in LMS score is similar between benralizumab and placebo. H1: The change from baseline in LMS score is different between benralizumab and placebo.
    [24] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal.

    Secondary: Proportion of subjects with NP surgery

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    End point title
    Proportion of subjects with NP surgery
    End point description
    The proportion of patients who had nasal polyposis (NP) surgery or systemic corticosteroids use for nasal polyposis (SCS_NP) surgery up to week 56 was summarized and analyzed using the Cochran–Mantel–Haenszel test stratified by region (US vs non-US) and baseline comorbid asthma status (yes vs no).
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207
    203
    Units: participants
    33
    37
    Statistical analysis title
    CMH
    Statistical analysis description
    The odds ratio estimate was obtained from the Cochran-Mantel-Haenszel test controlling for region (US/non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    = 0.5419 [26]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.43
    Notes
    [25] - This endpoint compared the proportion of subjects with NP surgery between benralizumab and placebo. H0: The proportion is similar between benralizumab and placebo. H1: The proportion is different between benralizumab and placebo.
    [26] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Proportion of subjects with SCS_NP

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    End point title
    Proportion of subjects with SCS_NP
    End point description
    The proportion of patients who had systemic corticosteroids (SCS) use for nasal polyposis (NP) surgery up to week 56 was summarized and analyzed using the Cochran–Mantel–Haenszel test stratified by region (US vs non-US) and baseline comorbid asthma status (yes vs no).
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207
    203
    Units: participants
    52
    66
    Statistical analysis title
    CMH
    Statistical analysis description
    The odds ratio estimate was obtained from the Cochran-Mantel-Haenszel test controlling for region (US/non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    = 0.0913 [28]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.06
    Notes
    [27] - This endpoint compared the proportion of subjects with SCS_NP between benralizumab and placebo. H0: The proportion is similar between benralizumab and placebo. H1: The proportion is different between benralizumab and placebo.
    [28] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Proportion of subjects with NP surgery or SCS_NP

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    End point title
    Proportion of subjects with NP surgery or SCS_NP
    End point description
    The proportion of patients who had nasal polyposis (NP) surgery or systemic corticosteroids use for nasal polyposis (SCS_NP) surgery up to week 56 was summarized and analyzed using the Cochran–Mantel–Haenszel test stratified by region (US vs non-US) and baseline comorbid asthma status (yes vs no).
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207
    203
    Units: participants
    72
    91
    Statistical analysis title
    CMH
    Statistical analysis description
    The odds ratio estimate was obtained from the Cochran-Mantel-Haenszel test controlling for region (US/non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    = 0.0362 [30]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    0.97
    Notes
    [29] - This endpoint compared the proportion of subjects with NP surgery or SCS_NP between benralizumab and placebo. H0: The proportion is similar between benralizumab and placebo. H1: The proportion is different between benralizumab and placebo.
    [30] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Time to first SCS_NP up to week 56

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    End point title
    Time to first SCS_NP up to week 56
    End point description
    The time to first systemic corticosteroids for use for nasal polyposis (SCS_NP) up to week 56 was calculated based on the earliest occurrence of SCS_ NP and was calculated as follows: Time to first SCS_NP = Earlier of (Start date of first SCS use for NP) – date of randomization + 1. For patients who did not experience any SCS use for NP, the time to event was censored at earlier of (date of their week 56 visit, date of discontinuation). The time to first SCS use for NP surgery was analyzed using a Cox proportional hazard model with treatment arm, region (US vs non-US) and baseline comorbid asthma status (yes vs no) as covariates. A hazard ratio less than 1 indicates a lower rate of incidence for subjects on benra.
    End point type
    Secondary
    End point timeframe
    Baseline week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207
    203
    Units: participants
    52
    66
    Statistical analysis title
    Cox Regression
    Statistical analysis description
    A Cox proportional hazards model including covariates treatment group, region (US/Non-US) and baseline comorbid asthma status.
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    = 0.1505 [32]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.1
    Notes
    [31] - The endpoint compared the rate of incidence of SCS_NP use between benralizumab and placebo. H0: The rate is similar between benralizumab and placebo. H1: the rate is different between benralizumab and placebo. Hazard ratio (HR) is benralizumab vs placebo and HR less than 1 indicates longer time to event
    [32] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Total number of courses of SCS for NP

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    End point title
    Total number of courses of SCS for NP
    End point description
    The total number of courses of systemic corticosteroids (SCS) use for nasal polyposis (NP) was summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207
    203
    Units: number of courses
        arithmetic mean (standard deviation)
    1.7 ( 0.93 )
    1.6 ( 0.89 )
    No statistical analyses for this end point

    Secondary: Total SCS_NP dose (a) used (mg)

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    End point title
    Total SCS_NP dose (a) used (mg)
    End point description
    The total systemic corticosteroids (SCS) for nasal polyposis (NP) dose used (mg) was summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207 [33]
    203
    Units: dose
        arithmetic mean (standard deviation)
    1083.2 ( 4044.29 )
    435.2 ( 441.57 )
    Notes
    [33] - Data reported include an outlier with an incorrect dose of betamethasone of 500mg instead of 0.5mg
    No statistical analyses for this end point

    Secondary: Total duration of SCS_NP (days)

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    End point title
    Total duration of SCS_NP (days)
    End point description
    The total duration of systemic corticosteroids (SCS) for nasal polyposis (NP) in days was summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207
    203
    Units: duration
        arithmetic mean (standard deviation)
    17.6 ( 12.45 )
    20.1 ( 34.68 )
    No statistical analyses for this end point

    Secondary: Annual SCS_NP use rate comparison by period, negative binomial model

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    End point title
    Annual SCS_NP use rate comparison by period, negative binomial model
    End point description
    Annual systemic corticosteroids for nasal polyposis (SCS_NP) use rate =365.25×total number of courses of SCS_NP /total duration of follow-up within the treatment group (days). The estimated annual event rates, absolute differences, rate ratio and the corresponding confidence interval were based on a negative binomial model including covariates treatment group, region (US/non-US) and prior use of SCS_NP with total number of courses of SCS_NP as the outcome and the log of each subject’s corresponding follow-up time up to week 56 as an offset variable in the model to adjust for subject’s having different exposure times during which the events occur.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    207
    203
    Units: number of courses for each patient
        arithmetic mean (confidence interval 95%)
    0.40 (0.30 to 0.52)
    0.50 (0.38 to 0.65)
    Statistical analysis title
    Negative binomial model
    Statistical analysis description
    Model included treatment, US/non-US and prior use of SCS_NP with total number of courses of SCS_NP as outcome and log of follow-up time as an offset
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [34]
    P-value
    = 0.2189 [35]
    Method
    Negative Bionomial Model
    Parameter type
    Rate Ratio
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.15
    Notes
    [34] - The endpoint compared the rate of SCS_NP use between benralizumab and placebo. H0: The rate is similar between benralizumab and placebo. H1: the rate is different between benralizumab and placebo. Rate ratio is benralizumab vs placebo and Rate ratio less than 1 indicates less likely of SCS_NP use.
    [35] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Change from baseline in TSS at week 40

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    End point title
    Change from baseline in TSS at week 40
    End point description
    Change from baseline in total symptom score (TSS) at week 40 was defined as the endpoint at week 40 minus baseline value. The TSS is defined as sum of first 8 NPSD components. Severity of each nasal symptoms over the past 24 hours is rated using response options: 0–none; 1–mild; 2–moderate; 3–severe. The TSS and the change from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily TSS responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming MAR were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    181
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -3.20 ( 6.90 )
    -1.38 ( 6.29 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority [36]
    P-value
    = 0.0036 [37]
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    -1.854
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.101
         upper limit
    -0.608
    Notes
    [36] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo.
    [37] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Change from baseline in difficulty with sleeping due to nasal symptoms at week 40

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    End point title
    Change from baseline in difficulty with sleeping due to nasal symptoms at week 40
    End point description
    Change from baseline in difficulty with sleeping due to nasal symptoms score at week 40 was defined as the endpoint at week 40 minus baseline value. The score was captured by an item in NPSD. The severity of difficulty with sleeping due to nasal symptoms over past 24 hours was rated using options: 0–none; 1–mild; 2–moderate; 3–severe. The score and change from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    181
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.39 ( 1.06 )
    -0.19 ( 1.03 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority [38]
    P-value
    = 0.0941 [39]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.166
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.36
         upper limit
    0.028
    Notes
    [38] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo.
    [39] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Change from baseline in difficulty with daily activities due to nasal symptoms at week 40

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    End point title
    Change from baseline in difficulty with daily activities due to nasal symptoms at week 40
    End point description
    Change from baseline in difficulty with daily activities due to nasal symptoms score at week 40 was defined as the endpoint at week 40 minus baseline value. The score was captured by an item in NPSD. The severity of difficulty with daily activities due to nasal symptoms over the past 24 hours was rated using options: 0–none; 1–mild; 2–moderate; 3–severe. The score and change from baseline were summarized every two weeks (bi-weekly). Baseline was average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming MAR were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    181
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.35 ( 1.04 )
    -0.11 ( 0.99 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority [40]
    P-value
    = 0.0246 [41]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.213
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.399
         upper limit
    -0.027
    Notes
    [40] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo.
    [41] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Change from baseline in UPSIT score in males at week 40

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    End point title
    Change from baseline in UPSIT score in males at week 40
    End point description
    Change from baseline in University of Pennsylvania Smell Identification Test (UPSIT) score at week 40 was defined as the endpoint value at week 40 minus the baseline value. The UPSIT is quantitative test of olfactory function. Scores were based on number of correctly identified odors (score range 0 to 40). Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    109 [42]
    89 [43]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.20 ( 10.29 )
    0.09 ( 8.05 )
    Notes
    [42] - This analysis only includes Male.
    [43] - This analysis only includes Female.
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority [44]
    P-value
    = 0.5833 [45]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.672
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.73
         upper limit
    3.074
    Notes
    [44] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo.
    [45] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Change from baseline in UPSIT score in females at week 40

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    End point title
    Change from baseline in UPSIT score in females at week 40
    End point description
    Change from baseline in University of Pennsylvania Smell Identification Test (UPSIT) score at week 40 was defined as the endpoint value at week 40 minus the baseline value. The UPSIT is quantitative test of olfactory function. Scores are based on number of correctly identified odors (score range 0 to 40). Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    53 [46]
    74 [47]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    1.66 ( 8.86 )
    -1.32 ( 7.66 )
    Notes
    [46] - This analysis only includes females.
    [47] - This analysis only includes females.
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority [48]
    P-value
    = 0.0619 [49]
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    2.684
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.134
         upper limit
    5.502
    Notes
    [48] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo.
    [49] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Change from baseline in sinus severity score at EOT/IPD

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    End point title
    Change from baseline in sinus severity score at EOT/IPD
    End point description
    Change from baseline in sinus severity score at end of treatment (EOT)/investigational product discontinuation (IPD) was defined as the endpoint value at EOT/IPD minus the baseline value. Quantitative assessment of sinus CT image data was used to derive an objective measure of sinus disease burden called sinus severity score. The sinus severity score is defined as (sinus mucosal volume)/(sinus mucosal volume + sinus air volume)×100. A composite strategy was used for NP surgery. If a patient had NP surgery before EOT/IPD CT scan, the data was censored after the time of the first NP surgery and the worst possible value (WP) was imputed in its place. In calculation of summary statistics (mean and standard deviation), the WP for NP surgery rescued subjects was applied. In ANCOVA, following WP (WP for NP surgery rescued subjects), model included treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT/IPD
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    86
    84
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -3.48 ( 24.24 )
    0.79 ( 17.29 )
    Statistical analysis title
    ANCOVA
    Statistical analysis description
    Following WP (WP for NP surgery rescued subjects), model included treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
    Comparison groups
    Benra 30 mg v Placebo
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    superiority [50]
    P-value
    = 0.102 [51]
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    -5.057
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.129
         upper limit
    1.015
    Notes
    [50] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo.
    [51] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal.

    Secondary: Change from baseline in SF-36v2 physical component summary at week 56

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    End point title
    Change from baseline in SF-36v2 physical component summary at week 56
    End point description
    Change from baseline in SF-36v2 physical component summary (PCS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. PCS score is computed from 8 subscale scores to give a broader metric of physical health-related quality of life. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -1.557 ( 17.7075 )
    -3.185 ( 17.4189 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36v2 mental component summary at week 56

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    End point title
    Change from baseline in SF-36v2 mental component summary at week 56
    End point description
    Change from baseline in SF-36v2 mental component summary (MCS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. MCS score is computed from 8 subscale scores to give a broader metric of mental health-related quality of life. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -2.263 ( 18.4094 )
    -4.182 ( 19.3697 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36v2 physical functioning at week 56

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    End point title
    Change from baseline in SF-36v2 physical functioning at week 56
    End point description
    Change from baseline in SF-36v2 physical functioning score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Physical functioning is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.080 ( 14.8681 )
    -0.911 ( 14.6581 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36v2 role limitations due to physical health at week 56

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    End point title
    Change from baseline in SF-36v2 role limitations due to physical health at week 56
    End point description
    Change from baseline in SF-36v2 role limitations due to physical health score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Role limitations due to physical health is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    1.576 ( 13.4610 )
    0.025 ( 13.3886 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36v2 bodily pain at week 56

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    End point title
    Change from baseline in SF-36v2 bodily pain at week 56
    End point description
    Change from baseline in SF-36v2 bodily pain score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Bodily pain is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.982 ( 15.0935 )
    -1.066 ( 15.3689 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36v2 general health perceptions at week 56

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    End point title
    Change from baseline in SF-36v2 general health perceptions at week 56
    End point description
    Change from baseline in SF-36v2 general health perceptions score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. General health perceptions is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing are excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.445 ( 14.2295 )
    -1.064 ( 13.6387 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36v2 vitality at week 56

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    End point title
    Change from baseline in SF-36v2 vitality at week 56
    End point description
    Change from baseline in SF-36v2 vitality score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Vitality is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    1.913 ( 12.9999 )
    -0.594 ( 13.5861 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36v2 social functioning at week 56

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    End point title
    Change from baseline in SF-36v2 social functioning at week 56
    End point description
    Change from baseline in SF-36v2 social functioning score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 are used to compute an 8-domain profile of functional health and well-being scores. Social functioning is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.262 ( 15.1786 )
    -1.247 ( 15.9512 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36v2 role limitations due to emotional problems at week 56

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    End point title
    Change from baseline in SF-36v2 role limitations due to emotional problems at week 56
    End point description
    Change from baseline in SF-36v2 role limitations due to emotional problems score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Role limitations due to emotional problems is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.492 ( 17.1261 )
    -1.825 ( 16.6618 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36v2 mental health at week 56

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    End point title
    Change from baseline in SF-36v2 mental health at week 56
    End point description
    Change from baseline in SF-36v2 mental health score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Mental health is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
    End point type
    Secondary
    End point timeframe
    Baseline to week 56
    End point values
    Benra 30 mg Placebo
    Number of subjects analysed
    191
    185
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -1.506 ( 16.5930 )
    -3.308 ( 17.2382 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.

    Reporting group title
    Benra 30 mg
    Reporting group description
    Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.

    Serious adverse events
    Placebo Benra 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 203 (9.36%)
    25 / 207 (12.08%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of appendix
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucoepidermoid carcinoma of salivary gland
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (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
    Prostatitis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal leukoplakia
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar I disorder
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Compression fracture
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (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 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 207 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrospinal fistula
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Rhegmatogenous retinal detachment
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coeliac disease
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 207 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reflux gastritis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         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
    Back pain
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (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 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 207 (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 Benra 30 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 203 (40.89%)
    64 / 207 (30.92%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 203 (7.88%)
    7 / 207 (3.38%)
         occurrences all number
    18
    9
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    30 / 203 (14.78%)
    21 / 207 (10.14%)
         occurrences all number
    54
    30
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    43 / 203 (21.18%)
    37 / 207 (17.87%)
         occurrences all number
    54
    57
    Viral upper respiratory tract infection
         subjects affected / exposed
    14 / 203 (6.90%)
    7 / 207 (3.38%)
         occurrences all number
    15
    9

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2018
    Amended inclusion criterion 1 to highlight that nasal polyposis score (NPS) from V2 will be a randomization criterion. Amended to change the requirement for patients being on a stable dose of study provided intranasal corticosteroids (INCS) for 4 weeks prior to randomization to 4 weeks prior to V2. Information about Mometasone Furoate Nasal Spray (MFNS) intolerance was added. Additionally, information about systemic corticosteroids (SCS) intake during screening period and possible extension was added. Amended inclusion criterion 5 to include the requirement of 4 weeks of INCS intake prior V1. Updated Male contraception requirements in inclusion criterion 15. Amended exclusion criterion from 6 months to 3 months. Amended exclusion criterion 5 for asthma exacerbation asthma requiring systemic corticosteroids treatment or hospitalization for treatment asthma from 3 months to 4 weeks prior to V1. Amended exclusion criteria 16 to remove usage of SCS for condition other than short course of NP. Amended exclusion 17 to change the time period for previous use of biologic products from 4 to 6 months and to allow previous use of mepolizumab, reslizumab and dupliumab. Amended exclusion criterion 22 to change the time period for SCS intake from 2 months to 4 weeks prior V1. Note about sustained release steroids or depot injections was added. Amended to allow extension of the screening period and to clarify in which cases re-screening is allowed. Additionally, it was highlighted that patient can be considered for re-screening once under the specific conditions. Amended to remove Information that if patient experienced an asthma exacerbation and/or use of SCS during the screening, he/she should be screen failed.
    20 Sep 2019
    Updated of minimum observed mean difference that would be statistically significant at the two-sided alpha 0.05 level from -0.52 to -0.39 in total NPS and from ‒0.26 to –0.20 in nasal blockage score (NBS). Original critical values for two-sided alpha 0.01 level also included. The statistical methods were amended to add 2 endpoints, change from baseline in University of Pennsylvania smell identification test (UPSIT) score and time to nasal polyposis (NP) surgery and/or SCS use, to the multiplicity testing strategy and to update the power value from 95% to 99% and alpha level from 0.01 to 0.05. Amended to clarify disease under study definition and reporting criteria for adverse events. Amended to specify the estimate of the treatment effect at week 56 for SNOT-22 and UPSIT score for the analyses of key secondary endpoints was based on contrasts from the respective mixed-effects model for repeated measures (MMRM) models.
    31 Jul 2020
    Note: The actual protocol amendment date is 05-Aug-2020. The 31-Jul-2020 is the global end of trail date. Multiple changes were made to align the CSP with the amended SAP. These changes include changing the timepoint of primary analysis to week 40, updating the list of key secondary endpoints, updating the primary estimand, reverting power and type I error rate, updating model specification to ANCOVA, and adding a subgroup. Added total symptom score (TSS) as sum of first 8 items of nasal polyposis symptom scores diary (NPSD). Updated language of inclusion in extended follow-up (EFU) period for clarity. Added information about analysis of baseline PK samples and on-treatment PK samples. “A limited number of exploratory biomarkers may be reported in the CSR. Details regarding analyses can be found in the SAP. Any remaining exploratory biomarkers will be reported outside of the CSR.” - wording has been added. Additional text regarding Study Conduct Mitigation During evolving SARS-CoV-2 (COVID-19) pandemic or other study disruption has been added to maintain the conduct of study-related activities during crisis, while securing data integrity and patient safety.

    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.
    During COVID-19 pandemic, for ongoing patients, patient dosing, scheduled visits, and nasal endoscopies are inevitable impacted. Week 40 was made as the primary timepoint to mitigate the impact of COVID disruptions on the primary endpoint.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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